Barrett Esophagus 

Updated: Dec 29, 2017
Author: Mark H Johnston, MD; Chief Editor: Praveen K Roy, MD, AGAF 

Overview

Practice Essentials

In Barrett esophagus, healthy esophageal epithelium is replaced with metaplastic columnar cells—the result, it is believed, of damage from prolonged exposure of the esophagus to the refluxate of gastroesophageal reflux disease (GERD). The inherent risk of progression from Barrett esophagus to adenocarcinoma of the esophagus has been established.

Signs and symptoms

The classic picture of a patient with Barrett esophagus is a middle-aged (55 yr) white man with a chronic history of gastroesophageal reflux—for example, pyrosis, acid regurgitation, and, occasionally, dysphagia. Some patients, however, deny having any symptoms.

The features of GERD in relation to long-segment Barrett esophagus (LSBE, >3 cm) and short-segment Barrett esophagus (SSBE, < 3 cm) are quite different.

GERD in LSBE

  • Patients with LSBE tend to have a longer duration of reflux symptoms

  • When undergoing 24-hour esophageal pH monitoring, they have severe, combined patterns of reflux (supine and erect) and reduced lower esophageal sphincter (LES) pressures

  • Patients also tend to be less sensitive to direct acid exposure

GERD in SSBE

Patients are more sensitive to acid exposure but have had symptoms for a shorter duration, with normal LES pressures and only upright reflux on 24-hour esophageal pH testing.

See Clinical Presentation for more detail.

Diagnosis

The following techniques are used in the diagnosis and assessment of Barrett esophagus:

  • Esophagogastroduodenoscopy (EGD): The procedure of choice for the diagnosis of Barrett esophagus

  • Biopsy: The diagnosis of Barrett esophagus requires biopsy confirmation of specialized intestinal metaplasia (SIM) in the esophagus

  • Ultrasonography: When high-grade dysplasia or cancer is found on surveillance endoscopy, endoscopic ultrasonography (EUS) is advisable to evaluate for surgical resectability

The Practice Parameters Committee of the American College of Gastroenterology recommends that patients with long-standing GERD symptoms (>5 yr), particularly those aged 50 years or older, have an upper endoscopy to detect or screen for Barrett esophagus.

See Workup for more detail.

Management

Once Barrett esophagus has been identified, patients should undergo periodic surveillance endoscopy to identify histologic markers for increased cancer risk (dysplasia) or cancer that is at an earlier stage and is amenable to therapy. Dysplasia is the best histologic marker for cancer risk.

The management options for high-grade dysplasia include the following:

  • Surveillance endoscopy, with intensive biopsy at 3-month intervals until cancer is detected

  • Endoscopic ablation: In most major medical centers, ablation is first-line therapy

  • Surgical resection: While studies have shown surgery to be efficacious in the control of GERD symptoms, no good evidence indicates that surgical therapy provides regression in Barrett esophagus

Pharmacologic treatment for Barrett esophagus should be the same as that for GERD, although most authorities agree that treatment should employ a proton pump inhibitor (PPI) instead of an H2-receptor antagonist, due to the relative acid insensitivity of patients with Barrett esophagus. While PPIs have been found to be better than H2-receptor antagonists at reducing gastric acid secretion, the evidence as to whether PPIs induce regression of Barrett esophagus remains inconclusive.

Diet

The diet for patients with Barrett esophagus is the same as that recommended for patients with GERD. Patients should avoid the following:

  • Fried or fatty foods

  • Chocolate

  • Peppermint

  • Alcohol

  • Coffee

  • Carbonated beverages

  • Citrus fruits or juices

  • Tomato sauce

  • Ketchup

  • Mustard

  • Vinegar

  • Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

See Treatment and Medication for more detail.

Background

Barrett esophagus is well recognized as a complication of gastroesophageal reflux disease (GERD). Prolonged exposure of the esophagus to the refluxate of GERD can erode the esophageal mucosa, promote inflammatory cell infiltrate, and ultimately cause epithelial necrosis. This chronic damage is believed to promote the replacement of healthy esophageal epithelium with the metaplastic columnar cells of Barrett esophagus. Why only some people with GERD develop Barrett esophagus is not clear (see the image below).

Barrett esophagus (BE). The salmon-pink area has s Barrett esophagus (BE). The salmon-pink area has specialized intestinal metaplasia. The white area is squamous epithelium.

