Barrett's esophagus

Barrett's esophagus is an acquired metaplastic abnormality in which the normal stratified squamous epithelium lining of the esophagus is replaced by an intestinal-like columnar epithelium. While in itself a benign and asymptomatic disorder, the clinical importance of this relatively common condition relates to its role as a precursor lesion to esophageal adenocarcinoma, the incidence of which has dramatically increased in Western populations in recent years. Although known to arise as a consequence of chronic gastroesophageal reflux, the cellular and molecular mechanisms underlying development Barrett's esophagus and its progression to cancer remain unclear.     

Human papillomavirus and the risk of Barrett's esophagus

Human papillomavirus (HPV) is strongly associated with squamous esophageal cancer. The potential role of HPV in Barrett's esophagus (BE) has been examined but remains unclear. The aim of the study was to determine the prevalence of HPV in esophageal and gastric tissues obtained from patients with and without BE. We designed a cross‐sectional study was conducted with prospective enrollment of eligible patients scheduled for esophagogastroduodenoscopy (EGD). All participants had biopsies of endoscopic BE, squamous‐lined esophagus, and stomach. Immunohistochemistry (IHC) on formalin‐fixed and paraffin‐embedded tissue was conducted using monoclonal antibodies. Polymerase chain reaction (PCR) for HPV was performed on DNA extracted from esophageal biopsies snapped frozen within 30 minutes after endoscopic capture. The Roche HPV Linear Array Assay with PGMY primers that has high sensitivity for detecting 37 types of HPV was used. A total of 127 subjects were included: 39 with definitive BE had IHC done on samples from non‐dysplastic BE, squamous esophagus, gastric cardia, and gastric body; and 88 control patients without BE had IHC done on squamous esophageal samples, gastric cardia, and gastric body. HPV was not detected in any of the samples in either group. For confirmation, HPV DNA PCR was performed on randomly selected samples from 66 patients (both esophagus and BE from 13 patients with BE, and 53 esophagus from patients without BE); no sample had HPV DNA detected via PCR in the presence of adequate quality control. HPV infection does not play a role in the formation of non‐dysplastic Barrett's esophagus in men in the United States.     

Recent developments in gastroesophageal reflux disease and Barrett's esophagus: ANNO 2012

The incidence of gastroesophageal reflux disease (GERD) and esophageal columnar metaplasia is rising worldwide. Both mechanical and functional factors perturb the double sphincter barrier at the esophagogastric junction (EGJ). Discovery of the acid pocket is fundamental in understanding postprandial acid reflux. Adding impedencemetry to pH measurements allows detection of non-acid or weakly acidic reflux. Histologic and endoscopic injury of the squamous mucosa rises from dilation of the intercellular spaces, papillary extension, accentuated intrapapillary looping, red streaks, erosive tissue loss, etc., graded with the Los Angeles system. Seventy percent of patients have no recognizable abnormalities (non-erosive or neGERD). Treatment of GERD mainly relates to the control of acid secretion but a revival of alginate/antacid obliterating the acid pocket is to be expected. Weaker heartburn control in neGERD is a misnomer because most studies included patients with no evidence of reflux disease. Traditional (delayed-release) proton pump inhibitors (PPIs) are powerful suppressors of acid secretion but do have limitations such as gradual build up of acid control, weak control of nocturnal acid recovery, possibility of rebound, occasional need for dose escalation, etc. Barrett's esophagus (BE) is endoscopically diagnosed also in the absence of intestinal metaplasia. A prerequisite is the precise location of the EGJ (proximal end of gastric folds, esophageal sphincter pinch, distal extent of palisade vessels). BE is graded with the Prague C & M system. Barrett's cancer develops usually via low-grade and high-grade dysplasia. Endoscopic examination may indicate suspicious areas, amenable for targeted biopsy. Otherwise, four quadrant biopsies are obtained when searching for neoplasia. Low-grade dysplasia, especially when it is multifocal and p53 positive, high-grade dysplasia and mucosal cancer should be treated with endoscopic resection of the target area, followed by radiofrequency ablation of the adjacent non-neoplastic columnar mucosa, followed with powerful acid suppressant therapy. The long-term results of the combination of resection and ablation are exiting and at least comparable to surgical resection.     

