Barrett's esophagus and esophageal adenocarcinoma.

Barrett's esophagus is a condition in which the normal stratified squamous epithelium is replaced by a specialized metaplastic columnar epithelium. It develops as a consequence of chronic gastroesophageal reflux and predisposes to the development of esophageal adenocarcinoma. Adenocarcinoma develops in Barrett's esophagus by a multistep process in which specialized metaplasia progresses to dysplasia, then to early adenocarcinoma, and eventually to deeply invasive and metastatic disease. This neoplastic progression is associated with a process of genomic instability that generates abnormal clones of cells, some of which have aneuploid or increased G2/tetraploid DNA content. A systematic protocol of endoscopic biopsy can detect Barrett's adenocarcinomas at an early stage, when they may be curable.     

Lifetime risk of esophageal adenocarcinoma in patients with Barrett's esophagus

AIM: To investigate the lifetime risk of development of esophageal adenocarcinoma and/or high-grade dysplasia in patients diagnosed with Barrett’s esophagus.METHODS: Data were extracted from the United Kingdom National Barrett’s Oesophagus Registry on date of diagnosis, patient age and gender of 7877 patients from who had been registered from 35 United Kingdom centers. Life expectancy was evaluated from United Kingdom National Statistics data based upon gender and age at year at diagnosis. These data were then used with published estimates of annual adenocarcinoma and high-grade dysplasia incidences from meta-analyses and large population-based studies to estimate overall lifetime risk of development of these study endpoints.RESULTS: The mean age at diagnosis of Barrett’s esophagus was 61.6 years in males and 67.3 years in females. The mean life expectancy at diagnosis was 23.1 years in males, 20.7 years in females and 22.2 years overall. Using data from published meta-analyses, the lifetime risk of development of adenocarcinoma was between 1 in 8 and 1 in 14 and the lifetime risk of high-grade dysplasia or adenocarcinoma was 1 in 5 to 1 in 6. Using data from 3 large recent population-based cohort studies the lifetime risk of adenocarcinoma was between 1 in 10 and 1 in 37 and of the combined end-point of high-grade dysplasia and adenocarcinoma was between 1 in 8 and 1 in 20. Age at Barrett’s esophagus diagnosis is reducing and life expectancy is increasing, which will partially counter-balance lower annual cancer incidence.CONCLUSION: There is a significant lifetime risk of development of high-grade dysplasia and adenocarcinoma in Barrett’s esophagus.     

Advances in Barrett's esophagus and esophageal adenocarcinoma

Despite advances in diagnosis and therapy, esophageal adenocarcinoma remains an aggressive and usually lethal tumor. This review focuses on the epidemiology of esophageal adenocarcinoma and its presumed precursor lesion, Barrett's esophagus; the pathogenesis of the cancer; advances in treatment of adenocarcinoma and Barrett's esophagus; and strategies for cancer prevention. Emphasis is placed on recent literature. Although the absolute number of cases of adenocarcinoma in the United States is still small, the incidence of this cancer has increased dramatically in the last 40 years, and adenocarcinoma is now the predominant form of esophageal cancer in this country. Recent evidence suggests that Barrett's esophagus is more prevalent in asymptomatic individuals than previously appreciated. The pathogenesis of Barrett's esophagus is poorly understood. Given that some subjects will have repeated bouts of severe erosive esophagitis and never develop Barrett's esophagus, host factors must play an important role. The utility of neoadjuvant radiation and chemotherapy in those with adenocarcinoma, although they are widely practiced, is not of clear benefit, and some authorities recommend against it. Ablative therapies, as well as endoscopic mucosal resection, hold promise for those with superficial cancer or high-grade dysplasia. Most series using these modalities feature relatively short follow-up, and longer-term data will be necessary to better describe the effects of these therapies. The value of chemoprevention in subjects with dysplastic Barrett's esophagus by use of cyclooxygenase 2 inhibitors, nonsteroidal anti-inflammatory drugs, or proton pump inhibitors is unknown. Similarly, although endoscopic screening is widely practiced, its value in patients with chronic gastroesophageal reflux disease symptoms is of unproven value, and recommending bodies are divided as to its practice.     

