Barrett's Esophagus Notes

Barrett’s Esophagus

Definition and Characteristics

Barrett's esophagus (BE) is characterized by the replacement of the normal stratified squamous epithelium of the esophagus with columnar epithelium (intestinal metaplasia).
This transformation is due to chronic exposure to gastric contents, often in the context of gastroesophageal reflux disease (GERD).
Patients at risk for BE are screened via endoscopy and biopsy.
The major concern with BE is that it is a precursor lesion for esophageal adenocarcinoma (EAC), a disease with a poor prognosis and increasing incidence.
Identifying and eradicating BE before progression to adenocarcinoma is a top priority.
Endoscopic techniques have largely replaced esophagectomy for many patients, allowing for eradication of BE with less morbidity and fewer complications.

Progression

The natural progression of BE to carcinoma develops over time:
- Non-dysplastic columnar epithelium → Dysplasia → Carcinoma
- Within dysplasia: Low-grade dysplasia (LGD) → High-grade dysplasia (HGD)
LGD is differentiated from HGD by the degree of architectural and cytologic distortions; however, there is much reported interobserver variability.
The progression is driven by genetic and epigenetic events that lead to a loss of genetic stability.
The presence of BE can increase the risk for development of EAC by at least 40-fold compared with the general population, with some studies showing up to a 125-fold increase.

Surveillance

Once BE is identified, surveillance is crucial.
Endoscopic surveillance intervals, guided by current guidelines using the Seattle Protocol, vary with the presence and grade of dysplasia.
The Seattle protocol involves 4-quadrant jumbo biopsies every 1 cm.
After initial diagnosis, endoscopy is often repeated 1 year later to confirm the presence of BE and rule out dysplasia.
For patients with BE without dysplasia, surveillance endoscopy should be performed every 3 to 5 years.
For patients indefinite for dysplasia on endoscopy, repeat endoscopy should be performed 3 to 6 months after optimization of acid suppressive medications.
If the indefinite for dysplasia diagnosis is confirmed, surveillance endoscopy is recommended annually while indefinite for dysplasia.
In the presence of LGD, surveillance is performed every 6 to 12 months.
For patients with HGD who do not undergo intervention, surveillance is recommended every 3 months.
After intervention, continued surveillance is necessary.
A risk calculator has been developed to assign points to risk factors to identify a patient at low, intermediate, or high risk of progression.

Description Summary

True Barrett’s involves the replacement of stratified squamous epithelium that lines the distal esophagus with specialized columnar epithelium containing goblet cells (i.e., gastric metaplasia and specialized intestinal metaplasia (SIM)).
Short Barrett’s: 0-3 cm; most Barrett’s cases are short.
Long Barrett’s: >3 cm.
Sliding hiatus hernia should not be mistaken for Barrett’s. The true gastroesophageal junction (GOJ) begins when gastric folds finish.

Facts

Presents in 5% of the population, 10% of those with reflux symptoms.
Most are men >65 years old.
>95% will die from other causes.
200 to 400 ‘screening’ endoscopies have to be performed to detect 1 cancer.
Of the cancers detected, many are inoperable (patient fitness, advanced disease).
Mortality of esophagectomy is 5-10%.
Cancer risk increases with the length of Barrett’s.
Most cancers occur in short Barrett’s, as this is far more common.
Most effective analyses suggest surveillance only every 5 years.
Many patients are unhappy as that is too long of a wait time.
Its incidence increases with the duration of symptoms and increasing patient age.

Criteria for Screening

Length is 3cm or more.
Intestinal metaplasia.
Fit for surgery.
Aware of reasons for surveillance, risk of surgery, and benefit of screening.

Endoscopy Protocol

Four-quadrant biopsies are taken at 2cm intervals, beginning at 1cm below the GOJ and extending to 1cm above the squamocolumnar junction.
If no dysplasia, 3-year intervals.

Preoperative Testing

Barrett esophagus can only be diagnosed on endoscopy with confirmation of intestinal metaplasia on biopsy.
The finding of goblet cells intermingled in a columnar lining of the tubular esophagus is pathognomonic of Barrett esophagus.
The disease is considered to be a metaplastic response to severe GERD, and its clinical significance is the premalignant potential of the unstable epithelium.
The definition has changed slightly over the years, but biopsy is required for confirmation.
The finding of Barrett esophagus has significance outside its potential for malignancy, as patients with Barrett esophagus often have associated esophageal hypomotility and generally have severely abnormal esophageal exposure to both refluxed acid and duodenal contents.
Patients with Barrett esophagus may also have a shorter-than-normal esophagus, which may have implications for a planned surgical procedure.