Management of cancer risk in Barrett's esophagus

The importance of Barrett's esophagus (BE) lies in its potential to give rise to esophageal adenocarcinoma (EAC), postulated to be through a series of progressive degrees of dysplasia; from intestinal metaplasia to low-grade dysplasia, high-grade dysplasia, and subsequently, to cancer. The management strategies for the detection and treatment of dysplasia and early esophageal cancer on a background of BE have changed significantly in the last few decades, with the emergence of newer and less invasive non-operative alternatives. This review aims to outline BE and its relation to EAC, the rationale and cost-effectiveness of both screening and surveillance programs, methods of diagnosing and identifying dysplasia and early cancer in Barrett's, and approaches to individualizing their endoscopic and surgical management based on best-available staging techniques.     

Australian clinical practice guidelines for the diagnosis and management of Barrett's esophagus and early esophageal adenocarcinoma

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.     

p27 and Barrett's esophagus: a review*.

The rising prevalence of Barrett's esophagus and Barrett's associated adenocarcinoma in the Western world has stimulated increasing interest in this disease. This has resulted in a plethora of articles concerning its molecular biology, but the tumor suppressor gene, p27, has received little attention. In this article, we review the literature concerning the role of p27 in Barrett's esophagus and its malignant transformation, and we evaluate its possible role as an important clinical biomarker, as well as potential chemopreventive clinical agents aimed at substituting its antitumoral activity.     

Current status of Barrett's esophagus research in Asia

In Western countries, the epidemiology of esophageal cancer has changed considerably over the past decades with a rise in the ratio of adenocarcinoma to squamous cell carcinoma. Although the prevalence of gastroesophageal reflux is increasing in Asia, the prevalences of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) have remained low in most Asian countries. The Asian Barrett's Consortium recently conducted a review of published studies on BE from Asia to assess the current status of BE research in Asia, and to recommend potential areas for future BE research in the region. Differences in study design, enrolled population, and endoscopic biopsy protocols used have led to substantial variability in the reported BE prevalence (0.06% to 19.9%) across Asia. In particular, some Japanese studies used diagnostic criteria that differed considerably from what was used in most Asian studies. As in Western countries, increased age, male sex, tobacco smoking, reflux symptoms, and erosive esophagitis have been found to be risk factors for BE in several case-control studies from Asia. The Prague C and M criteria, developed to provide better interobserver reliability in diagnosis and grading of BE, are currently under extensive evaluation in the Asian population. There is a need for standardized protocols for endoscopic and histopathologic diagnosis before initiating collaborative projects to identify etiologic determinants of BE and its ensuing malignant transformation. At present, data regarding the management and long-term outcome of BE are extremely limited in Asia. More studies of BE in this geographic area are warranted.     

Structural alterations of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence

Background and Aim: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia‐dysplasia‐adenocarcinoma sequence. Methods: A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron‐microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. Results: The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P < 0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P < 0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P = 0.0043). Conclusions: The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia‐dysplasia‐adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.     

Endoscopic therapy in early adenocarcinomas (Barrett's cancer) of the esophagus

The incidence of early esophageal adenocarcinoma has been increasing significantly in recent decades. Prognosis depends greatly on the choice of treatment. Early cancers can be treated by endoscopic resection, whereas advanced carcinomas have to be sent for surgery. Esophageal resection is associated with high perioperative mortality (1–5%) even in specialized centers. Early diagnosis enables curative endoscopic treatment option. Patients with gastrointestinal symptoms and a familial risk for esophageal cancer should undergo upper gastrointestinal endoscopy. High‐definition endoscopes have been developed with technical add‐on that helps endoscopists to find fine irregularities in the esophageal mucosa, but interpreting the findings remains challenging. In this review we discussed novel and old diagnostic procedures and their values, as well as our own recommendations and those of the authors discussed for the diagnosis and treatment of early Barrett's carcinoma. Endoscopic resection is the therapy of choice in early esophageal adenocarcinoma. It is mandatory to perform a subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions.     