Histologic characteristics

The definition of Barrett esophagus (BE) has evolved considerably over the past 100 years. In 1906, Tileston, a pathologist, described several patients with "peptic ulcer of the oesophagus" in which the epithelium around the ulcer closely resembled that normally found in the stomach. The debate for the next 4 decades centered on the anatomic origin of this mucosal anomaly. Many investigators, including Barrett in his treatise published in 1950, supported the view that this ulcerated, columnar-lined organ was, in fact, the stomach tethered within the chest by a congenitally short esophagus.[1]

In 1953, Allison and Johnstone argued that the columnar organ was more likely esophagus, because the intrathoracic region lacked a peritoneal covering, contained submucosal glands and muscularis propria characteristic of the esophagus, and could harbor islands of squamous cells within the columnar segment.[2] In 1957, Barrett agreed and suggested that the condition that bears his name be referred to as "lower esophagus lined by columnar epithelium."[3] For the next 2 decades, descriptions of the histology of Barrett esophagus varied considerably from acid-secreting, fundic-type epithelium to intestinal-type epithelium with goblet cells.

Finally, in 1976, Paull et al published a report on the histologic spectrum of Barrett esophagus in which they used manometric guidance for their biopsies.[4] The study’s patients had 1 or a combination of 3 types of columnar epithelium; ie, a gastric fundic-type, a junctional type, and a distinctive type of intestinal metaplasia the investigators called "specialized columnar epithelium." This specialized intestinal metaplasia (SIM), complete with goblet cells, has become the sine qua non for the diagnosis of Barrett esophagus.

Endoscopic characteristics

However, while Paull et al’s study clarified the nature of the histologic lesion, the endoscopic definition of Barrett esophagus has continued to change. Many people believed that the distal esophagus could contain a normal region of columnar mucosa. In addition, determining the exact location of the esophagogastric junction (EGJ) in patients with Barrett esophagus often is difficult. To avoid false-positive diagnoses, investigators selected arbitrary lengths of columnar-lined esophagus to establish a diagnosis for their studies. Eventually, community endoscopists embraced this practice, and biopsy of the so-called normal distal columnar-lined esophagus was avoided.

Convincing evidence indicates that SIM, the hallmark histologic lesion of Barrett esophagus, predisposes to dysplasia and cancer regardless of the endoscopic location. Thus, the definition of Barrett esophagus currently is the finding of SIM anywhere within the tubular esophagus.

Etiology

As previously stated, Barrett esophagus is well recognized as a complication of GERD. Patients with GERD who develop Barrett esophagus tend to have a combination of clinical features, including hiatal hernia, reduced lower esophageal sphincter (LES) pressures, delayed esophageal acid clearance time, and duodenogastric reflux (as documented by the presence of bile in the esophageal lumen).

Increasing trends for obesity and its associations with GERD and Barrett esophagus are risk factors for esophageal adenocarcinoma.[5] Abdominal obesity is in itself independently increases the risk of Barret esophagus.[5]

Pathogenesis of GERD

An understanding of the pathogenesis of GERD is necessary to understand the relationship between GERD and Barrett esophagus. Esophageal defense mechanisms against the noxious substances in the refluxate include an antireflux barrier, an efficient clearing mechanism, and epithelial defense factors.

The antireflux barrier is a high-pressure zone at the EGJ that is generated by tonic contraction of the LES coupled with extrinsic compression by the right crus of the diaphragm. The phrenoesophageal ligament, intra-abdominal location of the LES, and maintenance of an acute angle of entry into the stomach help to reinforce this barrier.

This system is imperfect due to the existence of physiologic transient LES relaxations (TLESRs). TLESRs occur primarily after meals but in the absence of a preceding swallow. Studies indicate that about 95% of reflux episodes in healthy controls occur during the TLESR. Most reflux in patients with GERD occurs via this same mechanism. The duration of esophageal acidification, and not the frequency, correlates best with presence of erosive esophagitis.

A healthy individual clears the esophagus through various means, including gravity, bicarbonate secretion from the salivary and esophageal glands, and peristalsis. Dysfunctional esophageal motility with failed or weak peristalsis is a contributing factor in 34-48% of patients with GERD.

An acid (pH < 4) contact time of 1-2 hours per day is considered normal in the distal esophagus. This physiologic reflux occurs in completely asymptomatic individuals. The esophagus, therefore, must have additional local means of protection.

The esophagus is composed of a thick epithelial layer, with cells joined by tight junctions with lipid-rich intercellular spaces. This arrangement resists the diffusion of noxious substances by limiting entry of H+ into cells and intercellular spaces. In addition, scattered submucosal glands in the distal esophagus that secrete bicarbonate and have an adequate blood supply to deliver bicarbonate and remove H+ help to maintain tissue acid-base balance.

