cells is seen. This is intestinal metaplasia, which is the histologic hallmark of Barrett esophagus. To the right of the

photomicrograph, cardiac epithelium is present.

Treatment. The relief of symptoms remains the primary force driving antireflux surgery in patients

with Barrett esophagus. Healing of esophageal mucosal injury and the prevention of disease progression

are important secondary goals. In this regard, patients with Barrett esophagus are no different than the

broader population of patients with gastroesophageal reflux. Antireflux surgery should be considered

when patient factors suggest severe disease or predict the need for long-term medical management,

both of which are almost always true in patients with Barrett esophagus.

PPI therapy, both to relieve symptoms and to control any coexistent esophagitis or stricture, is an

acceptable treatment option in patients with Barrett esophagus. Once initiated, however, most patients

with Barrett esophagus will require life-long treatment. Complete control of reflux with PPI therapy can

be difficult, however, as has been highlighted by studies of acid breakthrough while on therapy. Katzka

and Castell, and Ouatu-Lascar and Triadafilopolous have shown that 40% to 80% of patients with

Barrett esophagus continue to experience abnormal esophageal acid exposure despite up to 20 mg twice

daily of PPI.135,136 Ablation trials have shown that mean doses of 56 mg of omeprazole are necessary to

normalize 24-hour esophageal pH studies.137 Antireflux surgery likely results in more reproducible and

reliable elimination of reflux of both acid and duodenal content, although long-term outcome studies

suggest that as many as 25% of patients postfundoplication will have persistent pathologic esophageal

acid exposure confirmed by 24-hour pH studies.138

An important consideration is that patients with Barrett esophagus generally have severe GERD, with

its attendant sequelae such as large hiatal hernia, stricture, shortened esophagus, and poor motility.

Compared to mild and nonerosive reflux disease, severe erosive disease and Barrett esophagus are

associated with significantly greater loss of the mechanical antireflux barrier because of associated

hiatal hernias and a hypotensive lower esophageal sphincter. Surgical treatment with a laparoscopic

Nissen fundoplication reduces the hiatal hernia, improves the antireflux barrier, and consequently

provides similarly excellent symptom control.139 Large studies in patients with typical acid reflux

symptoms have been published from the United States and Europe.140–143 In patients having

laparoscopic Nissen fundoplication at Emory University, relief of heartburn and regurgitation occurred

in 90%, and 70% were off all reflux medications at a mean follow-up of 11 years.144 These results

emphasize the durability of the procedure as well as the persistent relief of typical symptoms. Risk

factors for persistent use of antacids after antireflux surgery include a partial fundoplication, older age,

and female gender.145

Studies focusing on the symptomatic outcome following antireflux surgery in patients with Barrett

esophagus document excellent to good results in 72% to 95% of patients at 5 years following

surgery.138–140 The outcome of laparoscopic Nissen fundoplication in patients with Barrett esophagus has

been assessed at 1 to 3 years after surgery. Hofstetter et al. reported the experience at the University of

Southern California (USC) in 85 patients with Barrett esophagus at a median of 5 years after surgery.

Fifty-nine had long- and 26 short-segment Barrett esophagus and 50 underwent a laparoscopic antireflux

procedure.138 Reflux symptoms were absent postoperatively in 79% of the patients. Postoperative 24-

hour pH was normal in 17 of 21 patients (81%). Ninety-nine percent of the patients considered

themselves cured or improved and 97% were satisfied with the surgery. In addition to symptomatic

improvement in reflux after surgery, there is evidence that mediators of esophageal inflammation

implicated in carcinogenesis are decreased as well. Cyclooxygenase-2 (COX-2) gene expression is

elevated in the distal esophagus of reflux patients, but the expression of COX-2 and another

inflammatory mediator, interleukin 8, can be decreased in the distal esophageal mucosa after a

fundoplication.146–148

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Figure 42-33. Histologic appearance of Barrett esophagus. To the left of the photograph, columnar mucosa with abundant goblet

cells is seen. This is intestinal metaplasia, which is the histologic hallmark of Barrett esophagus. To the right of the

photomicrograph, cardiac epithelium is present.