Case of Barrett's adenocarcinoma with marked endoscopic morphological changes in Barrett's esophagus over a long follow‐up period of 15 years

The natural history of Barrett's esophagus (BE) is unclear. We herein describe a case of Barrett's adenocarcinoma (BAC) in which we could closely observe marked morphological changes in BE over a long follow‐up period of 15 years. A man in his seventies received routine esophagogastroduodenoscopy (EGD) and was diagnosed as having reflux esophagitis and short‐segment BE. The BE gradually became elongated, and BAC was detected 9 years following the initial EGD examination with continued administration of a proton pump inhibitor. We witnessed that BE elongated sporadically over time and mucosal breaks of reflux esophagitis were detectable several years before elongation. The patient underwent endoscopic submucosal dissection for BAC and has been monitored by EGD every year thereafter. These remarkable morphological changes may be representative of the natural history of BE and aid in deciding long‐term disease management.     

Critical reappraisal of current surveillance strategies for Barrett's esophagus: analysis of a large German Barrett's database

Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE). Based on a large database, gathered from predominantly community‐based practices in Germany, we aimed to investigate the time‐course of malignant progression and apply these findings to current clinical practice. Data of 1438 patients with BE from a large German BE database were analyzed. Patients with at least one follow‐up endoscopy/biopsy were included. Detection of ‘malignant Barrett’ (either high‐grade intra‐epithelial neoplasia or invasive adenocarcinoma) was considered as study end‐point. Of 1438 patients with BE, 57 patients had low‐grade intra‐epithelial neoplasia (LG‐IN) on initial biopsy and 1381 exhibited non‐neoplastic BE. ‘Malignant Barrett’ was detected in 28 cases (1.9%) during a median follow‐up period of 24 months (1–255), accounting for an incidence of 0.95% per patient year of follow‐up. The frequency of ‘malignant Barrett’ was significantly higher (P < 0.001, χ²‐test) in the LG‐IN group (n = 11, 19.3%) compared with the non‐neoplastic BE group (n = 17, 1.2%). In the non‐neoplastic BE group, ‘malignant Barrett’ was predominantly found during re‐endoscopy within the first year of follow‐up (12 of 17; 70.6%), in contrast to the LG‐IN group, in which ‘malignant Barrett’ was observed predominantly after a time exceeding 12 months (8 of 11, 72.7%; P = 0.05, Fisher's exact test). Initial endoscopic evaluations seem to play the most crucial role in managing BE. After 1 year of follow‐up, endoscopic surveillance should be focused on patients with LG‐IN. In patients with repeatedly proven non‐neoplastic BE, elongation of the follow‐up intervals to the upper limit of current guidelines, that is, 5 years, might be justified.     

Lower esophageal palisade vessels and the definition of Barrett's esophagus

SUMMARY. The designated area of the columnar‐lined esophagus (CLE) is anatomically defined by the distal limit of the lower esophageal palisade vessels (LEPV) and the term ‘Barrett's esophagus’ is equally used along with the name CLE in Japan. The aim of this study was to investigate the actual prevalence of CLE based on the Japanese criteria and to evaluate the criteria per se. A total of 42 esophagi consecutively resected at this institute were included. All subjects underwent a surgical resection for squamous cell carcinoma of the esophagus. The position of the LEPV, squamocolumnar junction, the prevalence of CLE and intestinal metaplasia were investigated both pre‐ and postoperatively. Preoperative endoscopy revealed CLE based on the Japanese criteria in half of all patients. In the resected specimens the distal limit of LEPV was lower than the squamocolumnar junction in 95.2%. In other words, almost all cases had CLE (equivalent to Barrett's mucosa in Japanese criteria). However, most of the CLE areas were very short and their average maximum length was only about 5 mm. In addition, no intestinal metaplasia was observed in any of the CLE cases. Almost all individuals might therefore be diagnosed to have CLE or Barrett's mucosa based on precise endoscopic observations in Japan. The CLE located in a small area, e.g. less than 5 mm, defined according to the LEPV criteria without any other factor concerning typical Barrett's esophagus such as signs of gastroesophageal reflux should therefore be excluded from consideration as a high‐risk mucosa.     

Squamous cell carcinoma in Barrett's esophagus: field effect versus metastasis

Barrett's esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE.     