Alteration of the esophageal microbiota in Barrett's esophagus and esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma(EAC) has increased in recent decades, and its 5-year survival rate is less than 20%. As a well-established precursor, patients with Barrett's esophagus(BE) have a persistent risk of progression to EAC. Many researchers have already identified some factors that may contribute to the development of BE and EAC, and the identified risks include gastroesophageal reflux(GER), male sex, older age, central obesity,tobacco smoking, Helicobacter pylori(H. pylori) eradication, and the administration of proton pump inhibitors(PPIs) and antibiotics. The human gut harbors trillions of microorganisms, the majority of which are bacteria. These microorganisms benefit the human host in many ways, such as helping in digestion, assisting in the synthesis of certain vitamins, promoting the development of the gastrointestinal immune system, regulating metabolism and preventing invasion by specific pathogens. In contrast, microbial dysbiosis may play important roles in various diseases, such as inflammation and cancers. The composition of the microbiota located in the normal esophagus is relatively conserved without distinct microbial preferences in the upper, middle and lower esophagus. Six major phyla constitute the esophageal microbiota, including Firmicutes,Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria and TM7, similar to the oral microbiota. Streptococcus dominates the esophageal microbiota. However, the microbiota varies in different esophageal diseases compared to that in the healthy esophagus. The type Ⅰ microbiota, which is primarily composed of gram-positive bacteria, is closely associated with the normal esophagus, while type Ⅱ microbiota has enriched gram-negative bacteria and is mainly associated with the abnormal esophagus. These increased gram-negative anaerobes/microaerophiles include Veillonella, Prevotella, Haemophilus, Neisseria, Granulicatella and Fusobacterium, many of which are associated with BE. The microbial diversity in the esophagus is decreased in EAC patients, and Lactobacillus fermentum is enriched compared to that in controls and BE patients. Furthermore, the microbiota may be associated with BE and EAC by interacting with their risk factors, including central obesity, GER, H. pylori, administration of PPIs and antibiotics. Therefore, a large gap in research must be bridged to elucidate the associations among these factors. Some studies have already proposed several potential mechanisms by which the microbiota participates in human carcinogenesis by complicated interactions with the human host immune system and signaling pathways. The activation of the LPS-TLR4-NF-κB pathway may contribute to inflammation and malignant transformation. This exciting field of gastrointestinal microbiota allows us to unravel the mystery of carcinogenesis from another perspective. Further studies are needed to explore whether the microbiota changes before or after disease onset, to improve our understanding of the pathogenesis, and to find novel targets for prevention, diagnosis and therapy, which could offer more cost-effective and relatively safe choices.     

From reflux esophagitis to Barrett's esophagus and esophageal adenocarcinoma

The occurrence of gastroesophageal reflux disease is common in the human population.Almost all cases of esophageal adenocarcinoma are derived from Barrett's esophagus,which is a complication of esophageal adenocarcinoma precancerous lesions.Chronic exposure of the esophagus to gastroduodenal intestinal fluid is an important determinant factor in the development of Barrett's esophagus.The replacement of normal squamous epithelium with specific columnar epithelium in the lower esophagus induced by the chronic exposure to gastroduodenal fluid could lead to intestinal metaplasia,which is closely associated with the development of esophageal adenocarcinoma.However,the exact mechanism of injury is not completely understood.Various animal models of the developmental mechanisms of disease,and theoretical and clinical effects of drug treatment have been widely used in research.Recently,animal models employed in studies on gastroesophageal reflux injury have allowed significant progress.The advantage of using animal models lies in the ability to accurately control the experimental conditions for better evaluation of results.In this article,various modeling methods are reviewed,with discussion of the major findings on the developmental mechanism of Barrett's esophagus,which should help to develop better prevention and treatment strategies for Barrett's esophagus.     