Management of Barrett’s Esophagus without Dysplasia

The principle treatment goal is to provide relief of the patient’s GERD symptoms while protecting the esophageal mucosa and BE from progression to dysplasia from continued reflux injury.
Medical therapy with proton pump inhibitors (PPIs) has been considered the first-line therapy for any patient with BE to control GERD.
The American College of Gastroenterology Clinical Guidelines recommends patients with BE should receive once-daily PPI therapy for chemoprevention.
Twice-daily dosing is not recommended unless necessitated by poor control of reflux symptoms or esophagitis.
Medical therapy with PPIs treats esophagitis and therefore allows for more accurate surveillance of the esophagus.
A 2004 US study demonstrated a 75% reduction in the development of dysplasia in PPI users versus nonusers.
Overall, PPIs are generally well tolerated by patients; however, the long-term safety of PPIs has been called into question.

Management of Barrett’s Esophagus with Low-Grade Dysplasia

LGD is associated with an increased risk for progression to adenocarcinoma compared with nondysplastic BE.
Given the high interobserver variability in diagnosing LGD in BE from inflammatory atypia, there is controversy on the best treatment when LGD is found on biopsy.
Professional societies agree on the need for confirmation of LGD by two skilled pathologists.
If patients are not already on a PPI, one should be started, or the dose escalated if already prescribed.
After interventions to control the underlying reflux, a repeat endoscopy within 6 months to evaluate response to treatment is recommended.
If there is resolution of LGD on surveillance biopsies, then patients can be maintained on PPI therapy; alternatively, antireflux surgery with Nissen fundoplication can also be performed to control reflux.
Medical therapy with high-dose PPIs was compared with Nissen fundoplication to evaluate regression of LGD. Regression of LGD to BE without dysplasia was seen more frequently in patients who received a Nissen fundoplication, $P = .03$ .
If the diagnosis of LGD is persistent, endoscopic ablation therapy is recommended in the absence of mucosal abnormality.
Radiofrequency ablation (RFA) resulted in a reduced risk of neoplastic progression over 3 years of follow-up compared with surveillance alone.
After RFA is performed, patients require ongoing surveillance to detect any further progression or new lesions of dysplasia and a discussion about long-term management of their GERD with PPIs or antireflux surgery.
The detection of LGD should prompt a course of high-dose acid suppression with a PPI for 8–12 weeks, followed by repeat endoscopy with extensive biopsies.
If LGD persists, then surveillance endoscopy should be repeated at 6-monthly intervals, and the patient should remain on a PPI.
If regression to metaplasia without dysplasia occurs on two consecutive examinations, then the surveillance interval may return to 2-yearly.

Management of Barrett’s Esophagus with High-Grade Dysplasia

The first step in management of patients with HGD is careful repeat endoscopy to map out the locations of any nodules or lesions such as ulcers within the columnar mucosa using both white light endoscopy and narrow band imaging.
The additional use of chromoendoscopy can aid in the identification of any lesions within the mucosa.
HGD is an indication for intervention in the vast majority of patients because of the high risk for progression to EAC.
Endoscopic mucosal resection should be used to excise small discrete mucosal nodules, with a good specimen including mucosa and submucosa with a clean base of muscle seen at the resection site.
In lesions larger than 1 to 2 cm, endoscopic ultrasound should be used to evaluate the depth of invasion and presence of enlarged lymph nodes; if the lesion identified is small or there is no lesion, endoscopic ultrasound is not useful because the accuracy of T-staging is poor.
Patients found to have HGD alone or adenocarcinoma confirmed at the mucosa level only (T1a) without lymphovascular invasion are candidates for endoscopic therapy to preserve the esophagus.
Invasion into the submucosa (T1b), however, should lead to esophagectomy and lymph node dissection in most patients because of the increased likelihood of nodal metastases once the cancer reaches the submucosa.
Patients undergoing esophageal preservation should have complete endoscopic resection of all raised lesions in one or more sessions 6 to 8 weeks apart until all dysplastic tissue has been eradicated.
Even after complete endoscopic resection, a concomitant mucosal ablative procedure with RFA is frequently required to assure complete eradication of disease because of the frequent multifocality of BE.
RFA is performed at 8-week intervals until all the intestinal metaplasia has been eradicated.
After complete eradication of both dysplasia and intestinal metaplasia, ongoing surveillance is recommended every 3 months for the first year, every 6 months for the second year, and annually thereafter because there is a risk for recurrence or inadequately treated lesions.
Furthermore, patients undergoing endoscopic therapy should be on maximum medical therapy (e.g., esomeprazole 40 mg twice daily) and long-term GERD control after endoscopic therapy either in the form of PPIs or antireflux surgery.

