Columnar Mucosa and Intestinal Metaplasia of the Esophagus

Columnar Mucosa and Intestinal Metaplasia ofthe EsophagusFifty Years of Controversy

Steven R. DeMeester, MD,* and Tom R. DeMeester, MD†

From the Departments of *Cardiothoracic Surgery and †Surgery, The University of Southern California School of Medicine,Los Angeles, California

ObjectiveTo outline current concepts regarding etiology, diagnosis, andtreatment of intestinal metaplasia of the esophagus and cardia.

Summary Background DataPreviously, endoscopic visualization of columnar mucosa ex-tending a minimum of 3 cm into the esophagus was sufficientfor the diagnosis of Barrett’s esophagus, but subsequentlythe importance of intestinal metaplasia and the premalignantnature of Barrett’s have been recognized. It is now apparentthat shorter lengths of intestinal metaplasia are common, andshare many features of traditional 3-cm Barrett’s esophagus.

MethodsThemes and concepts pertaining to intestinal metaplasia ofthe esophagus and cardia are developed based on a reviewof the literature published between 1950 and 1999.

ResultsCardiac mucosa is the precursor of intestinal metaplasia ofthe esophagus. Both develop as a consequence of gastro-

esophageal reflux. Intestinal metaplasia, even a shortlength, is premalignant, and the presence of dysplasia indi-cates progression on the pathway to adenocarcinoma. An-tireflux surgery, as opposed to medical therapy, may in-duce regression or halt progression of intestinalmetaplasia. The presence of high-grade dysplasia is fre-quently associated with an unrecognized focus of adeno-carcinoma. Vagal-sparing esophagectomy removes thediseased esophagus and is curative in patients with high-grade dysplasia. Invasion beyond the mucosa is associatedwith a high likelihood of lymph node metastases and re-quires lymphadenectomy.

ConclusionsDespite improved understanding of this disease, controversyabout the definition and best treatment of Barrett’s esopha-gus continues, but new molecular insights, coupled with care-ful patient follow-up, should further enhance knowledge ofthis disease.

Originally the term “Barrett’s esophagus” was used todescribe an esophagus in which a portion of the normalsquamous mucosa was replaced by columnar epithelium.Since the 1950s, when the term became popularized, muchhas been learned about this condition, and new conceptscontinue to emerge that force reevaluation of this disorder.In fact, the meaning of the term Barrett’s esophagus isperhaps more ambiguous now than ever before.

HISTORY

Stomach Versus Esophagus

Since the early 1900s, the presence of ulcers within acolumnar epithelial-lined, tubular structure of the foreguthave been described. In the mid-1900s, the debate ragedover whether these ulcers were located in a tubularizedportion of stomach or in the esophagus. Using criteria“relevant to the physiologist, surgeon, and physician,” Dr.Norman Barrett, an influential British surgeon, wrote in1950 that sections of the gastrointestinal tract are defined bytheir mucosa, and therefore the esophagus is “that part of theforegut distal to the cricopharyngeal sphincter which islined by squamous epithelium.”1 He went on to state that

Correspondence: Steven R. DeMeester, MD, Dept. of Cardiothoracic Sur-gery, Norris Comprehensive Cancer Center, 1441 Eastlake Ave., MS74, Los Angeles, CA 90033.

Accepted for publication November 4, 1999.

ANNALS OF SURGERYVol. 231, No. 3, 303–321© 2000Lippincott Williams & Wilkins, Inc.

REVIEW

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when ulcers are found below the squamocolumnar junction,they represent gastric ulcers within “a pouch of stomach . . .drawn up by scar tissue into the mediastinum” or morelikely represent “examples of a congenital short esopha-gus.”

In 1953, Allison and Johnstone demonstrated that thetubularized portion of the foregut declared by Dr. Barrett tobe stomach had no peritoneal covering, normal esophagealmusculature, and typical esophageal mucous glands. Theyconcluded that “it appears better to refer to that congenitalabnormality which from the outside looks like esophagusand from the inside looks like stomach as ‘esophagus linedwith gastric mucous membrane.’ ”2 Although they calledthe mucosa “gastric,” they recognized that oxyntic cellswere not present.