The aggressors in the GERD battle reside in the refluxate. Mucosal injury depends on the pH of the refluxate and the duration of contact with the esophageal mucosa. Lower pH of the refluxate and extended contact with the esophagus increases the time required for intraesophageal pH to return to normal and increases the risk for mucosal injury.

Refluxate exposure and Barrett esophagus

Prolonged exposure of the esophagus to the refluxate can erode the esophageal mucosa, promote inflammatory cell infiltrate, and ultimately cause epithelial necrosis. This chronic damage is believed to promote the replacement of healthy esophageal epithelium with the metaplastic columnar cells of Barrett esophagus, the cellular origin of which remains unknown. This likely is an adaptive response of the esophagus, which, if not for the increased risk of cancer, would have been beneficial. GERD symptoms and strictures are less common in the columnarized segment.

Interestingly, the features of GERD in relation to long-segment Barrett esophagus (LSBE >3 cm) and short-segment Barrett esophagus (SSBE < 3 cm) are quite different. Patients with LSBE tend to have a longer duration of reflux symptoms, and, when undergoing 24-hour esophageal pH monitoring, they have severe, combined patterns of reflux (both supine and erect) and low LES pressures. They also tend to be less sensitive to direct acid exposure. On the other hand, patients with SSBE are more sensitive to acid exposure but have had symptoms for a shorter duration, with normal LES pressures and only upright reflux on 24-hour esophageal pH testing.

Current clinical practice guidelines recommend screening for Barrett esophagus in patients with GERD when the patients have had long-standing symptoms (>5 y); this is especially recommended in patients older than 50 years.

Oral bisphosphonate use and Barrett esophagus

Use of oral bisphosphonates was associated with an increased risk of Barrett esophagus, especially among patients with GERD, in a case-control analysis of US veterans, including 285 with definitive Barrett esophagus, 1,122 endoscopy controls, and 496 primary care controls.[6, 7] Overall, 54 (2.8%) of the study participants had filled prescriptions for oral bisphosphonates.

More patients with Barrett esophagus (4.6%) than controls combined (2.5%) had filled prescriptions for any oral bisphosphonate, and significantly more patients with Barrett esophagus (4.2%) than controls (2.2%) had alendronate prescriptions.[6, 7] In a model adjusted for age, sex, race, proton-pump (PPI) inhibitor use, hiatal hernia, H pylori infection, and GERD symptoms, oral bisphosphonates were associated with a significant 2.33-fold increase in the risk of Barrett esophagus. This association increased to 3.29-fold when analyses were limited to patients with GERD symptoms, but there was no association among patients without GERD symptoms.[6, 7] Similarly, the risk was increased 2.71-fold among PPI users, but it was not significantly increased in patients without PPI use.

Epidemiology

The average age of patients with Barrett esophagus is 55-65 years. The condition occurs in a 2:1 male-to-female ratio, with white males making up more than 80% of cases. Some studies indicate a higher prevalence of smoking, alcohol intake, and obesity in persons with the disease.[5]

Estimates of the prevalence of Barrett esophagus vary considerably and range from 0.9-10% of the general adult population. A study from Sweden by Ronkainen and colleagues estimated the prevalence to be approximately 2% in the adult population.[8] This particular study is believed to be one of the more reliable because of the means by which the epidemiologic data could be assessed in Sweden. In US population terms, this prevalence would equate to approximately 3 million adults with Barrett esophagus.

The prevalence of LSBE in patients undergoing endoscopy for any clinical indication has been reported at 0.3-2% but is much higher, 8-20%, in patients with symptoms of GERD. A study conducted at the Mayo Clinic showed an autopsy prevalence about 17 times higher than a clinically matched population, suggesting that most cases of LSBE are asymptomatic and thus unrecognized. In patients undergoing endoscopy, the prevalence of SSBE ranges from 5-30%. The combined prevalence of SSBE and cardia-SIM is 7-8 times greater than LSBE, but the prevalence of dysplasia and cancer is much less.

In a study of 120 young patients (range, 16-19 years; mean age, 16.5 ± 1.4 years) treated for esophageal atresia, Barrett esophagus was associated with eosophageal atresia without fistula, previous multiple antireflux surgery, esophageal dilation, suspicion of BE at endoscopy , and histologic esophagitis.[9]

Prognosis

The most significant morbidity associated with Barrett esophagus is the development of adenocarcinoma in the esophagus.[5] However, most patients with Barrett esophagus will not develop esophageal cancer, with the risk of progression to adenocarcinoma of the esophagus being estimated at approximately 0.5% per year in patients without dysplasia on initial surveillance biopsies.

