Barrett Esophagus

Etiology

Most patients with Barrett esophagus have a known history of chronic GERD, the reflux of gastric acid and bile through the lower esophageal sphincter and into the distal esophagus. The stomach lining is a mucinous columnar epithelium that can withstand the acidic environment required for digestion, and the esophagus is lined by a squamous epithelium; as a response to the acidic irritant, the squamous epithelium becomes inflamed. Continued exposure to acids leads to persistent inflammation and a columnar metaplastic reaction with the eventual development of an intestinal-type phenotype characterized by goblet cells.[6]

Why Barrett esophagus develops in some patients with GERD and not in others remains unclear. However, additional risk factors for developing Barrett esophagus include the following:

• Male genotype
• Non-Hispanic White race
• Age older than 50 years
• Central obesity
• Past or present smoking history
• Family history of either Barrett esophagus or esophageal adenocarcinoma in a first-degree relative
• Genetics: inconclusive evidence that specific genetic mutations may increase the risk of Barrett esophagus

Patients with chronic reflux and at least 3 of these other risk factors are considered to be at high risk and should undergo screening endoscopy.[2]

Epidemiology

Barrett esophagus is usually but not always found in patients with GERD. The prevalence is 0.8% in the general population, 3% in patients with GERD, 12.2% with GERD plus any other risk factor, 23.4% with a family history of Barrett esophagus or esophageal adenocarcinoma, 6.1% in individuals older than 50, 1.9% in people with obesity, and 6.8% in men. The prevalence of Barrett esophagus increases linearly with more risk factors, with each additional risk factor adding 1.2%.[7] The condition is the only known endoscopically identifiable precursor lesion for esophageal adenocarcinoma. Both Barrett esophagus and adenocarcinoma are much more common in men than in women, by ratios of 2:1 and 9:1, respectively.

The overall incidence of GERD, Barrett esophagus, and esophageal adenocarcinoma has been increasing significantly over the last 3 to 5 decades, partially attributable to increased numbers of endoscopies. However, fewer than 5% of patients with Barrett esophagus will develop esophageal adenocarcinoma. Study results indicate the absolute annual risk of adenocarcinoma in nondysplastic Barrett esophagus is 0.1% to 0.5% per year, a highly variable 1% to 43% per year for low-grade dysplasia, and 23% to 60% per year for high-grade dysplasia. A greater extent of dysplasia has a significantly higher risk of cancer, as well as the presence of an endoscopic abnormality, such as a nodule or mass.[8][9]

Pathophysiology

The exact pathogenesis of Barrett esophagus remains to be elucidated; however, it is believed to be a response to long-standing GERD. Some progress has been made in determining the molecular alterations and primary cell types involved. Study results have indicated that exposure to acid induces the squamous epithelial cells to secrete inflammatory cytokines such as interleukin 8 and interleukin 1b, which act to mediate the inflammatory response and signal T lymphocytes and neutrophils to migrate into the epithelium. Bile acids, specifically, have been shown to upregulate CDX2, the intestinal differentiation factor, and MUC2, the goblet cell-specific gene, within normal columnar and esophageal cancer cell lines.

Up to 90% of affected patients have a detectable clonal aberration of the p16 tumor suppressor gene. CDX2 and TP53 mutations are early molecular alterations found in metaplastic columnar epithelium even before morphologic dysplasia is recognized. However, immunohistochemical staining to evaluate these markers is not currently recommended in routine diagnostic cases of Barrett esophagus.