Patients with Barrett's esophagus perceive their risk of developing esophageal adenocarcinoma as low

BACKGROUND: The risk of developing esophageal adenocarcinoma (EAC) for patients with Barrett's esophagus (BE) is approximately 0.5% per year. OBJECTIVE: To investigate how patients with BE estimate and perceive their risk of developing EAC. DESIGN: Questionnaire study. SETTING: Patients with BE who were undergoing surveillance endoscopy based on histologic and flow cytometric results. PATIENTS: A total of 192 patients with BE were included. MAIN OUTCOME MEASUREMENTS: Individual patients were asked to estimate the numerical risk to develop EAC for patients with BE in general and for themselves. How patients perceived their own risk was measured on a scale from "very small" to "very large." RESULTS: At least 1 question was filled out by 169 patients (88% response). Sixty percent of respondents underestimated the numerical risk for patients with BE, in general, to develop EAC, while even more patients (69%) underestimated their own risk. Most respondents perceived their own risk as very small or small (63%). LIMITATIONS: Risk estimations may depend on the response scale used. CONCLUSIONS: Most patients with BE underestimated the numerical risk and perceived their risk of developing EAC as (very) low. Despite a low perceived risk, all patients in this group adhered to endoscopic surveillance.     

Gastric surgery is not a risk for Barrett's esophagus or esophageal adenocarcinoma.

BACKGROUND & AIMS: The contribution of duodeno-gastroesophageal reflux to the development of Barrett's esophagus has remained an interesting but controversial topic. The present study assessed the risk for Barrett's esophagus after partial gastrectomy. METHODS: The data of outpatients from a medicine and gastroenterology clinic who underwent upper gastrointestinal endoscopy for any reason were analyzed in a case-control study. A case population of 650 patients with short- segment and 366 patients with long-segment Barrett's esophagus was compared in a multivariate logistic regression to a control population of 3047 subjects without Barrett's esophagus or other types of gastroesophageal reflux disease. RESULTS: In the case population, 25 (4%) patients with short-segment and 15 (4%) patients with long-segment Barrett's esophagus presented with a history of gastric surgery compared with 162 (5%) patients in the control population, yielding an adjusted odds ratio of 0.89 with a 95% confidence interval of 0.54-1.46 for short-segment and an adjusted odds ratio of 0.71 (0.30-1.72) for long-segment Barrett's esophagus. Similar results were obtained in separate analyses of 64 patients with Billroth-1 gastrectomy, 105 patients with Billroth-2 gastrectomy, and 33 patients with vagotomy and pyloroplasty for both short- and long-segment Barrett's esophagus. Caucasian ethnicity, the presence of hiatus hernia, and alcohol consumption were all associated with elevated risks for Barrett's esophagus. CONCLUSIONS: Gastric surgery for benign peptic ulcer disease is not a risk factor for either short- or long-segment Barrett's esophagus. This lack of association between gastric surgery and Barrett's esophagus suggests that reflux of bile without acid is not sufficient to damage the esophageal mucosa.     

Photodynamic therapy for mucosal esophageal adenocarcinoma and dysplastic Barrett's esophagus

Photodynamic therapy is a novel endoscopic technique that combines a photosensitizer and laser light to destroy target cells. Photodynamic therapy has been used in Europe, North Africa and Japan to treat esophageal neoplasms and dysplastic Barrett's esophagus. This paper summarizes the available published experience of photodynamic therapy for the treatment of each esophageal cancer and Barrett's esophagus. These studies suggest that photodynamic therapy is a promising modality for esophageal mucosal disease. More long-term studies, however, are needed to document the efficacy of photodynamic therapy in reducing the morbidity and mortality from esophageal cancer for patients with high-grade dysplasia and early adenocarcinoma in Barrett's esophagus.     