Even so, the incidence of esophageal adenocarcinoma is rising faster than that of any other cancer in the United States. From 1926-1976, 4 large surgical series reported that only 0.8-3.7% of esophageal cancers were adenocarcinomas. From 1979-1992, this increased to 54-68%.

Blot et al, in a review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute, determined that the incidence of esophageal adenocarcinoma in 1988-1990 was 3 times that in 1976-1978.[10]

In Olmstead County, Minnesota, Pera et al conducted a population-based study and found that the incidence of esophageal adenocarcinoma rose from 0.13 cases per 100,000 person-years in 1935-1971 to 0.74 cases per 100,000 person-years in 1974-1989.[11] The incidence of adenocarcinoma of the cardia rose from 0.25 to 1.34 cases per 100,000 person-years in the same time period, an increase of more than 5-fold for both locations. Patients with LSBE have the greatest risk for development of dysplasia and adenocarcinoma of the esophagus.

Studies report the prevalence of dysplasia in LSBE at 20-35%, in SSBE at 6-8%, and in cardia-SIM at 0-6%, with the prevalence of adenocarcinoma being 7-15 times greater in LSBE than in SSBE and cardia-SIM. However, the total number of patients with SSBE and cardia-SIM is 7-8 times that of LSBE. Thus, even with a higher prevalence of dysplasia and cancer in the LSBE population, a greater total number of patients are likely to develop cancer from within the SSBE and EGJ-SIM group.

 

Presentation

History and Physical Examination

History

The classic history for a patient with Barrett esophagus is a middle-aged (55 y) white man with a chronic history of gastroesophageal reflux; for example, pyrosis, acid regurgitation, and, occasionally, dysphagia. Although this is a classic history, some patients may deny any symptoms.

Physical

No unique physical examination characteristics are evident in patients with Barrett esophagus other than those that would be found in patients with chronic GERD.

 

Workup

Approach Considerations

The association of chronic GERD with Barrett esophagus and the inherent risk of progression from Barrett esophagus to adenocarcinoma of the esophagus have been established. Consequently, any patient aged 50 years or older, male or female, with a history of chronic GERD should have at least a 1-time upper endoscopy to screen for Barrett esophagus.

Esophagogastroduodenoscopy

Esophagogastroduodenoscopy (EGD) is the procedure of choice for the diagnosis of Barrett esophagus. The diagnosis requires biopsy confirmation of SIM in the esophagus. An upper gastrointestinal series (UGI) or barium swallow cannot reliably establish the diagnosis of Barrett esophagus.

In cases of erosive esophagitis, a healing of the mucosa is required prior to EGD to ensure a lack of Barrett mucosa underneath the inflammation.

Histologic findings

The presence of SIM in the esophagus is required for the diagnosis of Barrett esophagus.

Ultrasonography

When high-grade dysplasia or cancer is found on surveillance endoscopy, endoscopic ultrasonography (EUS) is advisable to evaluate for surgical resectability.

Fluorescence in situ hybridization

A commercial four-color fluorescence in-situ hybridization (FISH) probe set to 9p12 (CDKN2A), 17q11.2-12 (HER2), 8q24.12-13 (CMYC), and 20q13.2 (ZNF217) appears to be able to detect aneusomy in Barrett esophagus.[12] In a study consisting of 20 cases of Barrett esophagus, significant increases inHER2, CMYC, and ZNF217 copy number were found in dysplastic mucosa compared with nondysplastic mucosa. However, non-detection of aneusomy did not rule out dysplasia.[12]

 

Treatment

Approach Considerations

The diagnosis of Barrett esophagus does not lead to specific therapy. Little evidence supports the assumption that antisecretory agents or antireflux surgery prevents the occurrence of adenocarcinoma or leads to regression of Barrett esophagus.[13]

In the early to mid-1980s, histamine 2 (H2)-receptor antagonists were the most commonly prescribed agents for treatment of GERD. However, a number of studies were conducted with either cimetidine or ranitidine, and none documented regression of Barrett esophagus.

In the late 1980s, proton pump inhibitors (PPIs) were introduced and proved to be much more efficacious at reducing gastric acid secretion. Even so, the supposition that better acid suppression could induce Barrett esophagus regression was met with optimism, and studies on this to date have been inconclusive. Only 2 of 7 investigators demonstrated some regression. Most were unable to detect any regression, despite documentation of complete normalization of esophageal pH by pH testing.

Currently, the indications for medical therapy in Barrett esophagus—control of symptoms and healing of esophageal mucosa—are the same as those for GERD. An important, as yet unanswered, question is whether abolishing acid completely with high-dose PPIs decreases the risk for adenocarcinoma of the esophagus and warrants the cost and possible adverse effects of this therapy.

