Barrett's esophagus: a comprehensive review and update

Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. In the United States, a prevalence of up to 25% is reported in high risk populations and it is identified in about 5% of patients with gastroesophageal reflux disease (GERD). The diagnosis of BE requires endoscopically identifying columnar (“salmon colored”) mucosa, taking biopsies from targeted areas and then confirming histologically. The American College of Gastroenterologists updated its criteria in 2016, introducing a length requirement. This brief review addresses diagnosis of BE and its various associated challenges; identifying dysplasia, grading it, and management.     

Adenomas arising in Barrett's esophagus

Three cases of the unusual esophageal adenoma are described. The patients included two men and one woman, with a mean age of 61 years, who presented with dysphagia or heartburn. Histologically, the esophageal adenomas were composed of dysplastic epithelium in a polypoid configuration, similar to adenomas elsewhere in the gastrointestinal tract. All three adenomas arose within Barrett's esophagus (columnar epithelium-lined distal esophagus), and dysplastic Barrett's mucosa was found in the adjacent mucosa of each case. Critical review of the literature identified three additional cases; similar clinicopathologic features were described. Esophageal adenomas are a complication of Barrett's esophagus and are best considered as macroscopic variants of epithelial dysplasia rather than as isolated adenomatous polyps. As such, they likely represent premalignant lesions.     

Proliferative characteristics of intestinalized mucosa in the distal esophagus and gastroesophageal junction (short-segment Barrett's esophagus): a case control study

Intestinalized epithelium in traditional long-segment Barrett's esophagus (BE) shows increased proliferative activity, which is postulated to be an early step in the metaplasia-dysplasia-carcinoma sequence. The aim of this study was to evaluate the proliferative activity of intestinalized epithelium of the distal esophagus and gastroesophageal junction (IMEGEJ). Tissue sections from 78 consecutive patients (20 with IMEGEJ, 58 without IMEGEJ) who had elective upper gastrointestinal endoscopy over a 6-month period were immunohistochemically stained with MIB-1, the Ki-67 proliferation-antigen-associated marker, for evaluation of the crypt MIB-1 proliferation index (PI), size of the proliferative zone (PZ), and the presence of surface epithelial staining. Data from the IMEGEJ and non-IMEGEJ groups, and from 15 age-matched patients with traditional long-segment BE (>3.0 cm), were compared statistically. IMEGEJ patients showed a statistically significant increase in the mean crypt PI compared with non-IMEGEJ controls (21.9+/-19.5 v 14.3+/-9.3; P=.01). In addition, IMEGEJ cases showed an increase in the mean crypt PZ (52.3+/-16.4 v 45.2+/-17.2; P=.05), and a trend toward an increase in the percentage of cases with MIB-1-positive surface epithelial cells (50% v 33%, P=.18). Patients with IMEGEJ did not differ from patients without IMEGEJ with respect to any other clinical or histological feature, including signs or symptoms of gastroesophageal reflux disease and presence or absence of esophagitis or carditis. The MIB-1 results of the patients with long-segment BE (MIB-1 PI = 22.6+/-20.5, MIB-1 PZ = 51.8+/-19.6, proportion of cases with MIB-1-positive surface cells = 66%) were similar to those with IMEGEJ. Intestinalized epithelium in the distal esophagus or gastroesophageal junction shows increased proliferative activity in comparison with patients without intestinalized epithelium. This finding supports an increased risk of carcinogenesis in patients with IMEGEJ.     

Pathologic anatomy of Barrett's esophagus

It is most substantiated to define Barrett's esophagus as intestinal metaplasia of esophageal cardiac mucosa irrespective of its association with the endoscopically detected esophageogastric junction, which develops as a result of gastroesophageal reflux. There is a need for further investigations of the specific features of the cardiac-type mucosa. During endoscopic study, it is important to be alert when identifying short and ultrashort Barrett's esophagus and to sample sufficient biopsy material. A pathologist must differentiate three major types of the cylindrical epithelium of the esophagus: cardiac, acid-producing cardiac, and intestinal metaplasia, by diagnosing Barrett's esophagus in the latter case. Patients with the esophageal cardiac mucosa should be referred to as a risk group for its development.     