Results from a recent study described a population of possible embryonic stem cells at the squamocolumnar junction. In contrast, other studies suggest that stem cells derived from undifferentiated mesenchymal cells in the lamina propria of the esophagus or the bone marrow may be the cell of origin for Barrett esophagus. Columnar epithelium develops first in the esophagus, possibly beginning as gastric-type mucinous epithelium, reprogramming to intestinal differentiation and, ultimately, goblet cells.[10] There is evidence of a type of epithelium known as multilayered epithelium, which shows combined squamous and columnar features, likely representing an intermediate phase within the metaplastic reaction. The multilayered epithelium is strongly associated with reflux esophagitis and expresses a mucin and cytokeratin profile similar to Barrett esophagus columnar epithelium and intestinal transcription factors. Further studies are needed to understand the complete mechanism of pathogenesis.[6][5]

Histopathology

In Barrett esophagus, the normal esophageal squamous epithelium is replaced by intestinal-type mucosa characterized by columnar epithelium and usually with goblet cells (see Image. Barrett Esophagus). Nondysplastic Barrett epithelium may demonstrate nuclear enlargement and stratification in the basal glands, but the surface is mature. Dysplasia is identified by neoplasia limited to the basement membrane. Characteristic pathologic features include:

• Indefinite dysplasia: This type of neoplasia cannot be described as gastric, intestinal, or serrated differentiation. This terminology may be chosen if there is extensive regenerative change so much that the atypia present slightly overlaps with low-grade dysplasia. Still, unequivocal pathologic evidence of dysplasia is not found.                                                                                                                                                                          
• Low-grade intestinal dysplasia: Goblet cells with enlargement and elongation of nuclei, increased numbers of lymphocytes, an increased nuclear-to-cytoplasmic ratio, and nuclear stratification involving the basal half of cellular cytoplasm characterize this type of dysplasia. Increased mitoses are mostly limited to the crypts, with few, if any, atypical mitoses.                                                                                                                                                                     
• High-grade intestinal dysplasia: This type of dysplasia includes a greater degree of nuclear enlargement and number of lymphocytes; nuclear stratification of the full thickness of the mucosa with nuclear pleomorphism, irregular nuclear shapes, and significant loss of nuclear polarity; mitoses are seen on the surface with atypical mitoses.[10]                                                                                                                                                                                                    
• Intramucosal carcinoma: In this carcinoma, lamina propria is invaded by individual neoplastic cells with no connection to the crypts, sheeting out of malignant cells, irregular and angulated glands located in the lamina propria or muscularis mucosae—a complex anastomosing pattern of glands within the lamina propria, and/or back-to-back glands or cells in an irregular architectural pattern.[11][12]

Gastric metaplasia of the distal esophagus is distinguished from intestinal metaplasia, and the risk of esophageal adenocarcinoma is much lower with gastric metaplasia than with intestinal metaplasia. There is uncertainty about whether gastric metaplasia increases the risk of esophageal adenocarcinoma significantly or not. This concept is supported by the evidence that intestinal metaplasia demonstrates certain genomic hallmarks of esophageal adenocarcinoma, which is much less significant than gastric metaplasia in the absence of intestinal metaplasia.[13]

History and Physical

Most patients with Barrett esophagus will exhibit symptoms of GERD, such as heartburn (retrosternal burning), especially after eating. Acid regurgitation is another likely symptom. Other possible symptoms, though less common, include dysphagia, a sore throat, hoarseness, chest pain, chronic cough, melena, or weight loss. Some patients are asymptomatic. Typically, patients will have a chronic history of GERD symptoms with no specific physical examination findings.

Evaluation

In 2022, the American College of Gastroenterology (ACG) published new clinical guidelines for diagnosing and managing Barrett esophagus. No randomized controlled trials have confirmed that screening patients with Barrett esophagus reduces mortality from esophageal adenocarcinoma; screening, endoscopic surveillance, and endoscopic eradication therapy have been shown to reduce the incidence of esophageal adenocarcinoma and improve early detection. The ACG now recommends screening for Barrett esophagus in people with chronic symptoms of GERD who also have at least 3 additional risk factors, including male genotype, age older than 50, White race, past or present tobacco smoking, central obesity, or a history of Barrett esophagus or esophageal adenocarcinoma in a first-degree relative.[3][14][15][16] 

