Barrett's Esophagus: A Comprehensive and Contemporary Review for Pathologists

Abstract

This review provides a summary of our current understanding of, and the controversies surrounding, the diagnosis, pathogenesis, histopathology, and molecular biology of Barrett's esophagus (BE) and associated neoplasia. BE is defined as columnar metaplasia of the esophagus. There is worldwide controversy regarding the diagnostic criteria of BE, mainly with regard to the requirement to histologically identify goblet cells in biopsies. Patients with BE are at increased risk for adenocarcinoma, which develops in a metaplasia-dysplasia-carcinoma sequence. Surveillance of patients with BE relies heavily on the presence and grade of dysplasia. However, there are significant pathologic limitations and diagnostic variability in evaluating dysplasia, particularly with regard to the more recently recognized unconventional variants. Identification of non-morphology-based biomarkers may help risk stratification of BE patients, and this is a subject of ongoing research. Because of recent achievements in endoscopic therapy, there has been a major shift in the treatment of BE patients with dysplasia or intramucosal cancer away from esophagectomy and toward endoscopic mucosal resection and ablation. The pathologic issues related to treatment and its complications are also discussed in this review article.

Figure 1

Barrett’s esophagus. The epithelium is composed of columnar epithelium with goblet cells as well as intervening non-goblet columnar cells. Paneth cells are present as well. The crypts show slight architectural irregularity and budding. The lamina propria shows a mild lymphoplasmacytic infiltrate. A few mucous glands are present in the basal portion of the mucosa (A) The glandular compartment in this case shows a mixture of mucus and oxyntic glands (B).

Figure 2

Barrett’s esophagus with pseudogoblet cells. Distinction between pseudogoblet cells (arrow) and true goblet cells (asterisk) is difficult and subject to observer variability. In contrast to the latter, pseudogoblet cells are often arranged in linear rows, and show distended cytoplasm without the characteristic triangle-shaped nucleus of true goblet cells.

Figure 3

A) Biopsy of the squamocolumnar junctional mucosa in a patient with an irregular Z-line. Squamous epithelium is present adjacent to mucinous columnar epithelium. A mixture of mucous and oxyntic glands are present in the lamina propria. There is a mild degree of inflammation in the lamina propria. Histologically, it is not possible to determine whether the columnar mucosa in this biopsy represents metaplastic esophageal columnar epithelium or proximal gastric (cardia) mucosa. This distinction is best performed endoscopically by determining if this biopsy was obtained proximal or distal to the gastroesophageal junction. Landmarks of esophageal location, such as esophageal submucosal glands or ducts (B, arrow) or multilayered epithelium (C) are not present in this biopsy. Goblet cells are not present in these cases.

Figure 4

Pathways of Cellular Reprogramming in Barrett’s Metaplasia. Potential pathways include A) Transdifferentiation, the process in which one fully differentiated cell type (i.e. squamous) changes directly into another columnar cell, without undergoing cellular division. B) Transdifferentiation can also involve de-differentiation of squamous cells to acquire properties that it had during development. This transitional cell has morphological and molecular features that are a hybrid of both cell phenotypes (i.e. squamous and columnar cells). This transitional cell can re-differentiate into its earlier columnar cell phenotype, with further transdifferentiation into gastric and intestinal-type cells, or if the inflammation subsides, re-differentiate back into squamous cells. C) Transcommitment is the process in which immature progenitor cells are reprogrammed in order to give rise to multiple cell types that comprise gastric type and then intestinal type metaplasia. Proposed origins of progenitor cells include the esophageal squamous epithelium or submucosal gland/ducts, gastric cardia epithelium or circulating bone marrow derived cells. Relevant transcriptions factors that determine a columnar or intestinal phenotype are indicated in bold.

Figure 5

Spectrum of dysplasia in BE. A) Negative. Although a mild degree of nuclear enlargement and hyperchromasia is noted, it is limited to the normal proliferative zone and there is evidence of surface maturation. B) Low grade dysplasia. The epithelium shows hyperchromatic, slightly stratified, enlarged and elongated nuclei with increased mitosis. Note the sharp transition from the non-dysplastic epithelium on the left to the dysplastic area on the right. C) High grade dysplasia. Overall, there is greater degree of cytologic and architectural atypia. The nuclei are larger in size, the N/C ratio is increased and there is significant loss of nuclear polarity, and crowded architecture. D) Intramucosal adenocarcinoma. Features may include dilated glands with intraluminal debris, fused tumor glands, and abortive glands infiltrating the lamina propria.

Figure 6

Crypt dysplasia, low grade. The epithelium shows cytologic features of low grade intestinal-type dysplasia (nuclear enlargement, hyperchromasia, and elongation, stratification, mucin depletion) limited to the basal portions of the crypts (surface maturation is present). Note the absence of active inflammation in the lamina propria.

Figure 7

Unconventional types of dysplasia. A and B) Foveolar dysplasia, low grade. The cells contain mucin reminiscent of gastric foveolar epithelium. C) Foveolar dysplasia, high grade. There is more architectural complexity with back-to-back crypts composed of cuboidal cells with enlarged rounded nuclei and increased N/C ratio. Note the lack of nuclear stratification characteristic of conventional intestinal-type dysplasia. D) Serrated dysplasia, low grade. The epithelium has a luminal saw-tooth appearance, abundant hypereosinophilic cytoplasm, and nuclear stratification.

Figure 8

Molecular biology of neoplastic progression in Barrett’s esophagus. Some of the major genetic alterations, and the histologic stage at which each genetic change has been identified during progression to cancer are illustrated. These genetic alterations allow benign Barrett’s cells to acquire core cancer hallmarks. The two enabling hallmarks of cancer are also depicted. COX-2, cycloxygenase-2; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; APC, adenomatous polyposis coli; MMP, matrix metalloprotease.

Figure 9

Endoscopic mucosal resection specimen showing a superficial well-differentiated adenocarcinoma. Note the presence of a duplicated muscularis mucosa (MM), consisting of a new (superficial) layer (arrows) and the original (deep) layer (asterisk). Note the presence of fragmentation and duplication of the muscularis mucosa (asterisks). In this case, adenocarcinoma has infiltrated into, and through, the superficial MM and into the “neo”-lamina propria. The original MM is also present as a fragmented layer at the bottom of the image. This cancer is still considered “intramucosal” because it has not penetrated the original MM.