Characteristics of patients with columnar-lined Barrett＇s esophagus and risk factors for progression to esophageal adenocarcinoma

AIM: To determine the risk factors for the development of esophageal adenocarcinoma in these patients with columnar-lined esophagus (CLE). METHODS: Data collected retrospectively on 597 consecutive patients diagnosed at endoscopy and histology to have CLE at Leeds General Infirmary between 1984 and 1995 were analyzed. Factors evaluated included age, sex, length of columnar segment, smoking, and drinking habits, history of non-steroidal ingestion, presence of endoscopic esophagitis, ulceration or benign strictures and presence of Helicobacter pylori in esophageal biopsies. Univariate and multivariate analyses were performed to identify risk factors for the development of adenocarcinoma. RESULTS: Forty-four patients presented or developed esophageal adenocarcinoma during follow-up. Independent risk factors for the development of adenocarcinoma in patients with CLE were males (OR 5.12, 95%CI 2.04-12.84, P = 0.0005), and benign esophageal stricture (OR 4.37, 95%CI 2.02-9.45, P = 0.0002). Male subjects and patients who developed benign esophageal stricture constituted 86% (n = 38) of all patients who presented or developed esophageal adenocarcinoma. The presence of esophagitis was associated with a significant reduction in the development of esophageal carcinoma (OR 0.28, 95%CI 0.13-0.57, P = 0.0006). No other clinical characteristics differentiate between the non-malignant and malignant group. CONCLUSION: In patients with CLE, endoscopic surveillance for the early detection of adenocarcinoma may be restricted to male subjects, as well as patients who develop benign esophageal strictures.     

Esophageal adenocarcinoma and Barrett's esophagus

Esophageal adenocarcinoma (EAC) is the most rapidly rising incidence cancer associated with a poor 5-year survival rate. Barrett's esophagus (BE) is a well established premalignant condition for the development of EAC and hence it is imperative that patients with BE or at risk for developing BE should be identified and managed appropriately. The endoscopic recognition of BE should include the assessment of the circumferential (C) and maximum (M) extent of the endoscopically visualized BE segment as well as endocsopic landmarks (The Prague C&M criteria). Although controversial, clinical strategies of screening and surveillance have focused on identification of esophageal neoplasia at an early asymptomatic and curable stage with the ultimate goal of preventing deaths from this cancer. Risk stratification that involves screening and surveillance of high risk individuals may improve the efficacy and effectiveness of these programs. The future of this endeavor lies in the identification and validation of biomarkers coupled with enhanced endoscopic techniques such as narrow band imaging, autofluorescence imaging, confocal laser endomicroscopy etc. Endoscopic therapies (endoscopic mucosal resection, ablative therapies) have become attractive alternatives for the treatment of high grade dysplasia and/or early EAC in BE patients. The main stays of treatment of advanced cancers are debulking surgery, chemotherapy, radiotherapy and palliative care measures.     

Risk factors for the development of esophageal adenocarcinoma in Barrett's esophagus

OBJECTIVE: To identify risk factors for esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). METHODS: A hospital-based case-control study was performed in which 91 cases with EAC and 244 controls with histologically confirmed BE (>2 cm) with no dysplasia or low-grade dysplasia were included. Information on demographic, anthropometric, and lifestyle characteristics, physical activity levels, working posture, family history, gastroesophageal reflux disease (GERD) symptoms, and medication use was collected by questionnaire. RESULTS: Cases more often were current smokers (odds ratio 3.7, 95% confidence interval 1.4-9.9), more often had a body mass index >25 assessed at age 20 (2.6, 1.2-5.5), and more frequently had been working in a stooped posture at age 20 (2.0, 1.1-3.9), compared to controls. In addition, cases less often experienced symptoms of heartburn (0.3, 0.2-0.5) and less frequently used proton pump inhibitors (0.1, 0.05-0.2), compared to controls, whereas use of nonsteroidal anti-inflammatory drugs/aspirin was more common among cases (1.8, 1.1-3.2). Cases more often were men, compared to controls (91%vs 67%, p < 0.001). CONCLUSION: In patients with BE, the risk of EAC is related to risk factors for GERD, which is, however, asymptomatic. As these risk factors are common in Western countries, they are probably not helpful in individualization of surveillance intervals.     