Personal and family history of cancer and the risk of Barrett's esophagus in men

The association between Barrett's esophagus (BE) and a personal or family history of cancer other than gastroesophageal remains unknown. To evaluate the effect of personal and family history of certain cancers and cancer treatments on the risk of BE, we analyzed data from a Veterans Affairs case‐control study that included 264 men with definitive BE (cases) and 1486 men without BE (controls). Patients with history of esophageal or gastric cancer were excluded. Patients underwent elective esophagogastroduodenoscopy or a study esophagogastroduodenoscopy concurrently with screening colonoscopy to determine BE status. Personal and family history of several types of cancer was obtained from self‐reported questionnaires, supplemented and verified by electronic medical‐record reviews. We estimated the association between personal and family history of cancer or radiation/chemotherapy, and BE. Personal history of oropharyngeal cancer (1.5% vs. 0.4%) or prostate cancer (7.2% vs. 4.4%) was more frequently present in cases than controls. The association between BE and prostate cancer persisted in multivariable analyses (adjusted odds ratio 1.90; 95% confidence interval 1.07–3.38, P = 0.028) while that with oropharyngeal cancer (adjusted odds ratio 3.63; 95% confidence interval 0.92–14.29, P = 0.066) was attenuated after adjusting for retained covariates of age, race, gastroesophageal reflux disease, hiatal hernia, and proton pump inhibitor use. Within the subset of patients with cancer, prior treatment with radiation or chemotherapy was not associated with BE. There were no significant differences between cases and controls in the proportions of subjects with several specific malignancies in first‐ or second‐degree relatives. In conclusion, the risk of BE in men may be elevated with prior personal history of oropharyngeal or prostate cancer. However, prior cancer treatments and family history of cancer were not associated with increased risk of BE. Further studies are needed to elucidate if there is a causative relationship or shared risk factors between prostate cancer and BE.     

Esophageal eosinophilia after radiofrequency ablation for Barrett's esophagus

Radiofrequency ablation (RFA) with HALO system has been developed as a new treatment option for Barrett's esophagus (BE). It had been observed that some patients had esophageal eosinophilia (EE) infiltration after RFA. The incidence and features of EE after RFA were systematically determined. From a prospectively compiled database, data on 148 patients who underwent RFA for BE were analyzed. Biopsies were taken pre‐ and post‐RFA from the BE segment, and histological sections of the biopsy specimens were stained with hematoxylin and eosin, and examined by a gastrointestinal pathologist. The incidence of EE post‐RFA was then determined. Of the 148 patients, 120 (81%) were men, 137 (92%) were white, 64 (43%) were overweight and 49 (33%) obese, and 128 (86%) were over 50 years of age or more. Four (2.7%) of the patients developed post‐RFA EE, but none had symptoms of eosinophilic esophagitis. All patients except one had a history of seasonal allergies. All four were taking proton pump inhibitor before and after RFA. Two patients with EE drank alcohol, one of which was a smoker. EE is a potential adverse event of RFA for BE. The absence of esophageal dysfunction symptoms suggests a different clinicopathological entity from eosinophilic esophagitis. Further studies should be done to assess its clinical significance, if therapy is needed, or if it may eventually lead to eosinophilic esophagitis.     

Volumetric laser endomicroscopy in Barrett's esophagus: a feasibility study on histological correlation

Volumetric laser endomicroscopy (VLE) is a novel balloon‐based optical coherence tomography (OCT) imaging technique that may improve detection of early neoplasia in Barrett's esophagus (BE). Most OCT studies lack a direct correlation between histology and OCT images. The aim is to investigate the optimal approach for achieving one‐to‐one correlation of ex‐vivo VLE images of endoscopic resection (ER) specimens with histology. BE patients with and without early neoplasia underwent ER after delineating areas with electrocoagulation markers (ECM). After ER, specimens underwent additional ex‐vivo marking with several different markers (ink, pin, Gold Probe) followed by ex‐vivo VLE scanning. ER specimens were carefully sectioned into tissue blocks guided by the markers. Histology and VLE slides were considered a match if ≥ 2 markers were visible on both modalities and mucosal patterns aside from these markers matched on both histology and VLE. From 16 ER specimens 120 tissue blocks were sectioned of which 23 contained multiple markers. Fourteen histology–VLE matches were identified. ECMs and ink markers proved to be the most effective combination for matching. The last 6/16 ER specimens yielded 9/14 matches, demonstrating a learning curve due to methodological improvements in marker placement and tissue block sectioning. One‐to‐one correlation of VLE and histology is complex but feasible. The groundwork laid in this study will provide high‐quality histology–VLE correlations that will allow further research on VLE features of early neoplasia in BE.