In 1957, Dr. Barrett accepted the viewpoint that insome patients the columnar epithelium extended furtherproximally into the esophagus than could be accountedfor by a hiatal hernia. Further, he concurred with Allisonand Johnstone that the columnar mucosa, despite its“gastric” appearance, did not contain oxyntic cells anddid not function like gastric mucosa. He agreed to theterm “columnar-lined lower esophagus,” and subse-quently his name became synonymous with the condi-tion.

Congenital Versus Acquired

In their 1953 report, Allison and Johnstone had noted thatthe presence of a columnar-lined esophagus was usuallyassociated with a hiatal hernia, and that all of the patientshad reflux esophagitis. Still, like Dr. Barrett, they consid-ered it to be of congenital origin. Later Dr. Barrett, whilestill favoring a congenital etiology, conceded that “if thecardiac valve of a normal person were to become incompe-tent and if the lower esophagus were, as a result, to bebathed for a long time by digestive gastric juice, the squa-mous epithelium could be eaten away and totally replacedby columnar cells.”3

In 1959, Moersch et al4 reviewed the specimens from36 patients who had undergone esophageal resections atthe Mayo Clinic for esophagitis. They noted that “cellsresembling young columnar cells were seen occasionally,and thus the question of inflammatory metaplasia had tobe considered.” This was the first convincing evidencethat the columnar epithelium of Barrett’s esophagus wasacquired, and that it was caused by repetitive exposure ofthe distal esophagus to refluxed gastric juice. Subse-quently several studies, including the 1970 landmarkexperimental report by Bremner et al,5 confirmed theassociation between a columnar-lined esophagus and gas-troesophageal reflux disease (GERD), and the congenitaltheory was discarded.

Evolving Definition

The 3-cm Rule

In the late 1950s, the term Barrett’s esophagus was un-derstood to mean a columnar-lined esophagus, and thisrather vague definition persisted until the 1980s. Refine-ments in the definition came about as a result of two issues.The first was that as endoscopy became more common, itwas recognized that many patients had hiatal hernias andesophagitis, and that it was difficult and error-prone for anendoscopist to determine precisely where the esophagusended and the stomach began. In addition, Hayward in19616 had written that the “normal” esophagus could have1 to 2 cm of columnar mucosa at the distal end. Therefore,to avoid an overdiagnosis of Barrett’s resulting either fromfailure to recognize a tubularized portion of herniated stom-ach on endoscopy, or from failure to allow for the “normal”2 cm of columnar mucosa in the distal esophagus, a 3-cmrule was introduced in the early 1980s. This rule stipulatedthat a diagnosis of Barrett’s esophagus required a minimumof 3 cm of columnar mucosa to be present above theperceived gastroesophageal junction. Although various au-thors used between 2 and 5 cm of columnar mucosa, someminimum length requirement was adopted by most physi-cians and persists in the minds of many people to this day.

Importance of Intestinal Metaplasia

The second issue that forced refinement in the definitionof Barrett’s esophagus was the identification of a subset ofpatients with a columnar-lined esophagus who were at riskfor developing adenocarcinoma. In 1951, Bosher and Tay-lor7 described goblet cells indicative of intestinal metaplasiawithin a columnar-lined esophagus. In subsequent publica-tions Allison, Barrett, and others noted that the columnarmucosa of Barrett’s esophagus, although “gastric” in ap-pearance, was not normal gastric mucosa.2,3 Despite theseobservations, most physicians paid no particular attention tothe histology of the columnar lining within the esophagus.This changed in 1976 after a report by Paull et al8 describedthe results of manometrically guided biopsies at multiplelevels from 11 patients with a columnar-lined esophagus.Each patient was found to have one or a combination ofthree histologic types of columnar epithelium: a gastricfundic type composed of chief and parietal cells; a junc-tional type composed of mucous glands without parietalcells; and a specialized type with intestinal characteristicsincluding villiform surface, mucous glands, Alcian blue-staining goblet cells, and no parietal or chief cells. In these11 patients, Paull et al noted that the most prevalent type ofcolumnar epithelium was the specialized type, and whenpresent, the specialized mucosa was always found adjacentto the squamous epithelium in the most proximal portion ofthe columnar epithelium. If the specialized mucosa did notinvolve the entire columnar segment, then junctional mu-cosa was present below the specialized mucosa, and thegastric fundic type of epithelium was found most distal. The