Esophagectomy in High Grade Dysplasia

Although endoscopic treatments have become the standard of care, there is still a role for esophagectomy in the treatment of HGD.
Advantages of esophagectomy include immediate disease eradication and no need for further surveillance; however, it carries the potential morbidity associated with the surgery.
Operative mortality for esophagectomy in HGD and early tumors is low, at less than 1% at high-volume centers.
Esophagectomy should be strongly considered in patients with the following characteristics:
1. Poor prognostic risk factors of the lesion: large (>2 to 3 cm), lymphovascular invasion, multifocality
2. Patient prefers surgery
3. Unable to comply with the repeat endoscopic treatments and surveillance
4. Inability to eradicate HGD and/or adenocarcinoma or progression of disease
5. Failed ablation techniques
6. End-stage esophageal function (from motility disorder, stricture, obstructed hiatal hernia)
For these patients, the best surgical approach is often a minimally invasive vagal-sparing esophagectomy that can eradicate disease while minimizing potential morbidity by sparing both vagal nerves.

Surgical Considerations and the Role of Antireflux Surgery in Management of Barrett’s

Patients with GERD and BE have been shown to have an increased amount of reflux compared with patients with GERD alone, as well as a higher prevalence of incompetent LES, impaired esophageal motility, and hiatal hernias, making it difficult to control reflux with medical management alone.
Antireflux surgery has several theoretical benefits in the management of GERD, including:
1. The control of both acid and biliopancreatic substrates that are contributing to the mucosal injury and therefore reducing inflammatory markers that are key in the development of BE, including interleukin-8 and Cox-2.
2. Furthermore, antireflux surgery aims to fix the incompetent LES and hiatal hernia if present.
3. The complete reflux control can prevent progression of BE and even lead to regression and healing of Barrett’s mucosa, as shown in several studies.
The esophageal injury sufficient to cause mucosal injury leading to BE can also cause edema, spasm, fibrosis, strictures, and shortening of the esophagus, leading to a more complex fundoplication.
In addition, patients with BE more often have a hiatal hernia.
These issues lead to a higher failure rate for fundoplication in the setting of BE at 15% to 20% at 3 to 5 years postoperatively (compared with 5% to 10% for those patients without BE).
A failed fundoplication is a risk factor for disease progression because there is continued postoperative acid exposure to the distal esophagus.
Careful selection of patients for fundoplication is critical and postoperative surveillance with serial endoscopies is mandatory.
For those patients considering antireflux surgery, further workup should include high-resolution manometry and video-esophagram.
We favor obtaining a pH test, not to diagnose GERD, but to provide a baseline measurement of the patient’s reflux. This allows comparison to any post-fundoplication confirmatory testing that is performed.
If esophageal dysmotility is a significant problem, a partial fundoplication can be performed to prevent postoperative problems with dysphagia; however, the efficacy of a partial fundoplication in patients with BE is questionable, with some studies suggesting decreased long-term control of reflux. Patients in this situation should be selected carefully and informed that they likely will need to remain on PPIs to ensure control of their GERD.
Patients who remain incompletely controlled on PPI therapy with reasonable motility are considered for fundoplication after intervention with RFA or endoscopic resection and surveillance of at least 1 year.
Fundoplication after endoscopic therapy results in similar durability and recurrence of BE when compared with patients managed with PPIs; however, fundoplication seemed to prevent further progression and the development of cancer.

Conclusion

Management of the patient with BE is intimately tethered to the treatment of the patient’s underlying chronic GERD.
When presenting this complex problem to the patient, it can often be broken down into two separate but related pathways: treatment and subsequent surveillance of the Barrett’s metaplasia and treatment of the underlying GERD.
Antireflux surgery can be beneficial to eradicate GERD symptoms and even induce regression of existing dysplasia and prevent progression. Patients must be carefully selected for surgery because those with BE are more likely to have a fundoplication failure and recurrence of hiatal hernia compared with those patients without BE.
Endoscopic treatments have transformed management of dysplastic Barrett’s and now allow preservation of the esophagus in most patients, but esophagectomy continues to have a role in selected patients not amenable to or cured by endoscopic therapy.