Esophagogastroduodenoscopy with forceps biopsies is the gold-standard diagnostic test. Wide-area transepithelial sampling with brushing of the entire surface of the Barrett epithelium may add to the yield of standard endoscopy with forceps biopsies; this technique has not yet been incorporated into the ACG guideline. High-definition white light and chromoendoscopy, using topical acetic acid or electronic chromoendoscopy, increase sensitivity and specificity for identifying dysplasia and adenocarcinoma.[17] Artificial intelligence is being evaluated in the United States and the Netherlands to develop a system that will identify neoplasia and the most abnormal areas as the optimal sites for biopsy.[18] However, the cost of sedated endoscopy and the small risk of complications have raised interest in developing alternative diagnostic testing. Such alternatives include unsedated transnasal endoscopy that non-clinicians can perform and the use of one of several commercially available swallowable capsule sponges combined with a biomarker such as a methylated deoxynucleic acid marker or trefoil factor 3.

In cases of Barrett esophagus, the pathologist must determine whether dysplasia or carcinoma is present. Study results suggest that the extent of dysplasia also correlates with the risk of cancer, so it may be valuable for pathologists to comment not only on the presence of but also on the extent of dysplasia (such as focal or diffuse). Sometimes, there may be a specific concern for dysplasia if an area of nodularity or ulceration is noted during endoscopy.

Barrett esophagus-related dysplasia is often flat and not apparent on endoscopy. The major histologic pattern of dysplasia is intestinal, therefore resembling an adenoma of the colon. Non-intestinal dysplasia also exists, including foveolar and serrated patterns; validated criteria for classification as either low- or high-grade dysplasia only exist for intestinal-type dysplasia. The distinction between high-grade dysplasia and intramucosal carcinoma suffers from a high degree of interobserver variability.[11][12]

The diagnosis of Barrett esophagus requires the endoscopic appearance of at least a 1-cm length of "salmon-pink" columnar metaplasia proximal to the esophagogastric junction, defined as the top of the gastric folds, with confirmation of intestinal metaplasia with goblet cells on biopsy evaluation. The British Society of Gastroenterology and the GERD Society Study Committee in Japan do not require the presence of goblet cells to diagnose Barrett esophagus, and they base the diagnosis solely on columnar metaplasia. Due to the controversy over the significance of goblet cells, another alternative classification has been proposed, which allows the pathologist to state that there is columnar metaplasia and then further specify whether goblet cells are present or absent.

To maximize the possibility of finding Barrett esophagus, dysplasia, and adenocarcinoma, the ACG recommends a minimum of 8 biopsies, 2 from each quadrant, at 2 cm intervals for shorter segments of Barrett mucosa.[19][20] The Seattle protocol calls for segments greater than 4 cm long. The Seattle protocol involves taking biopsies of visible lesions, followed by 4-quadrant biopsies every 1 to 2 cm. Mixed results are seen when comparing the Seattle protocol to narrow-band imaging (NBI). Although NBI demonstrated endoscopically visible lesions and dysplasia better than simply utilizing the Seattle protocol, NBI has not yet been incorporated into current guidelines.[21]

The extent of Barrett esophagus is graded by the Prague criteria, specifying the circumferential length of Barrett epithelium at and above the top of the gastric folds (C) and the maximum extent (M) of Barrett mucosa. The M criterion includes finger-like projections of Barrett epithelium proximal to the circumferentially involved segment. Islands of intestinal metaplasia are not considered in the Prague criteria, even if they are proximal to what would otherwise be considered the full length of Barrett mucosa. If the circumferential length is 6 cm and the maximal length is 8 cm, then the Prague classification would describe this lesion as C6M8.[22][23]

Treatment / Management

Multiple study results have initially suggested that endoscopic surveillance of patients with Barrett esophagus is associated with decreased esophageal adenocarcinoma-related deaths; this was not confirmed when adjustments were made for lead and length time biases. Based on a systematic review of the literature and evaluation of the level of evidence, the ACG made several changes to the recommended management in its newest guidelines. High-definition white-light endoscopy is a novel endoscopic technology recommended for routine surveillance beyond electronic chromoendoscopy. When Barrett esophagus is found, the patient should be placed on long-term proton pump inhibitor therapy, regardless of the presence of reflux symptoms, due to evidence of a chemopreventive effect of proton pump inhibitors, where the risk of progression to neoplastic disease is reduced compared to no acid suppression or H2 blocker treatment.