304 DeMeester and DeMeester Ann. Surg. ● March 2000

importance of the specialized or intestinal type of epithe-lium within a columnar-lined esophagus was hinted at inthis report, in which 1 of the 11 patients was noted to havemarked dysplastic changes within an 8-cm segment of spe-cialized columnar-type epithelium. Subsequently, Haggittsuggested and Skinner and then Reid confirmed that theintestinal type of columnar mucosa was premalignant, andfurther was the only type associated with malignant degen-eration.9–11

Traditional Definition of Barrett’s

After these reports, the histology of the columnar-linedesophagus assumed great importance, and the definition ofBarrett’s esophagus evolved again to require both 3 cm ofcolumnar mucosa within the esophagus and intestinal meta-plasia in histology. Consequently, a biopsy was now nec-essary to make a diagnosis of Barrett’s. Since the mid-1980s, most physicians have restricted the term Barrett’sesophagus to patients meeting these criteria; however, itremains important even now to scrutinize the definition ofBarrett’s esophagus used when reviewing any paper writtenon the subject.

Short-Segment Barrett’s and IntestinalMetaplasia of the Cardia

Recently, with continued improvements in endoscopicequipment and the availability of potent acid-suppressionmedication capable of healing esophagitis, it has becomeevident that short tongues of columnar mucosa can be foundextending up from a well-defined gastroesophageal junc-tion. Further, biopsies from a normal-appearing gastro-esophageal junction have been found to contain microscopicfoci of intestinal metaplasia within cardiac mucosa, a con-dition referred to as intestinal metaplasia of the cardia.There is increasing evidence that, similar to traditionalBarrett’s, these short lengths of intestinal metaplasia areassociated with gastroesophageal reflux and may have ma-lignant potential.12

Current Definition

The relation between intestinal metaplasia present only atthe gastroesophageal junction, short-segment (,3 cm) Bar-rett’s, and traditional ($3 cm) Barrett’s remains controver-sial. However, an acceptable current definition of Barrett’sis a change from the normal esophageal squamous mucosato columnar mucosa of any length that is visible endoscop-ically and that on biopsy demonstrates intestinal metapla-sia.13 Using this definition, intestinal metaplasia confined tothe gastroesophageal junction would not be considered Bar-rett’s.

EPIDEMIOLOGY

The prevalence of Barrett’s esophagus is unknown, butany estimate depends significantly on the definition one uses

for Barrett’s. Using the traditional definition of at least 3 cmof columnar mucosa above the gastroesophageal junction,Barrett’s has been reported in 0.45% to 2.2% of all patientsundergoing upper endoscopy and in up to 12% of patientsundergoing endoscopy for symptoms of reflux.14 If all pa-tients with a biopsy showing intestinal metaplasia, regard-less of length, were included in the definition, then theincidence increases to 9% to 32% of unselected patientsundergoing upper endoscopy.15 Based on an autopsy series,Cameron et al16 estimated the prevalence of traditionalBarrett’s in the general population to be 376 cases per100,000 population. Consequently, they suggested that forevery known patient with Barrett’s, there might be 20 ormore unrecognized ones in the general population. It islikely that the prevalence of any length of intestinal meta-plasia within the esophagus is even greater.

ETIOLOGY

Gastroesophageal Reflux

Typically, patients with Barrett’s esophagus have theclassic gastroesophageal reflux symptoms of heartburn andregurgitation, with or without dysphagia. Often these pa-tients describe a longer duration of reflux symptoms than dopatients with reflux disease without Barrett’s.17 AmbulatorypH monitoring demonstrates excessive acid reflux into thedistal esophagus in nearly all patients with Barrett’s. Theabnormal acid exposure is primarily due to a structurallydefective lower esophageal sphincter (LES), with defects inlength, pressure, or both demonstrated manometrically inmore than 90% of patients with Barrett’s.18 In addition,patients with Barrett’s frequently have impaired esophagealmotility with low contraction amplitudes and an increasedfrequency of abnormal waveforms in the distal esophaguscompared with normal subjects.19,20 As a consequence,refluxed material is poorly cleared from the esophagus. Thecombination of frequent reflux episodes and poor clearanceallows prolonged bathing of the distal esophagus in refluxedgastric juice, resulting in severe mucosal injury.