Principles of Endoscopic Therapies

The current evidence suggests that endoscopic therapy should be used for patients with BE who have LGD, HGD, and for some patients with early intramucosal (T1a) EAC because the risk of lymph node metastasis is nonexistent for LGD and HGD and is low for intramucosal EAC.
Endoscopic techniques work by either removing it before the development of invasive disease or destroying abnormal tissue (ablative techniques). The intestinal metaplasia is then replaced with normal appearing squamous epithelium.

Endoscopic Resection Techniques

Endoscopic Mucosal Resection (EMR): allows removal of lesions within segments of BE for complete histologic analysis, including dysplasia and superficial T1a adenocarcinoma. It offers an advantage over ablative techniques because it allows for examination of tissue specimens, rather than just destroying them.
The ACG recommends EMR as the initial treatment modality for patients with nodular BE.
For patients without high-risk features (submucosal invasion, poor differentiation, or lymphatic vascular invasion), EMR has a 98.8% eradication rate of BE.
In patients with high-risk features, the rate is 80.6%.
For T1a tumors, EMR has a 91% to 98% eradication rate.
Endoscopic Submucosal Dissection (ESD): allows for complete, en bloc resection of suspicious lesions to allow for thorough histologic evaluation. When compared to EMR, it also allows for complete resection of lesions, rather than having to resect lesions in a piecemeal fashion, especially for larger lesions (>1.5–2 cm).
The primary indication for ESD is resection of nodular lesions within a segment of BE to allow for complete histologic evaluation. Given the relative technical difficulty of this procedure, as well as the concern for significant adverse events, it is not as widely used.

Argon Plasma Coagulation

Argon plasma coagulation (APC) uses a beam of argon gas to conduct an electrical current, resulting in a noncontact form of thermal electrocoagulation.
The depth of necrosis is relatively shallow (2–3 mm) and can be useful in conditions such as BE that involve the mucosa.
In the initial randomized controlled trial (RCT), patients treated with APC achieved complete macroscopic ablation 60% of the time, with the remaining patients achieving a significant decrease in the size of their BE. At the 1-year follow-up, 58% of patients had no macroscopic evidence of disease compared with only 15% in the surveillance group. At 5-year follow-up, 70% of patients in the APC group had sustained at least a 95% reduction in the surface area of BE, and 40% had no histologic or macroscopic disease compared with only 25% and 15%, respectively, in the surveillance group.
There were no early complications, and long-term complications included strictures that were managed with endoscopic dilation. Other reported complications include chest pain, odynophagia, ulceration, bleeding, perforation, and death.
One advantage of APC is that the equipment is widely available and is relatively inexpensive; however, as noted in the RCTs, it often requires multiple treatments over time to achieve regression of disease.

Cryotherapy

Cryotherapy directly destroys tissue by freezing it, resulting in both immediate and delayed tissue destruction.
In a retrospective study of patients treated with liquid nitrogen, after an average of four treatments, 97% of patients had resolution of HGD, 87% had resolution of intestinal dysplasia, and 57% had resolution of intestinal metaplasia. There were no serious complications, but 3% of patients developed strictures that were managed with endoscopic dilation.
At the 5-year follow-up, 93% of patients had complete resolution of high-grade dysplasia, 88% had resolution of dysplasia, and 75% had resolution of intestinal metaplasia, although some of these patients underwent “touch-up” therapy after the initial round of treatment.
One advantage of cryotherapy is that it can be used both as a first-line treatment for BE with dysplasia, and as a second-line treatment in patients who have failed other treatments; as with other therapies, however, it often requires multiple treatments to completely eradicate the disease.
In a recent review of liquid nitrogen cryotherapy, the complication rate ranged from 0% to 3%, with the most frequent complication being pain requiring narcotics (10% of patients), followed by stricture requiring dilation (up to 9%), then bleeding and perforation.

Conclusion

The management of BE continues to evolve as new technology and more effective treatments become available.
Compared with esophagectomy, endoscopic techniques have the advantage of being less invasive with fewer complications; however, in all cases, it is important to ensure that the correct technique is being used, which requires a baseline understanding of each technique.
In general, patients with nodular disease should have this resected, and patients with early esophageal cancer should be referred for discussion at a multidisciplinary cancer group or tumor board to discuss alternative therapies to endoscopic ones.