Surgery

In addition to acid, the reflux of pancreatic and biliary secretions into the esophagus has been implicated in the pathogenesis of Barrett esophagus. Because medications are effective at reducing only the acid component in reflux, surgical therapy may have an advantage.

However, while studies have shown surgery to be efficacious in the control of GERD symptoms, the results regarding Barrett esophagus regression are inconclusive. No good evidence indicates that surgical therapy provides regression in Barrett esophagus. Thus, antireflux surgery, such as Nissen fundoplication, is not indicated for eradication of Barrett esophagus, but it certainly is reasonable for appropriate patients who desire surgery for control of GERD symptoms.

With relation to reduction of cancer risk in Barrett esophagus, evidence remains insufficient to recommend surgery over medical therapy, although regression of features associated with cancer risk appears to be more common following surgical intervention than medical therapy.[14]

When high-grade dysplasia is discovered and confirmed by a second pathologist, endoscopic ablation is the standard of care.

A systematic review found relatively high pooled incidence rates of recurrence of intestinal metaplasia after achieving complete remission through radiofrequency ablation (9.5% per patient year) and endoscopic therapy (7.1% per patient year) of Barrett esophagus.[15] Predictors of recurrence were increasing age and length of Barrett esophagus. Other pooled incidence rates of recurrence (per patient year) included the following[15] :

  • Dysplastic Barrett esophagus: 2.0% for radiofrequency ablation; 1.3% for endoscopic therapy
  • High-grade dysplasia/esophageal adenocarcinoma: 1.2%for radiofrequency ablation; 0.8% for endoscopic therapy

Diet

Data remain inconclusive regarding the relationship between Barrett esophagus and dietary fruit, fat, and red/processed meat intake, although dietary vegetable intake may lower the risk.[16] Thus, the diet for patients with Barrett esophagus is the same as that recommended for patients with GERD. Patients should avoid the following:

  • Fried or fatty foods

  • Chocolate

  • Peppermint

  • Alcohol

  • Coffee

  • Carbonated beverages

  • Citrus fruits or juices

  • Tomato sauce

  • Ketchup

  • Mustard

  • Vinegar

  • Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

Patients also should decrease the size of portions at mealtime, avoid eating 3 hours prior to bedtime, elevate the head of the bed 6 inches, lose weight (if overweight), and stop smoking.

Barrett Esophagus Screening and Surveillance

The Practice Parameters Committee of the American College of Gastroenterology recommends that patients with long-standing GERD symptoms (>5y), particularly those aged 50 years or older, have an upper endoscopy to detect or screen for Barrett esophagus. Once identified, patients with Barrett esophagus should undergo periodic surveillance endoscopy to identify histologic markers for increased cancer risk (dysplasia) or cancer that is at an earlier stage and is amenable to therapy. Preliminary data suggest that surveillance endoscopy does just that. Still, esophageal cancer is an uncommon cause of death.

In a cohort study of patients with Barrett esophagus not undergoing surveillance, only 2.5% of 155 patients died as a result of esophageal cancer, with a mean of 9 years follow-up. Patients with Barrett esophagus should be considered candidates for surveillance only if a potential to prolong life expectancy exists and only if they are eligible for therapy when dysplasia or early cancer is detected. Age and comorbidity are important factors to consider.

The goal of surveillance is the detection of dysplasia or early cancer. Currently, dysplasia is the best histologic marker for cancer risk. The appropriate surveillance interval is based on published data on the natural history of dysplasia and primarily is a function of the grade of dysplasia. Surveillance involves repeated upper endoscopy with systematic 4-quadrant biopsies at 2cm intervals along the entire length of the segment of Barrett esophagus, with additional biopsy of any mucosal abnormalities.

Patients with Barrett esophagus in whom dysplasia is lacking for 2 consecutive yearly endoscopies may be extended to follow-up at 3-year intervals. Patients with persistent low-grade dysplasia on repeat endoscopy should undergo surveillance every 6 months for 2 cycles; if no progression of disease is noted, surveillance may be extended to yearly follow-up. Management of high-grade dysplasia is more controversial.

Managing high-grade dysplasia

Observer variation is a problem in the grading of dysplasia, and the first step in management of a patient with high-grade dysplasia always is confirmation of the diagnosis by a pathologist who is an expert at reading esophageal biopsies. The surgical literature suggests that as many as 40% of patients who undergo esophagectomy for high-grade dysplasia have concomitant cancer in the resected specimen.