In addition to an increased amount and exposure time ofrefluxed gastric juice, the composition of the refluxed juicelikely contributes to the pathogenesis of Barrett’s esopha-gus. The observations that gastric hypersecretion can beassociated with Barrett’s and that Barrett’s has developedafter total gastrectomy suggest that acid gastric juice is notthe sole factor responsible for this disease.21 Recent reportsare focusing on the importance of refluxed duodenal secre-tions in the development of intestinal metaplasia. Patientswho reflux both gastric and duodenal juice have been foundto have a higher prevalence of esophagitis and Barrett’sesophagus than do patients who reflux gastric juice alone.18

Analysis of the composition of reflux in 281 patients withGERD demonstrated that the patients with the greatestdegree of mucosal injury were more likely to have bothgastroduodenal and acid reflux as opposed to pure gastric

Vol. 231 ● No. 3 Columnar Mucosa and Intestinal Metaplasia of the Esophagus 305

reflux (Table 1).22 In addition, patients with Barrett’s had asignificantly higher prevalence and duration of abnormalesophageal bilirubin exposure, which is a tag for duodenaljuice, compared with patients with only esophagitis.23

Among patients with Barrett’s, significantly greater esoph-ageal bilirubin exposure has been demonstrated in those inwhom dysplasia develops (Fig. 1).

Role of Bile

Evidence is accumulating that bile salts are the noxiouscomponent in refluxed duodenal juice, and that their abilityto cause cellular injury is pH-dependent. For bile salts to

enter mucosal cells and cause injury, they must be solubleand unionized. At pH 7, greater than 90% of bile salts are insolution and completely ionized. Acidification of bile to apH of less than 2 produces irreversible precipitation. Thus,under normal physiologic gastric conditions, bile acids pre-cipitate and are of minimal significance. However, in a morealkaline gastric environment, as can occur with the use ofacid-suppression medication, bile salts are partially dissoci-ated. At a critical pH between 3 and 5, a mixture of ionizedsalt and the lipophilic, unionized acid is present. Unionizedbile salts can rapidly cross mucosal cell membranes. Onceinside the alkaline environment of the cell, they are con-verted back into their ionized form. Consequently, theybecome trapped within the cell, accumulate, and ultimatelybecome toxic to the mitochondria (Fig. 2). For bile salts toremain completely ionized and innocuous in a patient withreflux disease taking acid-suppression medication, a gastricpH of 7 must be maintained 24 hours a day, 7 days a weekfor the patient’s lifetime. Kuo and Castell24 have demon-strated that normal volunteers taking 20 mg omeprazoletwice a day spend more than 30% of a 24-hour monitoringperiod with a gastric pH of less than 4. Thus, it is likely thatsuch strict control of gastric acidity is not only impractical,but impossible unless very high doses of medication areused. Insufficient doses of medication may allow esopha-geal mucosal cell injury to occur while the patient remainsrelatively asymptomatic.25

Cellular Origin of Barrett’s

It is generally accepted that Barrett’s esophagus is anacquired condition that occurs as a consequence of gastro-esophageal reflux. This implies that these patients at onetime had normal squamous epithelium in their esophagus,and that this epithelium subsequently was replaced. Al-though most clinicians accept this concept, the sequence bywhich this occurs is controversial. Contained within thecontroversy are two issues: whether injured squamous mu-

Table 1. PREVALENCE OF INCREASEDESOPHAGEAL ACID EXPOSURE BY 24-

HOUR pH MONITORING, INCREASEDESOPHAGEAL BILIRUBIN EXPOSURE BYBILITEC PROBE, AND STRUCTURALLY

DEFECTIVE LES BY MOTILITY INPATIENTS WITH INCREASING MUCOSAL

INJURY SECONDARY TO GERD

Group

Prevalence ofIncreased

AcidExposure (%)

Prevalence ofIncreasedBilirubin

Exposure (%)

Prevalenceof

DefectiveLES (%)

1. No mucosal injury 35.4 30.0 51.52. Esophagitis 80.0* 61.4* 85.7*3. Short-segment

Barrett’s93.3* 73.3* 73.3*

4. Long-segmentBarrett’s

96.9‡ 84.4‡ 93.8†

GERD, gastroesophageal reflux disorder; LES, lower esophageal sphincter. Datafrom reference 22.* P , .05 vs. group 1; ‡P , .05 vs. groups 1 and 2; ‡ P , .05 vs. groups 1 and

3.

