Barrett's Esophagus Esophageal Adenocarcinoma Research Articles

What Constitutes Optimal Management of T1N0 Esophageal Adenocarcinoma?

Esophageal adenocarcinoma (EAC) develops as a consequence of gastroesophageal reflux disease and Barrett's esophagus (BE). While combination therapy with chemotherapy or concurrent chemoradiotherapy followed by esophagectomy improves survival in more advanced tumors, the optimal treatment strategy for early-stage EAC is undefined. Endoscopic eradication therapy, consisting of endoscopic resection and mucosal ablation, has revolutionized therapy for superficial (T1a) EAC in BE and allows for esophageal preservation in appropriate patients at low risk for lymph node metastasis (LNM). This review critically examines the literature regarding evaluation, treatment, and outcomes in patients with T1 EAC. The literature was queried via the PubMed database to include articles published between 1990 and 2017. Search terms were generated from the key statements "Endoscopic eradication therapy results in equivalent overall survival when compared to esophagectomy for clinical T1aN0 EAC" and "Esophagectomy provides better overall survival than endoscopic eradication therapy for cT1b EAC". Abstracts were reviewed and included according to predefined selection and exclusion criteria, and were then assessed according to the GRADE system. In patients with T1aN0 EAC, overall survival with endoscopic eradication therapy is equal to esophagectomy. Given the substantial risk of LNM in patients with submucosal (T1b) EAC, esophagectomy remains the standard of care for surgical candidates. In the case of inoperability or low-risk lesions, endoscopic resection may be considered adequate therapy. Chemotherapy and radiation can be offered as primary therapy for non-surgical candidates with lesions not amenable to endoscopic therapy, but does not have a clear role in the adjuvant setting after either endoscopic or surgical resection.

Animal Model: Reflux Models in Esophageal Adenocarcinoma.

Many mouse models have been developed to mimic the inflammation-metaplasia-dysplasia-carcinoma sequence seen in the gastroesophageal reflux disease (GERD)-Barrett's esophagus-esophageal adenocarcinoma progression. Surgical reflux models in mice are technically challenging due to the small size and intolerance to surgical stress of mice. Herein, we detail three representative surgical procedures that allow for creation of an esophageal adenocarcinoma model in mice, either with or without the use of carcinogens. Additionally, we describe a genetic model that shows spontaneous development of esophageal adenocarcinoma.

MicroRNA Expression Signatures During Malignant Progression From Barrett's Esophagus.

The rapid increase and poor survival of esophageal adenocarcinoma (EAC) have led to significant efforts to promote early detection. Given that the premalignant lesion of Barrett's esophagus (BE) is the major known risk factor for EAC, multiple investigators have studied biomarker signatures that can predict malignant progression of BE to EAC. MicroRNAs, a novel class of gene regulators, are small non-coding RNAs and have been associated with carcinogenesis. MicroRNAs are ideal biomarkers because of their remarkable stability in fixed tissues, a common method for collection of clinical specimens, and in blood either within exosomes or as microRNA-protein complexes. Multiple studies show potential of microRNAs as tissue and blood biomarkers for diagnosis and prognosis of EAC but the results need confirmation in prospective studies. Although head-to-head comparisons are lacking, microRNA panels require less genes than messenger RNA panels for diagnosis of EAC in BE. MicroRNA diagnostic panels will need to be compared for accuracy against global measures of genome instability that were recently shown to be good predictors of progression but require sophisticated analytic techniques. Early studies on blood microRNA panels are promising but have found microRNA markers to be inconsistent among studies. MicroRNA expression in blood is different between various microRNA sub-compartments such as exosomes and microRNA-protein complexes and could affect blood microRNA measurements. Further standardization is needed to yield consistent results. We have summarized the current understanding of the tissue and blood microRNA signatures that may predict the development and progression of EAC.

Myo9B is associated with an increased risk of Barrett's esophagus and esophageal adenocarcinoma

Background.Reflux esophagitis (RE) and Barrett's esophagus (BE) are predisposing factors for development of esophageal adenocarcinoma (EAC), the solid tumor with the fastest rising incidence in the Western world. This RE–BE–EAC cascade involves multiple host factors and consequently multiple genes. Polymorphisms in the 3′ region of myosin IXB (Myo9B) are associated with chronic inflammatory gastrointestinal disorders like celiac disease and ulcerative colitis, assuming that variation in Myo9B influences the intestinal permeability. Aim.To determine esophageal expression and the genetic variation of the Myo9B gene in the RE–BE–EAC cascade. Methods.DNA from 886 Caucasian participants (198 non-reflux controls, 305 RE, 254 BE, 129 EAC) was collected for the determination of the Myo9B gene polymorphism (rs2305764). Esophageal Myo9B expression was determined on biopsies from normal, RE, BE and EAC epithelium. Results. Genotype G/G was more common in BE (p = 0.032) and EAC (p = 0.046), but not in RE (p = 0.126) compared with the control group. Cytoplasmic Myo9B expression was determined in RE, BE and EAC, but most prominent in epithelial cells of BE and EAC. Conclusions.Genetic variation of Myo9B may play a role in the etiology of BE and EAC by increasing the permeability of the epithelial barrier.

Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study

Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

S1064 Evaluation of Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) in Esophageal Adenocarcinoma in Barrett's Esophagus

Background:Epithelial mesenchymal transition(EMT) is a crucial event in the metastatisis of carcinoma. EMT enables epithelial tumors to invade into the mesenchymal submucosa. The key feature of EMT is E-cadherin down-regulation. Snail, Slug and Twist are well recognized transcriptional factors as repressors of E-cadherin expression. Recently, a direct link has been shown between the EMT and cancer stem cell(CSC). CSC has the ability to self-renew and continually sustain tumorigenesis. Cells undergoing an EMT could be the precursors to metastatic carcinoma, perhaps as CSCs. CD133 is recognized marker for gastrointestinal CSCs. Aim:To characterize expressions of Snail, Slug, Twist and CD133 in the metastatic esophageal adenocarcinoma(EAC) in Barrett's esophagus(BE). Method:Formalin-fixed, paraffin embedded specimens of surgically treated early EAC were used. All slides were first reviewed by a well experienced GI pathologist, then were immunohistochemically stained for primary antibodies to Snail, Slug, Twist and CD133. We assessed if invading edges of tumor in the submucosa were stained for each antibody, and if there were differences of intensity of staining between in intramucosal cancer cells and in submucosal metastatic cells. The slides were scored by (1) intensity of staining (0=negative, 1=weak, 2=moderate, 3= intense);(2) percentage of epithelial cells staining (0=0-5%, 1=6-25%, 2=26-50%, 3=5175%, 4=76-100%);(3) percentage of invading cancer cells staining (same as epithelial cells). Cellular localization (nuclear, cytoplasm, cell surface) and uniformity (focal, general) were also assessed. Result:10 patients were analyzed. All four proteins were expressed in the cancers with uniform staining in both the mucosa and submucosa with Snail being more localized in the nucleus while Slug, Twist and CD133 were exclusively in the cytoplasm. Intensity of staining of metastatic cancer cells in submucosa was similar to those in the mucosa. Semi-quantitative scored analyses of Snail, Slug, Twist and CD133 for overall intensity were 2.5, 2.8, 1.9, and 2.4, respectively. For epithelial tumor cells, the scores were 4.0, 3.8, 3.3, and 3.2, respectively, whereas for invading metastatic cells, 4.0, 3.6, 3.1, and 3.6. Conclusion:This is the first report assessing the expression of known E-cadherin repressors, Snail, Slug, Twist and CSC marker, CD133 in the development of EAC in BE. All invading edges of tumor were found to abundantly express Snail, Slug, Twist and CD133 suggesting that unlike late staged cancers, early staged cancers are predominantly made of cells with metastatic potential which emphasizes the need to completely remove these early cancers.

Extent of Low-Grade Dysplasia Is a Risk Factor for the Development of Esophageal Adenocarcinoma in Barrett's Esophagus

Previous studies that evaluated extent of high-grade dysplasia (HGD) as a risk factor for esophageal adenocarcinoma (EA) in Barrett's esophagus (BE) were conflicting, and no prior study has evaluated extent of low-grade dysplasia (LGD) as a risk factor. The aim of this discovery study was to evaluate the hypothesis that extent of LGD and HGD are risk factors for progression to EA. We evaluated baseline biopsies from 77 BE patients with dysplasia including 44 who progressed to EA and 33 who did not progress during follow-up. The total numbers of LGD and HGD crypts were determined separately by counting all crypts and the extent of LGD, HGD, and total dysplasia were correlated with EA outcome. Thirty-one and 46 patients had a maximum diagnosis of LGD and HGD, respectively. When the crypts were stratified by dysplasia grade, the mean number of LGD crypts per patient was borderline higher in progressors (93.9) compared with nonprogressors (41.2, P= 0.07), and the mean proportion of LGD crypts per patient was significantly higher in progressors (46.4%vs 26.0%, P= 0.037). Neither the mean number of HGD crypts per patient (P= 0.14) nor the mean proportion of HGD crypts per patient (P= 0.20) was significantly associated with EA outcome. The extent of LGD is a significant risk factor for the development of EA in BE in this study. Although the presence of HGD is significantly associated with a greater relative risk for development of EA, the extent of HGD was not an independent risk factor for progression.