Currently, 3 management options for high-grade dysplasia exist. One is surveillance endoscopy, with intensive biopsy at 3-month intervals until cancer is detected. The second is endoscopic ablation, and the third is surgical resection.

Because dysplasia and cancer are patchy and cannot be visualized endoscopically, the diagnosis is difficult with even the most intensive surveillance. Current research is focused on developing endoscopic techniques that will highlight dysplastic tissue to allow directed biopsy and also on finding surrogate cellular markers and the like that may help in predicting which patients will develop cancer in the absence of biopsy-proven dysplasia.

Ablative Therapy for Barrett Esophagus

The goal of ablative therapy is to destroy the Barrett epithelium to a sufficient depth to eliminate the intestinal metaplasia and allow regrowth of squamous epithelium. A number of modalities have been tried, usually in combination with medical or surgical therapy because successful ablation appears to require an antacid environment.

Human studies have been performed with radiofrequency ablation (RFA), photodynamic therapy (PDT), argon plasma coagulation (APC), multipolar electrocoagulation (MPEC), heater probes, various forms of lasers, endoscopic mucosal resection (EMR), and cryotherapy.

Ablative therapy is emerging as a viable alternative to surgical resection or esophagectomy for patients with high-grade dysplasia in Barrett esophagus. In fact, in most major medical centers ablation is first-line therapy. A study by Prasad found that the 5-year survival rate for patients with high-grade dysplasia in Barrett esophagus who were treated with PDT and EMR was comparable to that of patients treated with esophagectomy.[17]

A retrospective cohort study of 166 patients with dysplastic Barrett esophagus showed that endoluminal therapy combining endoscopic mucosal resection and ablation is a safe and effective treatment for Barrett esophagus.[18, 19]

Radiofrequency ablation

RFA is FDA approved for eradication of high-grade dysplasia in Barrett esophagus. It is also a treatment option for low-grade dysplasia in Barrett esophgus, provided the risks and benefits are thoroughly discussed with the patient.[20] RFA is a balloon-based, bipolar radiofrequency ablation system. This technique requires the use of sizing balloons to determine the inner diameter of the targeted portion of the esophagus. This is followed by placement of a balloon-based electrode with a 3-cm long treatment area that incorporates tightly spaced, bipolar electrodes that alternate in polarity. The electrode is then attached to a radiofrequency generator and a preselected amount of energy is delivered in less than 1 second at 350 W.

Shaheen et al demonstrated that RFA was associated with a high rate of complete eradication of dysplasia and intestinal metaplasia and a reduced risk of disease progression in patients with dysplastic Barrett esophagus.[21]

In the study, complete eradication occurred in 90.5% of patients with low-grade dysplasia who received radiofrequency ablation, compared with 22.7% of patients in the control group, who underwent a sham procedure. Among patients with high-grade dysplasia, complete eradication occurred in 81% of those in the ablation group, whereas complete eradication occurred in only 19% of patients in the control group.

Patients in the ablation group had less disease progression than did those in the control group (3.6% vs 16.3%, respectively) and fewer cancers than did patients in the control group (1.2% vs 9.3%, respectively).

In a randomized study of 136 patients with Barrett esophagus and low-grade dysplasia, Phoa et al found that in comparison with endoscopic surveillance, endoscopic radiofrequency ablation (RFA) significantly reduced the rate of neoplastic progression to high-grade dysplasia or adenocarcinoma.[22, 23, 24]

Over 3 years of follow-up, RFA reduced the risk of progression to high-grade dysplasia or adenocarcinoma from 26.5% to 1.5% (P < .001) and lowered the risk of progression to adenocarcinoma from 8.8% to 1.5% (P = .03).[23]  Among patients in the ablation group, the rate of complete eradication was 92.6% for dysplasia and 88.2% for intestinal metaplasia, compared with 27.9% for dysplasia and 0% for intestinal metaplasia among patients in the surveillance group.

Use of endoscopic mucosal resection before RFA appears to significantly reduce the risk of treatment failure for Barrett esophagus–associated dysplasia and  Barrett esophagus–associated intramucosal adenocarcinoma, whereas a significant predictor of treatment failure appears to be the presence of intramucosal adenocarcinoma involving 50% or more of the columnar metapastic area on index examination.[25]

PDT

PDT involves the use of a photosensitizing agent that accumulates in tissue and induces local necrosis through the production of intracellular free radicals following exposure to light at a certain wavelength. Typically, a hematoporphyrin is used as the photosensitizing agent because it has a greater affinity for neoplastic tissue.