The Development of Dysplasia in Barrett Esophagus. The prevalence of dysplasia at diagnosis in

patients presenting with Barrett esophagus ranges from 15% to 25%, and approximately 5% of patients

will develop dysplasia each year. The identification of dysplasia in Barrett epithelium rests on histologic

examination of biopsy specimens. The cytologic and tissue architectural changes are similar to those

described in ulcerative colitis (Fig. 42-33). By convention, Barrett metaplasia is currently classified into

four broad categories:

1. No dysplasia

2. Indefinite for dysplasia

3. Low-grade dysplasia

4. High-grade dysplasia

There are few prospective studies documenting the progression of nondysplastic Barrett epithelium to

low- or high-grade dysplasia. Those that are available suggest that 5% to 6% per year will progress to

dysplasia and 0.5% to 1% per year to adenocarcinoma (Table 42-2). Several newer studies have

suggested a lower rate, but these studies excluded patients that progressed within the first year of

follow-up, and in one study included those with a CLE with or without intestinal metaplasia. Once

identified, Barrett esophagus complicated by dysplasia should undergo aggressive therapy. Patients

whose biopsies are interpreted as indefinite for dysplasia should be treated with a medical regimen

consisting of 60 to 80 mg of PPI therapy for 3 months and rebiopsied. Importantly, esophagitis should

be healed prior to interpretation of the presence or absence of dysplasia. The presence of severe

inflammation makes the microscopic interpretation of dysplasia difficult. The purpose of acid

suppression therapy is to resolve inflammation that may complicate the interpretation of the biopsy

specimen. Persistent indefinite or low-grade dysplasia should be a relative indication for a Nissen

fundoplication given the evidence that in most patients low-grade dysplasia reverts to nondysplastic

intestinal metaplasia after a fundoplication. Alternatively, or if dysplasia persists after a fundoplication,

it should be ablated using radiofrequency or cryotherapy devices given evidence that ablation reduces

the risk of progression to cancer in these patients.

DIAGNOSIS

Table 42-2 Development of Dysplasia: Prospective Evaluation of 62 Patients

HGD should be confirmed by two pathologists knowledgeable in GI pathology. Numerous

esophagectomy series have shown that approximately 50% of patients thought to have only HGD will

harbor a focus of invasive carcinoma somewhere in the columnar mucosa.149–151 Any patient with

dysplasia, particularly HGD, requires careful endoscopic evaluation preferably with a high-definition

endoscope and NBI or similar technology to look for any nodules or lesions. These lesions are sites of

potential invasive cancer. If no lesion is present then the columnar mucosa should be ablated since

randomized trials have confirmed the benefit of ablation to reduce the risk of progression to cancer in

patients with HGD.

If a lesion is present it must be excised using ER techniques to determine if it is malignant and allow

assessment of the depth of invasion and tumor characteristics. The aim of EMR is to excise the area of

interest including the mucosal and submucosal layers down to the muscularis propria allowing optimal

histologic interpretation. Over a decade ago the authors showed in a small series that EMR reliable

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removed superficial esophageal adenocarcinomas and provided an excellent pathologic specimen for

evaluation. Until recently, esophagectomy was considered the standard of care for patients with HGD or

a superficial adenocarcinoma. Subsequently, high-volume esophageal centers in Europe and the United

States began offering endoscopic therapy for these lesions in appropriate patients. The authors have

confirmed that the oncologic outcome is similar in patients with HGD or intramucosal adenocarcinoma

whether they were treated with esophagectomy or endoscopic therapy, but the morbidity and mortality

rates were significantly lower with endoscopic therapy. The largest study on endoscopic therapy alone

for intramucosal adenocarcinoma comes from Wiesbaden, Germany. In this study of 1,000 patients there

was no procedure-related mortality and only a 2% major complication rate. After a mean follow-up

period of 56.6 months 96% of patients had achieved a complete response. Esophagectomy for failed

endotherapy was necessary in only 12 patients (3.7%). Metachronous lesions or local recurrence

developed in 140 patients (14.5%), but was successfully retreated endoscopically in 79% of patients.

