Barretts's carcinogenesis

Abstract

Barrett's esophagus is considered a precancerous lesion of esophageal adenocarcinoma (EAC). Long-segment Barrett's esophagus, which is generally associated with intestinal metaplasia, has a higher rate of carcinogenesis than short-segment Barrett's esophagus, which is mainly composed of cardiac-type mucosa. However, a large number of cases reportedly develop EAC from the cardiac-type mucosa which has the potential to involve intestinal phenotypes. There is no consensus regarding whether the definition of Barrett's epithelium should include intestinal metaplasia. Basic researches using rodent models have provided information regarding the origins of Barrett's epithelium. Nevertheless, it remains unclear whether differentiated gastric columnar epithelium or stratified esophageal squamous epithelium undergo transdifferentiation into the intestinal-type columnar epithelium, transcommittment into the columnar epithelium, or whether the other pathways exist. Reflux of duodenal fluid including bile acids into the stomach may occur when an individual lies down after eating, which could cause the digestive juices to collect in the fornix of the stomach. N-nitroso-bile acids are produced with nitrites that are secreted from the salivary glands, and bile acids can drive expression of pro-inflammatory cytokines via EGFR or the NF-κB pathway. These steps may contribute significantly to carcinogenesis.

Keywords: Barret's esophagus; bile acid, gastroesophageal reflux, metaplasia.

Figure 1

Definition of Barrett's esophagus. (a) Intestinal metaplasia with goblet cells. (b) Columnar epithelium without goblet cells. The American and German definition of Barrett's epithelium only considers intestinal metaplastic mucosa with goblet cells (a). In contrast, the Japanese and British definition of Barrett's mucosa does not require goblet cells (b). However, in the British Society of Gastroenterology includes a ≥ 1 cm segment length criterion.

Figure 2

Various rat reflux models of Barrett's esophagus leading to adenocarcinoma. F, forestomach; G, glandular stomach; T, treitz ligament. (a) Esophago‐jejunostomy after total gastrectomy.86, 87 (b) Esophago‐jejunostomy without gastrectomy.87, 88 (c) The esophagogastric junction was side‐to‐side anastomosed to a loop of jejunum.93

Figure 3

Neoplastic lesions developed in rat reflux models. (a) Dysplasia. (b) Mucinous adenocarcinoma.

Figure 4

Various candidate lesions about development of Barrett's epithelium. (a,c–e,g) HE stainings. (b) CDX2. (f) CK7 Visualization of immunochemical staining was performed using 3,3′‐diaminobenzadine (DAB). (a) Inflamed esophageal squamous epithelium. (b) Gastric mucosa (cardiac‐type mucosa) focally positive for CDX2 expression has the potential for intestinal differentiation. (Brown is the color of positive cells). (c) Esophageal gland duct. (d) Esophagogastric junction mucosa. (e,f) Twenty‐two‐week‐old human fetal esophagi. The epithelium has cilia, and it is positive for CK7. (f) Bone marrow.

Figure 5

Histological image of a site distant from the anastomotic region in a rat model that underwent esophago‐jejunostomy. Several columnar epithelia have developed within the squamous epithelium, as shown on the right side of the figure, while complete Barrett's epithelium (arrow) can be seen on the left side of the figure.

Figure 6

Surgical procedure of the rat model which mimics human gastroduodenal reflux: F, forestomach; G, glandular stomach; T, treitz ligament. Surgery proceeds from left to right. The final phase is shown on the extreme right. Firstly, we removed the forestomach which does not exist in the human stomach. Then, the esophagus was connected with the glandular stomach. The gastrointestinal tract is sectioned where the red double line is drawn in the second figure from the right and then anastomosed. In the final phase, the reflux of gastric fluid that contains duodenal fluid occurs from the glandular stomach to the esophagus (yellow arrow).

Figure 7

Cardiac‐type mucosa around the esophagoglandular‐stomach anastomosis developed in the rat reflux model. The right side of the figure is an oral side. Expansion of intrinsic gastric cardiac glands occurs to cover the defect of squamous epithelium during wound repair (arrow).

Figure 8

The mechanism of EAC and esophagogastric junction cancer development: A, aorta; L, liver; P, pancreas; S, stomach; f, food remnants. The figure is the schema from the left oblique position of the patient with GERD. The right side of the figure is a head side, and the left side is caudal. If the individual lies down immediately after eating, the food remains in the stomach and collects in the fornix on the dorsal side. The ventral side of the food remnants also includes a component that contains liquid or sludge‐like digestive juice, which would also include duodenal fluid including bile acids. The accumulated reflux fluid (arrow) would contain endogenous N‐nitroso‐bile acids, and carcinogenesis could then occur in the esophagogastric junction or esophagus.