Another agent, 5-aminolevulinic acid (ALA), which induces endogenous protoporphyrin IX and has selectivity for the mucosa over deeper submucosal layers, has also been used. The results have been promising for the regression of Barrett esophagus, as well as for the treatment of dysplasia and superficial carcinoma.

Using PTD to treat 100 patients—including 73 with high-grade dysplasia and 13 with superficial adenocarcinoma—Overholt et al found that Barrett mucosa was completely eliminated in 43 patients and dysplasia was eliminated in 78 patients.[26]

Other studies have shown similar response rates, but Barrett epithelium beneath the superficial squamous layer has been observed, indicating that deeper-placed pluripotent cells may be preserved. Additionally, PDT is an expensive and time-consuming endeavor, and early use was complicated by esophageal stricture requiring dilation in 58% of patients. PDT has been largely replaced by RFA in most medical centers performing ablation.

APC ablation

APC is a method of contact-free high-frequency current coagulation in which the burning of tissue stops as soon as the area is ablated. One study using high-power APC was reported to result in complete restoration of squamous mucosa in 33 out of 33 patients after a mean 1.96 sessions. The major complications were chest pain and odynophagia, which occurred in 57.5% of patients and lasted 3-10 days. Only 3 patients experienced stricture, which was treated easily with dilation. Only 1 endoscopic, as well as histologic, recurrence was observed at 10.6-month mean follow-up, but this was in a patient with an ineffective Nissen fundoplication.

Other studies have been less encouraging, with persistence of residual foci of Barrett epithelium under the neosquamous lining in 22-29%; deep esophageal ulceration with massive bleeding, perforation, and even death have been reported.

MPEC ablation

MPEC is a method in which the mucosa is ablated by direct contact with an electrocautery probe. Sampliner et al used this technique to treat 10 patients with LSBE, using half of the patient's own esophagus as an internal control, and found that all 10 patients had the treated segment eliminated by visual and biopsy criteria at 6 months; the untreated segment remained unchanged in the patients, despite acid suppression. Treatment took an average of 2.5 sessions, and 5 patients had complications in 75 total sessions (2 transient odynophagia, 1 transient dysphagia, 1 chest pain, and 1 upper gastrointestinal bleed).[27]

In a 10-year follow-up study of 139 patients with Barrett esophagus, MPEC ablative therapy was associated with complications (all minor) in less than 5% of patients.[28] Recurrent Barrett esophagus occurred in less than 5% of patients. No adenocarcinoma or high-grade dysplasia of the esophagus developed in any of the patients. These results indicated the long-term efficacy and safety of mucosal ablation in Barrett esophagus.

Laser ablation

Lasers have been used in numerous small studies for eradication of Barrett esophagus. Results were less consistent with this modality than with those listed above. Studies that demonstrated full or partial regression endoscopically were confounded by the persistence of glandular elements beneath the neosquamous epithelium in as many as one third of cases.

Cryoablation

One of the newer ablative techniques is low-pressure cryospray ablation using liquid nitrogen, pioneered at the author's institution. The components of the low-pressure spray cryoablation device are as follows:

  • Liquid nitrogen tank

  • Electronic console - For monitoring and controlling cryogen release

  • Dual foot pedal - For controlling cryogen release and heating of the catheter

  • Catheter - A multilayered, 7-9F, open-tipped catheter for spray of supercold nitrogen gas through an upper endoscope

The mechanism of injury is unique relative to other ablative techniques. Cryoablation induces apoptosis, causes cryonecrosis at supercold temperatures (-76°C to -196°C), results in transient ischemia, and can cause immune stimulation. The Barrett epithelium is resistant to apoptosis and, therefore, may be uniquely suited for treatment by cryoablation.

A pilot study at the author's institution using cryoablation in Barrett esophagus with degrees of dysplasia ranging from no dysplasia to multifocal, high-grade dysplasia achieved complete endoscopic reversal of Barrett esophagus in 78% of cases, with no subsquamous SIM or dysplasia at 6-month follow-up. These results will need confirmation at other institutions. (See the images below.)

Cryoablation of esophageal lining in Barrett esoph Cryoablation of esophageal lining in Barrett esophagus (BE). This is one of the newest experimental ablative therapies for the esophagus performed at the author's laboratory.
Blistering of the esophageal mucosal layer after c Blistering of the esophageal mucosal layer after cryoablation in Barrett esophagus (BE).
 

Medication

Medication Summary

The treatment for Barrett esophagus should be the same as that for GERD, although most authorities agree that treatment should employ a PPI instead of an H2-receptor antagonist due to the relative acid insensitivity of patients with Barrett esophagus. However, although PPIs have been found to be better than H2-receptor antagonists at reducing gastric acid secretion, the evidence remains inconclusive regarding whether PPIs induce regression of Barrett esophagus.