Endoscopic versus histological diagnosis of Barrett's esophagus: a cross-sectional survey

CONTEXT : Barrett's esophagus is a common pathological condition in patients with gastro-esophageal reflux disease. OBJECTIVE : The aim of this study was to compare endoscopic diagnosis versus histological confirmation. DESIGN : Cross-sectional. SETTING: Cancer Institute of the Imam Khomeini Hospital. MATERIAL AND METHODS : A total of 50 patients with a history of gastro-esophageal reflux were recruited and underwent upper endoscopy at this cross-sectional survey. Four-quadrant biopsy was taken from all suspected areas of intestinal metaplasia. Sections of blocks were stained with Mixed Alcian Blue (PH 2.5)/PAS and haematoxylin-eosin stainings for the diagnosis of intestinal metaplasia (complete vs. incomplete types) and goblet cell / columnar cell / dysplasia, respectively. Main outcome measure : The presence of Helicobacter pylori was assessed by Giemsa staining. RESULTS : There were 44 cases of short-segment Barrett's esophagus and 6 of long-segment Barretts esophagus by endoscopy. When examined by histologic examination, 12 patients with short-segment Barrett's esophagus and 4 with long-segment Barrett's esophagus had intestinal metaplasia. Haematoxylin-eosin staining diagnosed 12 cases of intestinal metaplasia, whereas mixed alcian blue/PAS was used to diagnose 16 cases (κ = 80%, p < 0.001). The positive predictive value in the diagnosis of goblet cell metaplasia and columnar cell metaplasia was 32% and 66%, respectively. Helicobacter pylori infection was observed in 10 cases of those with columnar cell metaplasia without goblet cells, while none of the patients with intestinal metaplasia were infected. CONCLUSION : Our findings suggest that biopsy taking is necessary in all patients with gastro-esophageal reflux disease, whose results suggest columnar cell lining in distal esophagus in endoscopy.     

Mucin histochemical analysis in the interpretation of Barrett's esophagus. Results of a multicenter study. The Operative Group for the Study of Esophageal Precancer.

A multicentric study of Barrett's esophagus (BE) was started in November 1987 to evaluate (1) the prevalence of BE among subjects undergoing upper gastrointestinal endoscopic examination; (2) the pathologic features of BE; and (3) the correlation between BE and early malignant changes. In 157 of 330 patients who underwent multiple standardized biopsies, BE was confirmed with histologic evaluation. Specialized intestinal-type BE was observed in 84 patients. By applying Alcian blue (pH 2.5)-periodate oxidation-Schiff, high-iron diamine-Alcian blue (pH 2.5), and periodate borohydride-saponification-periodate oxidation-Schiff techniques, the intestinal type of BE was subclassified into colonic and ileal types, both complete and incomplete. Fifty cases had incomplete colonic metaplasia with sulphomucins in the columnar cells and 64 had complete colonic intestinal metaplasia, 49 of them containing O-acetylated sialomucins in the goblet cells. These patients are being included in a short-term follow-up. Dysplasia (six low grade, two high grade) was observed in eight patients in areas of intestinal colonic-type epithelium; in these patients, a complete loss of O-acetylated sialomucins in the dysplastic areas and a remarkable reduction of these mucins in the surrounding tissue were observed. The reduction of O-acetylated sialomucins might indicate relative tissue immaturity, which could represent an early sign of neoplastic dedifferentiation. Therefore, the relevance of O-acetylated sialomucin content in BE, first demonstrated in intestinal type, is now evident, although its biologic importance is being studied.     

Barrett's esophagus: diagnostic challenges and recent developments

Inclusion of histologic classification into the risk assessment of adenocarcinoma arising from Barrett's esophagus (BE) has placed surgical pathologist in the center of clinical care and research endeavors. Recent advances in endoscopic diagnostic and therapeutic modalities demand additional proficiency in diagnosis and grading of dysplasia. The objectives of this study are as follows: (1) Discuss the definition of BE and features differentiating BE vs intestinal metaplasia involving cardia. (2) Describe the morphological approach of diagnosing and grading of dysplasia and differentiation of high-grade dysplasia from intramucosal carcinoma. (3) Role of special stains in diagnosis of BE and dysplasia. (4) Brief review the literature on histologic and endoscopic factors associated with progression of BE to adenocarcinoma. (5) Discuss the biomarkers in progression of BE to adenocarcinoma. The following conclusions from this review are important and should be applied in routine practice. Because of the controversy in defining BE, the histologic type of columnar mucosa and presence or absence of intestinal metaplasia should be specified in pathology report. The major limitations of appropriately diagnosing and grading dysplasia include technical problems related to biopsy processing and staining, presence of acute inflammation, and high interobserver variations among pathologists. The extent of high-grade dysplasia, high-grade dysplasia with certain endoscopic abnormalities, and low-grade dysplasia, when diagnosed with consensus by 2 or 3 gastrointestinal pathologists, has higher risk of progression to adenocarcinoma. All nonhistologic markers are still in the investigational phase and have not yet been validated in phase 3/4 prospective trials.     