Figure 1. Acid and bilirubin exposure times for patients with Barrett’sesophagus with and without complications. The presence of a stricture,ulcer, low-grade dysplasia, or high-grade dysplasia was considered acomplication. The median is indicated by a line, the interquartile rangeby a box.

Figure 2. Dissociation curve for bile acids demonstrating the critical pHrange from 3 to 6 where bile acids exist in their soluble, unionized formand can penetrate cell membranes, accumulate within mucosal cells,and become toxic to the mitochondria. At pH 2, bile acids irreversiblyprecipitate from solution, whereas at pH 7, bile acids exist in theirnoninjurious ionized form.


cosa is first replaced by or transformed into columnar mu-cosa, which then undergoes a second transformation intointestinalized columnar mucosa; and whether columnar ep-ithelium and intestinalization gradually involve more of theesophagus, or whether Barrett’s rapidly develops to its fullextent with little subsequent change. The answers to thesequestions are not known with certainty, but there is anever-increasing body of data that provides insight about theprocess of esophageal columnarization and intestinalization.

Columnar-Lined Esophagus

Step 1: Transition Zone From EsophagealSquamous Mucosa to Gastric ColumnarEpithelium

When considering the effects of acid reflux on squamousesophageal epithelium, a logical place to examine is theesophagogastric junction. Amazingly, despite years of in-terest and investigation, even the normal anatomy of thisarea remains somewhat of an enigma. In 1961, Hayward6

published a visionary treatise on this area that, althoughfascinating to read, is unfortunately devoid of any support-ing data. Careful review of the manuscript, however, sug-gests that his insight into this area was based on extensivedissection in probably many subjects. He began with adiscussion of the meaning of the cardia—something equallyrelevant today. He defined the cardia anatomically as thelower portion of the esophagus between the insertion of thephrenoesophageal ligament and the gastroesophageal junc-tion (Fig. 3). The squamocolumnar junction, he noted, wasusually located just distal to the insertion of the phrenoe-sophageal ligament, and consequently a portion of the car-dia was “normally” lined by a short segment of columnarepithelium extending from the gastroesophageal junctionproximally to the squamocolumnar junction. He called thiscolumnar mucosa junctional epithelium, and noted that ithad the following characteristics:

● It was histologically distinct from normal gastric fundicand pyloric epithelium.

● It did not secrete acid or pepsin but was resistant toboth.

● It was not congenital but acquired.● It was mobile and varied in length, creeping progres-

sively higher into the esophagus with continued gastro-esophageal reflux.

● It was potentially reversible with correction of reflux.

Hayward clearly placed the anatomic cardia and the lin-ing junctional mucosa within the lower esophagus. Unfor-tunately, there has been substantial confusion generated bythe terminology used to describe this area. The confusioncenters around the fact that anatomists have divided thestomach into five parts, with the area around the esophago-gastric junction labeled as the cardiac portion of the stom-ach. Despite the different names, there are no discernible

histologic differences between gastric mucosa in the fundusor body of the stomach, and the mucosa immediately distalto the gastroesophageal junction. All three sites are charac-terized by pure oxyntic mucosa. In contrast, the cardia, asdescribed by Hayward, refers to the lower end of the esoph-agus in the region of the LES. It was from this cardia region,or the distal esophagus near the gastroesophageal junction,that Hayward identified the histologically distinct epithe-lium that he called junctional mucosa. In the years sinceHayward’s article, junctional mucosa has come to be calledcardiac mucosa. Therefore, it is important not to confuse thecardiac region of the stomach, which is located distal to thegastroesophageal junction and has oxyntic mucosa, with thecardia, which is located at and proximal to the gastroesoph-ageal junction in the distal esophagus, and may be lined bycardiac (formally known as junctional) mucosa.

