Esophageal abnormalities and the risk for gastroesophageal cancers—a histopathology-register-based study in Sweden

Background The poor survival of patients with gastroesophageal cancers may improve if additional esophageal precursor lesions to Barrett’s esophagus and squamous dysplasia are identified. We estimated the risk for gastroesophageal cancers among patients with various histopathological abnormalities in the esophagus, including Barrett’s esophagus, subdivided by histopathological types. Methods Histopathology data from esophageal biopsies obtained 1979–2014 were linked with several national population-based registers in Sweden. Patients were followed from 2 years after the first biopsy date until cancer, death, emigration, esophagectomy/gastrectomy or end of follow-up, 31st of December 2016, whichever came first. We estimated standardized incidence ratios (SIRs) as measures of relative risk with the Swedish general population as reference. Results In total 367 esophageal adenocarcinoma (EAC) cases were ascertained during 831,394 person-years of follow-up. The incidence rate (IR) for EAC was 0.1 per 1000 person-years for normal morphology, 0.2–0.5 for inflammatory changes, and 0.8–2.9 for metaplasia. The IR was 1.0 per 1000 person-years (95% confidence interval 0.7–1.3) among patients with non-dysplastic intestinal metaplasia, 0.9 (0.8–1.1) in non-dysplastic gastric/glandular metaplasia and 2.9 (2.0–4.2) among columnar metaplasia patients with low-grade dysplasia. The SIRs were 11.7 (95% confidence interval 8.6–15.5), 12.0 (10.0–14.2) and 30.2 (20.5–42.8), respectively. The SIRs for gastric cardia adenocarcinoma (GCA) were moderately elevated. Conclusions For the first time, we demonstrate that patients with esophageal inflammatory and other metaplastic abnormalities than Barrett’s esophagus have an increased risk of EAC and GCA compared to the general population. Moreover, patients with different histopathologic subtypes of Barrett’s esophagus have a comparable risk for EAC.

The Evolution of the Definition and Diagnosis of Barrett Esophagus: A Historical Perspective

Historical definitions of Barrett esophagus (BE) have depended on 2 beliefs: the esophagus is a squamous lined tube and the stomach is a columnar lined sac. Norman Barrett, in 1957, recognized that columnar lining in the tubular esophagus was reflux-induced metaplasia of squamous epithelium, leading to the present definition of BE. Recent evidence that gastric overdistension results in acid exposure of distal esophageal squamous epithelium, causing progressive columnar metaplasia, damage to the lower esophageal sphincter, and dilatation of the abdominal esophagus. This is presently mistaken at endoscopy for proximal stomach. The future definition of BE will likely include intra-sphincteric BE.

Columnar metaplasia and Barrett’s esophagus: morphological heterogeneity and immunohistochemical phenotype

Barrett’s esophagus (BE) is a pathologically confirmed intestinal metaplasia (CM) of the distal esophagus. BE is recognized as a potential complication of gastroesophageal reflux disease (GERD) and a premalignant condition with a high risk of neoplastic progression. The aim of this study was to compare the morphology of biopsied BE segments and CM segments extending < 1 cm and > 1 cm above the gastroesophageal junction (GEJ), as well as to perform the immunohistochemical analysis of biopsies with BE and CM > 1 cm above GEJ with or without dysplasia. The study recruited 92 patients with GERD: 42 patients with BE, 24 patients with CM > 1 cm above GEJ (С0М1.5–С13M14) and 26 patients with CM < 1 cm above GEJ (С0М0.3–0.8). Comparative analysis of tissue morphology revealed an association between the reactive changes in the epithelium and the severity of esophagitis in all groups. Reactive changes were detected significantly more often in BE segments than in CM segments > 1 cm (Mann-Whitney U, p < 0.05). Eight patients with BE (19.05%) were found to have low-grade dysplasia. One patient with CM > 1 cm above GEJ (4.2%) had high-grade dysplasia with cardiac-type metaplasia and immunohistochemical features of submorphological enteralization. Immunohistochemical testing for the intestinal and gastric markers of cell differentiation revealed the signs of submorphological enteralisation in all esophageal specimens with cardiac and fundic type metaplasia and in the specimens with BE in the areas lacking goblet cells.