MicroRNAs, development of Barrett’s esophagus, and progression to esophageal adenocarcinoma

Barrett's esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esoph-ageal adenocarcinoma. Whilst it is well accepted that Barrett's esophagus is caused by gastroesophageal reflux, the molecular mechanisms of its pathogenesis and progression to cancer remain unclear. MicroRNAs (miRNAs) are short segments of RNA that have been shown to control the expression of many human genes. They have been implicated in most cellul...     

Epidemiologic risk factors for Barrett's esophagus and associated adenocarcinoma.

The incidence of esophageal adenocarcinoma (AC) has increased dramatically in the Western world over the past 20 years and the majority of these cancers arise on the background of the preinvasive lesion Barrett's esophagus. The epidemiologic factors that contribute to an individual's susceptibility for Barrett's esophagus and associated cancer are likely to be multifactorial. However, the short time frame over which the incidence of adenocarcinoma has increased, and the increase across populations, provides a strong argument for environmental factors as etiologic agents, perhaps interacting with genetically determined characteristics that define personal susceptibility. In this review we discuss the epidemiologic evidence for the proposed demographic and environmental risk factors for the development of both Barrett's esophagus and AC. The current evidence suggests that significant risk factors include male sex, Caucasian race, and the presence of duodenogastroesophageal reflux disease. The susceptibility for reflux disease may in turn be influenced by factors such as obesity, the use of drugs that lower the lower-esophageal sphincter tone, and a protective effect of Helicobacter pylori colonization. There appears to be a weak association between smoking and AC. The role of dietary factors has not been studied adequately and deserves further attention. An understanding of the factors that predispose to the development and progression of Barrett's esophagus is crucial to the implementation of effective screening and prevention programs.     

Circulating exosomal miRNAs as potential biomarkers for Barrett's esophagus and esophageal adenocarcinoma

Exosomes,a class of extracellular vesicles,are small membrane-bound vesicles derived from almost all cell types that can play important roles in intercellular communication.Exosomes contain proteins,lipids,and nucleic acids that are obtained from the parental cells and participate in various pathophysiological processes,including cell growth,migration,inflammation,immune regulation,and tumor pathogenesis.Moreover,exosomes might be applied in clinical settings,such as diagnosis,treatment,and outcome prediction of diseases,including various cancers.The incidence rates of Barrett's esophagus(BE) and esophageal adenocarcinoma(EAC) have increased in recent decades,and studies have proposed specific factors that may contribute to the development and progression of these diseases.However,how exosomes play a role in this pathological process needs to be clarified.Studies have identified candidate microRNAs(miRNAs) that might be related to BE/EAC.Further studies are needed to ascertain whether circulating exosomal miRNAs are altered before or after disease onset,which could also help understand the pathophysiology of and find potential targets for prevention,diagnosis,and therapy in BE/EAC.This review summarizes recent findings on the features of circulating exosomal miRNAs in BE/EAC,which could be valuable for the early diagnosis,therapeutic approaches,and outcome prediction of BE/EAC.     

Barrett's esophagus. Reducing the risk of progression to adenocarcinoma

Barrett's metaplasia develops in 6% to 14% of individuals with gastroesophageal reflux. Barrett's adenocarcinomas are increasing in epidemic proportions for, as yet unknown, reasons; approximately 0.5% to 1% of patients with Barrett's metaplasia develop adenocarcinoma. Heartburn duration and frequency (but not severity), male gender, and white race are major risk factors for developing cancer. Obesity and smoking are weak risk factors. Survival is determined by depth of tumor invasion (stage). Once invasion of the muscularis propria occurs, most patients have developed widespread metastasis, even when clinical staging studies are negative. No currently available therapy results in prolonged survival once metastases develop. Thus, the more widespread use of effective surveillance strategies is the only currently available means for reducing the morbidity and mortality associated with Barrett's adenocarcinoma.