Due to the significant impact on management, if Barrett esophagus is associated with dysplasia, the ACG emphasizes the importance of confirming any dysplasia diagnosis with a second expert pathologist with extensive experience in Barrett esophagus-related neoplasia. Surveillance protocols differ for the level of dysplasia seen as follows:

• No dysplasia: An endoscopy is recommended every 3 years if the Barrett segment is <3 cm long or every 5 years if the segment is at least 3 cm in length.
• Indefinite dysplasia: Guidelines recommend that endoscopy should be repeated in 6 months on twice-daily proton pump inhibitor therapy, with doses taken 30 to 45 minutes before a meal.[24] If the repeat endoscopy is unchanged, then the endoscopy should be repeated annually. If there is progression to low-grade dysplasia (LGD), then the LGD management guideline should be followed.[2]                                                                                                
• LGD: If endoscopic eradication therapy (EET) is declined or cannot be performed for any reason, endoscopy should be repeated in 6 months, then again 6 months later, and then annually if the assessment of dysplasia does not change. EET for LGD is the same as for high-grade dysplasia (HGD), as described below.
• HGD: If there is flat mucosa with HGD (no mucosal abnormality is visible), EET is done to eliminate the entire area of metaplasia and dysplasia. Esophagectomy is no longer the preferred initial approach to managing HGD or intramucosal cancer, as the procedure has a high risk of morbidity. However, it should be considered if intramucosal cancer has poor prognostic factors, such as lymphovascular invasion or poor differentiation, or if cancer involves the submucosa. Patients with significant comorbidities that limit their likely survival may not benefit from endoscopic therapies, with risks of the procedures being greater than potential gains.[2][25][26]

Endoscopic eradication therapy is used to treat LGD, HGD, and early-stage esophageal adenocarcinoma and is preferable to endoscopic surveillance and acid-suppressive medication alone.[27] These therapeutic techniques include:(A1)

• Radiofrequency ablation: Several (usually 3-4) applications of radiofrequency ablation are applied to the Barrett mucosa using devices that ablate 90°, 180°, or 360° of the affected area at a time. Complications of radiofrequency ablation include chest pain for up to 14 days, and less common but more serious complications include aspiration, bleeding, surface lacerations or deeper perforation, and strictures. This technique has effectively eradicated Barrett mucosa and dysplasia and is the preferred ablative modality for EET of flat dysplasia.[28]
• Cryotherapy: This can be performed using either liquid nitrogen cryospray or cryotherapy applied through an inflated balloon that compresses the Barrett segment.                                                                                                              
• Hybrid argon plasma coagulation: This technique can be used for small islands of intestinal metaplasia. However, if used circumferentially, it has a relatively high rate of strictures.                                                           
• Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is used to resect nodules or masses, followed by ablation of the remaining Barrett esophagus mucosa. EMR is preferred for smaller and more superficial neoplasia. At the same time, ESD is needed for more extensive lesions, if at least T1b a carcinoma invasion is highly suspected, or if EMR has failed to resect the lesion and all neoplastic tissue completely. If there is only a small Barrett esophagus patch around the visible lesion, complete resection using EMR or ESD is preferable to later radiofrequency ablation, which requires multiple endoscopic sessions.