H2-receptor antagonists

Class Summary

These agents are reversible competitive blockers of histamine at H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Ranitidine (Zantac)

Ranitidine inhibits histamine the stimulation of H2 receptors in gastric parietal cells, in this way reducing gastric acid secretion, gastric volume, and hydrogen concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at H2 receptors in gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Nizatidine (Axid)

Nizatidine competitively inhibits histamine at H2 receptors in gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Cimetidine (Tagamet)

Cimetidine inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Proton pump inhibitors

Class Summary

PPIs inhibit gastric acid secretion by inhibition of the H+/K+ -adenosine triphosphatase (ATPase) enzyme system in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients who do not respond to H2-antagonist therapy.

Omeprazole (Prilosec)

Omeprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Lansoprazole (Prevacid)

Lansoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Esomeprazole (Nexium)

Esomeprazole is an (S)-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system at the secretory surface of the gastric parietal cells.

Dexlansoprazole (Dexilant)

Dexlansoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Rabeprazole sodium (AcipHex)

Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Pantoprazole (Protonix)

Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Photosensitizers

Class Summary

These agents are used with PDT. Upon light absorption, a photosensitizer transforms to a short-lived singlet state, followed by a transition to a reactive triplet state. When in the triplet state, the photosensitizer produces reactive free radicals in the presence of oxygen; the free radicals react with cell membranes, causing direct damage to the mitochondria, endoplasmic reticulum, and/or plasma membranes.

Porfimer (Photofrin)

Porfimer is indicated to treat high-grade dysplasia in Barrett esophagus. It elicits a photosensitizing effect used in PDT.

 

Questions & Answers

Overview

What is Barrett esophagus?

What are the signs and symptoms of Barrett esophagus?

What are the features of gastroesophageal reflux disease (GERD) in long-segment Barrett esophagus (LSBE)?

What are the features of gastroesophageal reflux disease (GERD) in short-segment Barrett esophagus (SSBE)?

Which is included in the workup of Barrett esophagus?

How is Barrett esophagus managed?

Which foods should patients with Barrett esophagus avoid?

What is the Barrett esophagus?

What are histologic characteristics of Barrett esophagus?

What are endoscopic characteristics of Barrett esophagus?

What causes Barrett esophagus?

What is the pathogenesis of gastroesophageal reflux disease (GERD)?

What is the role of refluxate exposure to the esophagus in the etiology of Barrett esophagus?

What is the role of oral bisphosphonate in the etiology of Barrett esophagus?

What is the prevalence of Barrett esophagus?

What is the prognosis of Barrett esophagus?

Presentation

Which clinical history findings are characteristic of Barrett esophagus?

Which physical findings are characteristic of Barrett esophagus?

Workup

Who should be screened for Barrett esophagus?

What is the role of esophagogastroduodenoscopy (EGD) in the diagnosis for Barrett esophagus?

Which histologic findings are diagnostic of Barrett esophagus?

What is the role of ultrasonography in the evaluation of Barrett esophagus?

What is the role of fluorescence in-situ hybridization (FISH) in the diagnosis of Barrett esophagus?

Treatment

What are the treatment options for Barrett esophagus?

What is the role of surgery in the treatment of Barrett esophagus?

What is the recurrence rate of Barrett esophagus after surgery?

Which dietary modifications are used in the treatment of Barrett esophagus?

What are the American College of Gastroenterology (ACG) screening and surveillance guidelines for Barrett esophagus?

How is high-grade dysplasia managed in Barrett esophagus?

What is the role of ablative therapy in the treatment of Barrett esophagus?

What is the role of radiofrequency ablation in the treatment of Barrett esophagus?

What is the role of photodynamic therapy (PDT) in the treatment of Barrett esophagus?

What is the role of argon plasma coagulation (APC) in the treatment of Barrett esophagus?

What is the role of multipolar electrocoagulation (MPEC) ablation in the treatment of Barrett esophagus?

What is the role of laser ablation in the treatment of Barrett esophagus?

What is low-pressure cryospray ablation in the treatment of Barrett esophagus?

Medications

Which medications are used in the treatment of Barrett esophagus?

Which medications in the drug class Photosensitizers are used in the treatment of Barrett Esophagus?

Which medications in the drug class Proton pump inhibitors are used in the treatment of Barrett Esophagus?

Which medications in the drug class H2-receptor antagonists are used in the treatment of Barrett Esophagus?