Allaying uncertainty in diagnosing buried Barrett's esophagus

Subsquamous intestinal metaplasia (SSIM) in the setting of Barrett's esophagus (BE) is a technically challenging diagnosis. While the risk for progression of BE involving the surface mucosa is well documented, the potential risk for development of advanced neoplasia associated with SSIM has been controversial. This study aimed to determine the effects of specimen adequacy, presence of dysplasia, and interobserver agreement for SSIM interpretation. Adult patients (n = 28) who underwent endoscopic therapy for BE with high-grade dysplasia or intramucosal carcinoma (HGD/IMC) between October 2005 and June 2013 were included. Initial evaluation (n = 140 slides) by an experienced gastrointestinal pathologist was followed by an interobserver study by 8 pathologists. Forty-seven (34%) slides had insufficient subsquamous tissue to assess for SSIM. SSIM was found in 19% of all slides and 29% of slides with sufficient subsquamous tissue. At least one slide had SSIM in 54% to 64% of patients. Subsquamous low grade dysplasia (LGD) was found in 4 (15%) slides with SSIM and subsquamous HGD/IMC was found in 5 (19%) slides with SSIM. At the patient level, 8 (53%) had no dysplasia, 4 (27%) had LGD and 3 (20%) had HGD/IMC. Overall agreement for SSIM by slide was 92% to 94% (κ = 0.73 to κ = 0.82, moderate to strong agreement), and by patient was 82% to 94% (κ = 0.65 to κ = 0.87, moderate to strong agreement). This study confirms the need for assessing specimen adequacy and assessing the prevalence of SSIM and is the first to assess interobserver agreement for SSIM and dysplasia within SSIM.     

Genomic instability in patients with Barrett's esophagus

Our study aimed to determine, by counting sister chromatid exchange (SCE) and micronucleus (MN) frequencies, whether genetic impairment and DNA damage have an effect on the pathogenesis of Barrett's esophagus (BE). This study was conducted between June 2007 and November 2008 in the Erzurum Training and Research Hospital. We analyzed SCE and MN frequencies in 30 patients with BE, and in 30 control cases. SCE was significantly increased in BE patients compared with controls (6.89 ± 1.04 vs. 5.01± 0.88, P < 0.001). Similarly, MN was significantly increased in BE patients compared with controls (3.48 ± 1.08 vs. 1.83 ± 0.64, P < 0.001). Our data indicate that the increased SCE and MN rates in lymphocytes of patients with BE may reflect genomic instability or deficiency of DNA repair capacity.     

Claudin expression in Barrett's esophagus and adenocarcinoma

Claudins (CLDNs) are key molecules in cell adhesion, polarity, and control of paracellular solute transport. Several studies suggested that changes in claudin pattern have a role in cancer development. This study aimed to detect alterations in CLDN 1, 2, 3, 4, and 7 expression patterns in Barrett's esophagus (BE) and adenocarcinoma (ACC) compared with that in foveolar epithelium (FOV), normal squamous epithelium (SQ), and squamous cell carcinoma (SQCC). One hundred twenty five surgically or endoscopically removed, paraffin-embedded cases were studied by immunohistochemistry and analyzed statistically. BE, ACC, and FOV were dissected from 30 paraffin-embedded samples for further mRNA expression analysis. CLDN 7 was the dominating type in all epithelia and carcinomas, but its expression did not differ in normal and altered tissues. CLDN 1 expression was significantly increased in SQCC compared with that in SQ. CLDNs 3 and 4 were significantly elevated both in BE and ACC compared with that in FOV. CLDN 2 expression increased significantly in ACCs compared with that in BE. This is the first report proving similarities and differences regarding claudin expression pattern in BE and ACC compared with that in FOV and SQ. Our data prove a close link in CLDN pattern between BE and ACC, adding further evidence that BE is an alteration preceding esophageal ACC.     

