The poorly differentiated component in endoscopic biopsy predicts submucosal invasion in superficial Barrett's esophageal adenocarcinoma.

Issue Highlights

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana(®) immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.

American Gastroenterological Association Technical Review on the Management of Barrett's Esophagus

Objective. To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Material and methods. Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. Results. Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15–4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09–4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. Conclusions. Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.

SummaryBackgroundOesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma.MethodsWe did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms.FindingsOur sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation.InterpretationOur meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies.FundingUS National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

Background Obesity was known to be a risk factor of the incidence of Barrett’s esophagus (BE) and Barrett’s esophageal adenocarcinoma (BEA). Especially excessive visceral fat has recently reported to promote some cancers, including BEA. This study aimed to clarify the impact of abdominal fat distribution on the progression of BE to adenocarcinoma in long-segment BE (LSBE) and short-segment BE (SSBE). Methods Study 1: We retrospectively reviewed the 124 patients with pathologically defined superficial BEA who underwent endoscopic resection, including 4 endoscopic mucosal resection (EMR) and 85 endoscopic submucosal dissection (ESD), or surgical operation (35 esophagectomy) in our institution between January 2004 and December 2018. 124 BEA cases included 34 LSBE (length ≥ 3 cm) cases and 90 SSBE (length ≥ 1 and &amp;lt; 3 cm) cases. Using computed tomography volumetry, we measured areas of visceral (VFA) and subcutaneous (SFA) fat at the level of the umbilicus, and calculated the VFA/SFA ratio in each patient, defining high-VFA/SFA ratio (≧1.0) and low-VFA/SFA ratio (&amp;lt;1.0). VFA/SFA ratio were compared and analyzed between BEA with LSBE group and BEA with SSBE group. Study2: We divided 62 patients who had LSBE into two groups based on prognosis of BEA; BEA with LSBE (34 patients) and non-BEA with LSBE group (18 patients). Abovementioned parameters were compared and analyzed between these two groups. Study3: Abovementioned parameters were compared and analyzed between BEA with SSBE (90 cases) and non-BEA with SSBE group (100 controls). Results study1: High VS ratio were seen in 22 (64.7%) patients among BEA with LSBE group and 34 (37.8%) patients among BEA with SSBE group, which is statistically significant (p = 0.0072). Study2: High VS ratio were seen in 6 (33.3%) patients among non-BEA with LSBE group. This result was statistically significant compared to BEA with LSBE group (0.038). Study3: In non-BEA with SSBE, 32 patients (32.0%) had High VS ratio, showing no significant difference compared to BEA with SSBE. Conclusion High VFA/SFA ratio was significantly associated with progression of long-segment Barrett’s esophagus to esophageal adenocarcinoma.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma has increased in Western countries in recent decades. The aim of this study is to describe the changes in incidence and prevalence of BE diagnosis, dysplasia, and adenocarcinoma development in BE patients in a South-European Mediterranean area. Retrospective population-based analyses of endoscopy and pathology reports from 1976 to 2001 was performed. Data from patients with diagnosis of BE and/or esophageal carcinoma were collected. The study period was divided in four quartiles for statistical calculations; parametric and nonparametric tests were used. A 6.9-fold increase was found in the diagnosis of long-segment BE from the first to the fourth quartile, and a 9.3-fold increase in short-segment BE from 1995 to 2000, in contrast to a much smaller increase of 1.9-fold increase in the number of upper gastrointestinal endoscopies. The adjusted incidence of BE diagnosis increased from 0.73 to 9.73 cases/100,000 (first to fourth quartile, respectively) and the adjusted prevalence from 6.51 to 76.04 cases/100,000 (1985-2001). The incidence of dysplasia was 2.13% per year (95% confidence interval: 0.05-11.3%) - 1.78% for low-grade dysplasia and 0.36% for high-grade dysplasia - giving a total incidence of 1 per 47 patient-years. The incidence of adenocarcinoma during follow-up was 0.48% per year (95% confidence interval: 0.006-2.62%), for an incidence of 1 per 210 patient-years. Nineteen patients with BE (14 long-segment BE, 5 short-segment BE) were diagnosed with esophageal adenocarcinoma, with eight being diagnosed during endoscopic surveillance. Only 14 (8%) adenocarcinoma patients diagnosed during the study period had a history of BE. BE diagnosis has dramatically increased over recent decades in our population, unrelated to an increase in endoscopies. Progression to low-grade dysplasia and adenocarcinoma is rare. Surveillance may have a low impact on the survival of adenocarcinoma patients in Southern Europe.

Gene Expression Profiling Reveals Stromal Genes Expressed in Common Between Barrett’s Esophagus and Adenocarcinoma

Background: Superficial Barrett's esophageal adenocarcinoma (BEA) arising from short-segment Barrett's esophagus (SSBE) is visualized as a reddish lesion located on the right or anterior side wall of the esophagogastric mucosal junction (EGJ) and showing an elevated macroscopic appearance under conventional white light endoscopy (WLE). However, because the form and color are variable, misdiagnosis as reflux esophagitis or SSBE is frequent under WLE. The aim of this study is to clarify conventional WLE features of small superficial BEA. Summary: We retrospectively analyzed 30 lesions ≤20 mm in diameter in 30 patients who underwent endoscopic mucosal resection or endoscopic submucosal dissection at Toranomon Hospital between 2002 and 2014. Mean age of patients with small superficial BEA arising from SSBE was 64.3 ± 11.2 years, and mean tumor size was 12.0 ± 4.8 mm. Small superficial BEA fell into the following 4 categories based on WLE features: EGJ polyp type, 43.3% (13 of 30 lesions); triangular SSBE type, 43.3% (13 of 30 lesions); cardiac erosion type, 10.0% (3 of 30 lesions); and unclassified or mixed type, 3.4% (1 of 30 lesions). EGJ polyp-type tumors were located on the right or anterior side wall of the EGJ, and no tumors showed invasion to the submucosal layer. On the other hand, triangular SSBE-type tumors were located anywhere in the EGJ, and 38.5% showed submucosal invasion (5 of 13 lesions). Key Messages: We consider this classification significantly contributes to the detection of small superficial BEA arising from SSBE under WLE.