Endoscopic surveillance must be continued after complete eradication of intestinal metaplasia (CEIM) and complete eradication of neoplasia. Biopsies should be taken of any visible lesions randomly from the cardia and the distal 2 cm of the esophagus, where recurrences are most likely to occur.[29] Based on the most advanced histology found before EET, the recommended intervals are as follows:

• LGD: Repeat endoscopy 1 year after CEIM, then 2 years later, then at nondysplastic Barrett esophagus intervals (every 3 to 5 years) if there has been no recurrence of metaplasia or dysplasia.                                       
• HGD: Repeat endoscopy at 3, 6, and 12 months following CEIM. If there has been no recurrence at that point, the endoscopy should be repeated annually.
• Intramucosal esophageal adenocarcinoma: Repeat endoscopy at 3, 6, and 12 months following CEIM. If there has been no recurrence of dysplasia or malignancy at that point, endoscopy should be repeated annually.

EET is more cost-effective than endoscopic surveillance.[30] When well-experienced endoscopists perform EET, intestinal metaplasia and neoplasia recurrence rates are lower.[31] If EET fails to achieve CEIM, management options include improving reflux control with a higher proton pump inhibitor dose, changing to a potassium-competitive acid blocker (P-CAB), fundoplication surgery, or repeating EET. However, P-CAB medications have yet to be tested for this indication.[32]

Many case series report short-term Barrett outcomes; there are very few studies on long-term outcomes. Even though there are several types of treatments for Barrett and GERD, there is no solid evidence to indicate which one is the best or most effective. With the availability of EET, more long-term studies are needed to determine the safety of these procedures and their effectiveness in preventing the progression of Barrett esophagus to a malignancy.[33](A1)

Differential Diagnosis

When symptoms are present (eg, GERD) the differential diagnosis of Barrett esophagus is based on endoscopic findings and includes the following:

• Esophageal mucosa with gastric metaplasia: This is identical in endoscopic appearance to Barrett esophagus (intestinal metaplasia), but biopsies show gastric fundic- or junctional-type epithelium instead. These types of gastric metaplasia are not risk factors for esophageal cancer.
• Acute gastritis
• Chronic gastritis with or without Helicobacter pylori infection
• Coronary artery atherosclerosis
• Reflux esophagitis
• Esophageal cancer
• Esophageal motility disorders
• Gallstones

Prognosis

The prognosis of Barrett esophagus largely depends on the degree of dysplasia present at the time of diagnosis and the effectiveness of surveillance and treatment strategies. While Barrett esophagus itself is a premalignant condition, the risk of progression to esophageal adenocarcinoma increases with the severity of dysplasia. Patients with nondysplastic Barrett esophagus have a relatively low risk of cancer progression, estimated at less than 0.5% per year. However, the presence of low- or high-grade dysplasia significantly raises this risk, with high-grade dysplasia carrying the highest potential for malignancy.

Early detection and regular surveillance, along with timely endoscopic or surgical intervention, can improve the prognosis by preventing the progression to esophageal adenocarcinoma, a cancer associated with high morbidity and mortality. Advances in endoscopic eradication techniques have further enhanced outcomes, offering less invasive options with curative potential for patients with dysplastic Barrett esophagus. Therefore, the overall prognosis is favorable when Barrett esophagus is closely monitored and managed according to current guidelines. Average life expectancy with Barrett esophagus should be anticipated in the absence of malignancy or other life-threatening conditions. 

Complications

Untreated Barrett esophagus may progress into adenocarcinoma. However, the rate of progression is prolonged, and more than 95% of patients with Barrett esophagus will never develop malignancy. The number of adenocarcinoma cases has steadily increased over the past several decades.[34] There is an increasing risk of malignancy if Barrett mucosa is associated with greater degrees of dysplasia and with longer lengths of the Barrett segment. Complications of reflux esophagitis, such as bleeding or ulceration, may be somewhat more likely with Barrett esophagus than without it. Still, strictures and aspiration are no more frequent with Barrett esophagus than without it.