Absence of Campylobacter-like organisms in Barrett's esophagus

Barrett's esophagus is a chronic condition in which the normal squamous mucosal lining is replaced by columnar mucosa. Campylobacter-like organism (CLOs) are implicated in the pathogenesis of gastritis and peptic ulcer disease and have been identified in Barrett's esophagus. The purpose of this study was to examine the incidence of CLOs in Barrett's esophagus and to consider their role, if any, in the pathogenesis of the disease. None of the bacteria were identified in 38 specimens obtained from 34 patients with Barrett's esophagus. It is concluded that the incidence of CLOs in Barrett's esophagus must be low and that CLOs do not contribute to the natural history of the disease.     

Double muscularis mucosae in Barrett's esophagus.

To clarify the histology and morphogenesis of the double muscularis mucosae in Barrett's esophagus, eight specimens resected from patients with Barrett's esophagus were compared histopathologically with 352 specimens resected from patients without Barrett's esophagus. A double muscularis mucosae was observed in seven (87.5%) of the eight cases with Barrett's esophagus, but in none of the 352 cases without Barrett's esophagus. The mucosa in the segment of Barrett's esophagus consisted of columnar epithelium, a superficial lamina propria, a superficial muscularis mucosae, a deep lamina propria, and a deep muscularis mucosae. The distal end of the superficial muscularis mucosae was connected to the deep muscularis mucosae at the esophagogastric junction, and its proximal end was located in fibrous tissue below the squamocolumnar junction of the mucosal epithelium or the distal edge of the erosive lesion. The deep muscularis mucosae in the portion with Barrett's esophagus was continuous with the original muscularis mucosae of the proximal esophagus and muscularis mucosae of the stomach. Barrett's esophagus is considered to be not merely a metaplastic lesion within the epithelium, but a newly developed lesion containing columnar epithelium, lamina propria, and a superficial muscularis mucosae on the lamina propria of the esophageal mucosa.     

Barrett's esophagus and Barrett's-related dysplasia.

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopic abnormality in which a biopsy shows evidence of specialized columnar epithelium, characterized by the presence of acid mucin-containing goblet cells. Much of the controversy in this body of literature relates to the complex anatomy of the esophagogastric junction and the difficulty in precisely identifying this landmark at endoscopy. By definition, in Barrett's esophagus, the squamocolumnar junction is proximal to the esophagogastric junction. Although fundic-type or cardiac-type (junctional) columnar epithelium may be present in Barrett's esophagus, it is only the presence of specialized columnar epithelium that is diagnostic of this condition. Patients with Barrett's esophagus are at risk of progressing to esophageal dysplasia and adenocarcinoma. There are several problems with using dysplasia as a marker for increased cancer risk in these patients, including problems with sampling error and intra- and interobserver variation in the recognition of dysplasia. It may be difficult to distinguish regenerative epithelial changes from dysplasia, low-grade from high-grade dysplasia, and high-grade dysplasia from intramucosal adenocarcinoma. Finally, there are relatively few prospective data evaluating the natural history of high-grade dysplasia. The management of patients with Barrett's-related dysplasia is controversial and varies from institution to institution. Future emphasis should be on cost-effective techniques for sampling as much of the esophageal mucosa as possible in patients who are at the highest risk of progressing to dysplasia and adenocarcinoma. Identification of biomarkers that identify such patients before the histologic recognition of dysplasia will be an area of intensive research.     

Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus

In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment can lead to columnar-lined esophagus (CLE) including metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). This study describes the morphology and phenotypic features of CLE and EAC in the rat model and compares them with the corresponding lesions in human Barrett's esophagus (BE). Swiss roll preparations of esophagi of EGDA rats and biopsies from human BE containing specialized intestinal metaplasia (SIM) and EAC were examined. The esophagi of EGDA rats showed esophagitis, CLE, islands of multilayered epithelium (MLE), dysplasia and EAC. The CLE had features of specialized intestinal metaplasia. MLE frequently occurred at the neo-squamocolumnar junction and occasionally in the mid-esophagus in isolated foci. Scattered mucinous cells in esophageal squamous epithelium were also found. The CLE and MLE in EGDA rats resembled the lesions described in human BE in morphology, mucin features and expression of differentiation markers (CK7, CK20, Das-1, villin, and pS2/TFF1). Invasive EAC in EGDA rat is of well-differentiated mucinous type, which is in contrast to the variably differentiated glandular type of adenocarcinoma in human BE. p53, c-myc, and cyclooxygenase 2 are expressed in both the rat and human SIM and EAC. These studies indicate that, not withstanding small differences, SIM and EAC induced in EGDA rats are similar to the corresponding lesions in human BE. EGDA rats may serve as a useful model to study the pathogenesis, molecular biology, and chemopreventive interventions of human BE and EAC.