Cost-Effectiveness of Endoscopic Screening Followed by Surveillance for Barrett's Esophagus: A Review

Activation-induced cytidine deaminase (AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. We recently demonstrated that Helicobacter pylori infection and/or proinflammatory cytokine stimulation triggers aberrant AID expression in gastric epithelial cells, causing mutations in the tumour-suppressor TP53 gene. The findings of the present study provide evidence of ectopic AID expression in Barrett's oesophagus and Barrett's oesophageal adenocarcinoma, a cancer that develops under chronic inflammatory conditions. Immunoreactivity for endogenous AID was observed in 24 of 28 (85.7%) specimens of the columnar cell-lined Barrett's oesophagus and in 20 of 22 (90.9%) of Barrett's adenocarcinoma, whereas weak or no AID protein expression was detectable in normal squamous epithelial cells of the oesophagus. We validated these results by analysing tissue specimens from another cohort comprising 16 cases with Barrett's oesophagus and four cases with Barrett's adenocarcinoma. In vitro treatment of human non-neoplastic oesophageal squamous-derived cells with sodium salt deoxycholic acid induced ectopic AID expression via the nuclear factor-kappaB activation pathway. These findings suggest that aberrant AID expression occurs in a substantial proportion of Barrett's epithelium, at least in part due to bile acid stimulation. Considering the genotoxic activity of AID, our current findings suggest that aberrant AID expression might enhance the susceptibility to genetic alterations in Barrett's columnar-lined epithelial cells, leading to cancer development.

Barrett's oesophagus and oesophageal adenocarcinoma, although increasingly common, have no known genetic cause. In this report we describe a family with a remarkable history of Barrett's oesophagus and adenocarcinoma. The index case is a 76-year-old man with adenocarcinoma arising within Barrett's oesophagus. Two of his three brothers, aged 68 and 78 years, also developed adenocarcinoma arising in Barrett's oesophagus and the remaining 67-year-old brother has severe dysplasia in biopsies from Barrett's oesophagus. The sons and daughters of the index case requested screening and all had histologically confirmed short-segment Barrett's oesophagus. This kindred appears to be genetically susceptible to Barrett's oesophagus and oesophageal adenocarcinoma. Pooling of data from this and other Barrett's families may allow successful linkage analysis.

There has been a dramatic rise in incidences of Barrett's oesophagus and oesophageal adenocarcinoma. It has been suggested that the introduction and use of acid suppression therapy may be a factor in the rising incidences of Barrett's oesophagus and oesophageal adenocarcinoma. This was a record linkage study, using a prescribing database and an endoscopy database. Patients who had undergone their first endoscopy during the period 1992-1995 and received the diagnosis of Barrett's oesophagus or oesophagitis were identified. The prescribing of acid suppressants was compared for the 3 years prior to endoscopy, between those with Barrett's oesophagus and those with oesophagitis. There was no significant difference between the Barrett's patients and the oesophagitis patients in the proportion that had been exposed to acid suppression therapy (53.4% vs. 51.7%, P=0.704). The mean number of days of prescribing among those who had been exposed to acid suppression therapy was higher in the Barrett's group (340.5 vs. 237.0 days, P=0.001). Patients with Barrett's oesophagus have received more acid suppressant therapy prior to diagnosis. The reasons for this are not clear. However, 46.6% of Barrett's patients have not been exposed to acid suppressant therapy.

Molecular mechanisms of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remain unclear in Japanese patients. Japanese EACs frequently have underlying short length BE: short-segment BE(SSBE), for which, neoplastic potential remains unclear. We performed comprehensive methylation profiling of EAC and BE in Japanese patients, mostly comprised with SSBE. Using three different groups of biopsies obtained from non-neoplastic BE from patients without cancer (n = 50; N group), with EAC (n = 27; ADJ group) and EAC (n = 22; T group), methylation statuses of nine candidate genes (N33, DPYS, SLC16A12, CDH13, IGF2, MLF1, MYOD1, PRDM5, and P2RX7) were examined by the bisulfite pyrosequencing. Reduced representation bisulfite sequencingwas performed to characterize the genome-wide methylation status in 32 samples (12 from N, 12 ADJ, and 8 from T groups). In the candidate approach, methylation levels of N33, DPYS, and SLC16A12 were higher in ADJ and T groups compared to that in N group. The ADJ group was an independent factor for higher DNA methylation in non-neoplastic BE. The genome-wide approach demonstrated an increase of hypermethylation from ADJ to T groups relative to N group near the transcription start sites. Among gene groups hypermethylated in ADJ and T groups (n = 645) and T group alone (n = 1438), 1/4 and 1/3 were overlapped with downregulated genes in the microarray data set, respectively. Accelerated DNA methylation is observed in EAC and underlying BE in Japanese patients, mostly comprised with SSBE, highlighting the potential impact of methylation in early carcinogenesis.