The calculated 10-year overall survival was 75%, and only two patients died from esophageal

adenocarcinoma. These excellent results should make endoscopic therapy the preferred therapy for

intramucosal adenocarcinoma in appropriate patients. Risk factors for failure of endoscopic therapy are

still being identified, but include ultra–long segment (>8 cm) Barrett’s, poorly controlled reflux

disease, and high-grade tumor differentiation. Tumors associated with an increased risk for lymph node

metastases include those with lymphovascular invasion, size >2 cm, and invasion into the submucosa.

Treatment of Gastroesophageal Reflux Disease

Medical Treatment

GERD is one of the most prevalent conditions encountered in general medical practice. As a result,

medications for control of GERD comprise one of the largest pharmaceutical markets in the United

States and abroad. Since PPIs were introduced in the United States in 1989, a number of different agents

have emerged, each with substantial penetration in the marketplace. Data from the year 2004 reveal

that, of the top 10 expenditures for medications in the United States, the third highest dollar amount

was spent on Prevacid (lansoprazole, TAP Pharmaceutical Products, Inc., Lake Forest, Illinois; $4.0

billion), while the fourth highest was on Nexium (esomeprazole magnesium, AstraZeneca

Pharmaceuticals, Wilmington, Delaware; $3.6 billion).152,153

GERD is such a common condition that most patients with mild symptoms carry out self-medication,

particularly now that generic and over-the-counter H2

-receptor antagonists (H2RAs) and PPIs have

become widely available. When first seen with symptoms of heartburn or regurgitation without obvious

complications, patients can reasonably be placed on 8 to 12 weeks of acid suppression therapy before

extensive investigations are carried out. In many situations, symptoms successfully resolve. Patients

should be advised to elevate the head of the bed; avoid tight clothing; eat small, frequent meals; avoid

eating their nighttime meal shortly before retiring; lose weight; and avoid alcohol, coffee, chocolate,

and peppermints, which may aggravate the symptoms. Medications to promote gastric emptying, such

as metoclopramide, are beneficial in early disease but of little value in more severe disease.

The mainstay of maintenance medical therapy is acid suppression. Patients with persistent symptoms

should be given PPIs, such as omeprazole. In doses as high as 40 mg/day, they can effect an 80% to

90% reduction in gastric acidity. Such a regimen usually heals mild esophagitis, but healing may occur

in only three-fourths of patients with severe esophagitis. It is important to realize that in patients who

reflux a combination of gastric and duodenal juice, inadequate acid suppression therapy may give

symptomatic improvement while still allowing mixed reflux to occur. This can result in an environment

that allows persistent mucosal damage in an asymptomatic patient. Unfortunately, within 6 months of

discontinuation of any form of medical therapy for GERD, 80% of patients have a recurrence of

symptoms.154

In patients with reflux disease, esophageal acid exposure is reduced by up to 80% with H2RAs and up

to 95% with PPIs. Despite the superiority of the latter class of drug over the former, periods of acid

breakthrough still occur.155,156 Breakthrough occurs most commonly at nighttime and is some

justification for a split rather than a single dosing regimen. Katzka et al.155 studied 45 patients with

breakthrough reflux symptoms while on omeprazole 20 mg b.i.d. and found that 36 patients were still

refluxing, defined by a total distal esophageal acid exposure greater than 1.6%. Peghini et al.156

employed intragastric pH monitoring in 28 healthy volunteers and 17 patients with reflux disease and

found that nocturnal recovery of acid secretion (more than 1 hour) occurred in 75% of the individuals.

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