RA10.03: REGENERATING ESOPHAGEAL SQUAMOUS EPITHELIUM FROM SQUAMOUS PROGENITOR CELLS THROUGH BMP2/4 SIGNAL INHIBITION IN MODELS OF BARRETT's ESOPHAGUS: A PROMISING CHEMOPREVENTIVE TREATMENT FOR ESOPHAGEAL ADENOCARCINOMA

Background Barrett's esophagus is a metaplastic condition in which the esophageal normal squamous mucosa is replaced by metaplastic columnar type of epithelium, which is a the result of chronic duodeno-gastric reflux, which causes an inflammatory response. One way to divert the risk of malignant progression of Barrett's esophagus would be by re-establishing squamous epithelium through inhibiting Barrett cells. In earlier studies the SHH-BMP4 pathway has been identified as one of the critical pathways involved in the generation of columnar metaplasia. BMPs are secreted stromal factors for instance involved in development and homeostasis of columnar epithelia. Therefore targeting BMPs to modulate signaling and inhibit columnar cell growth and proliferation could be an attractive approach for diverting cancer risk of metaplastic columnar epithelia such as Barrett's esophagus. Methods We first set out to study BMP signaling through analysis of RNA sequencing to identify which BMPs are involved in Barrett's esophagus and in three different models we investigated the effects of specific BMP inhibition and neo-squamous regeration. We finally investigated the origin of the neo-squamous cells by lineage tracing in one of our models. Results We found that In a transgenic mouse model, conditional knock out of the BMP inhibitor Noggin increased BMP signaling and development of columnar metaplasia arising from multilayered glands glands at the squamo-columnar junction in the stomach (figure…). We demonstrate that inhibiting BMP2 and 4, drives development of squamous epithelium in these glands. In for its effect of epithelial healing in an cryo-ablation model. Additionally, to perform lineage tracing using K5-cre-Tomato-GFP lineage tracing mice to investigate the site of origin of the neo-squamous epithelium. Method: Cryoablation of the stomach epithelium in wild-type and CK5 lineage tracing mice was performed just distal of the squamo-columnar junction and mice were treated with saline or intraperitoneal injections of the BMP inhibitor for 0, 7, 14 and 21 days. The healing process of the ablated area was investigated by histology and immunohistochemistry (IHC) using a panel of both squamous (CK5 and p63) and columnar markers (Villin, CK19). Results: At 21 days post ablation, we observed that the inhibition of BMP4 promoted the re-generation of neo-sqaumous epithelium in the ablated area, while the control group showed re-generation of normal stomach epithelium. IHC showed that the neo-squamous epithelium was positive for the CK5 and p63 squamous markers. Lineage tracing indicated that the squamous cells originated for multilayered glands at the squamo-columnar junction and from the adjacent squamous epithelium (Figure 1). Conclusion Our results demonstrate that inhibition of BMP2/4 after ablation of columnar epithelium at the squamo-columnar junction, promotes development of neo-squamous epithelium from submucosal multi-layered glands residing at the SCJ and adjacent squamous epithelium, at the same time the regeneration of columnar epithelium is inhibited. These pre-clinical findings can be translated to a clinical setting in order to optimize ablative therapies for treatment of BE patients. Disclosure All authors have declared no conflicts of interest.

Carcinoma in situ within an area of Barrett esophagus in a dog with megaesophagus

A 10-y-old Irish Setter was presented with a history of recurrent episodes of regurgitation and vomiting, with more recent development of tachypnea. Megaesophagus had been diagnosed in the dog 2 y prior to this presentation. A solitary polypoid mass present immediately rostral to the lower esophageal sphincter was biopsied during percutaneous endoscopic gastrostomy tube placement. Barrett esophagus was diagnosed based on the observation of a polypoid mass with intestinal metaplasia that arose from the surrounding esophagus. Histology of the polypoid mass demonstrated squamous-to-columnar metaplasia, hyperplasia, dysplasia, and carcinoma in situ.

Notch Signaling Pathway Is Inhibited in the Development of Barrett’s Esophagus: An In Vivo and In Vitro Study

Objective. To explore the role of Notch signaling in the development of Barrett’s esophagus. Methods. Patients with esophagectomy and gastric interposition were recruited as a human model of gastroesophageal reflux disease. The expressions of Notch signaling genes in normal esophagus from surgical specimen and columnar metaplasia in the esophageal remnant after esophagectomy were evaluated by real time quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry (IHC). For in vitro experiments, Het-1A cells were treated with hydrochloric acid, deoxycholic acid, mixture of hydrochloric acid and deoxycholic acid, or Notch1-siRNA, and expressions of Notch1, Hes1, MUC2, and K13 were evaluated via RT-qPCR and western blot. Results. Samples were obtained from 36 patients with columnar metaplasia in the esophageal remnant. Both IHC and RT-qPCR indicated that Notch1 and Hes1 expressions were significantly higher in normal esophagus than that in metaplasia. Hydrochloric acid and deoxycholic acid suppressed Notch1, Hes1, and K13 expressions, in concert with increasing MUC2 expressions. Notch inhibition by Notch1-siRNA contributed to the downregulation of Notch1, Hes1, and K13 expressions, whereas MUC2 expression was enhanced. Conclusions. Both hydrochloric acid and deoxycholic acid could suppress Notch signaling pathway in esophageal epithelial cells, and inhibited Notch signaling has important functions in the development of Barrett’s esophagus.