Perhaps rather than focusing exclusively on the anatom-ical region, it would be best to combine the anatomic regionwith the histology at that location to distinguish reliablybetween distal esophagus and stomach. An important andunresolved issue is what is the “normal” mucosa at theesophagogastric junction. Recall that Hayward stated that“normally” the mucosa in this region was columnar, butdistinct from gastric fundic mucosa, and was not congenitalbut acquired. Perhaps by “normal” he meant common, be-

Figure 3. Hayward’s depiction of the gastroesophageal junction andregion of the cardia. Line X-Y crosses the esophagogastric junction.Everything above the line is esophagus, and everything below is stom-ach. From A to C is esophagus lined by squamous epithelium. Thephrenoesophageal ligament inserts at B. From B to D is the area of theesophagus called the cardia. It is partially lined by squamous epithelium(from B to C) and partially lined by cardiac mucosa (from C to D).Cardiac mucosa joins with fundic gastric mucosa at point E, whereaspure fundic mucosa is present at point F. (From Hayward J. The lowerend of the esophagus. Thorax 1961; 16:36–41. Reproduced with per-mission from the BMJ Publishing Group.)


cause he recognized that it was not present at birth. Re-cently, Chandrasoma26 conducted a review of the gastro-esophageal junction in a large number of autopsies in whichthere was no mention of GERD in the medical record. Hedetermined that in most children and adults younger than 20years of age, the squamous esophageal epithelium transi-tioned directly with oxyntic mucosa of the gastric fundus,with no interposed segment of cardiac (junctional-type)epithelium. Cardiac mucosa appeared in specimens fromthose older than 20 years, but its length was almost alwaysless than 1 cm. From this he concluded that in the normal,nonrefluxing state, squamous esophageal epitheliumchanges abruptly to oxyntic mucosa of the gastric fundus.However, the presence of a small length of cardiac mucosais common in adults.

Oxyntic mucosa, like that found in the stomach near thegastroesophageal junction, is not affected by acid. Conse-quently, it is logical to conclude that cardiac mucosa, if notpresent at birth, must develop from injured squamous epi-thelium. This likely involves a change in the direction ofdifferentiation of the germinative squamous epithelial cellstoward more acid-resistant columnar cells as a consequenceof repetitive exposure to acidic gastroesophageal reflux. Inkeeping with the concept that cardiac mucosa representstransformed squamous mucosa, cardiac mucosa is the sim-plest type of columnar epithelium. It is characterized histo-logically by the presence of only columnar cells and mucouscells. There are no specialized cells such as parietal cells,chief cells, or goblet cells.

The hypothesis that cardiac mucosa develops as a conse-quence of acid-induced injury to esophageal squamous ep-ithelium is supported by both animal and clinical evidence.Experimental evidence comes from a 1970 study by Brem-ner et al.5 In this study a series of dogs underwent strippingof the distal esophageal squamous mucosa with or withoutcreation of a cardioplasty to destroy the function of the LES.They noted extensive squamous cell reepithelialization inthe animals without gastroesophageal reflux, whereas squa-mous regeneration was absent or minimal in the animalswith cardioplasty-induced acid reflux. In the animals withreflux, the esophagus was reepithelialized by a columnarepithelium that lacked submucosal glands and parietalcells—the equivalent of cardiac mucosa in humans. Evi-dence that columnar mucosa can replace normal esophagealsquamous epithelium in humans comes from follow-upstudies in patients who have undergone partial esophago-gastrectomy with an intrathoracic anastomosis of the esoph-agus to the fundus of the stomach. This arrangement leadsto a near-constant bathing of the remaining esophagus inrefluxed gastric juice, and over months to years columnarepithelium histologically identical to cardiac mucosa hasdeveloped proximal to the anastomosis in what was unques-tionably the esophagus, and in what unquestionably hadbeen squamous epithelium. In a report by Lindahl et al,27

the mean time to detection of cardiac mucosa above theanastomosis was 8.2 years (range 2.2–13.9 years).

Therefore, it is our opinion that in the truly normal orcongenital state, squamous esophageal mucosa endsabruptly at the gastroesophageal junction and abuts theoxyntic mucosa of the stomach. However, in many or per-haps most older children and adults, chronic, low-levelreflux occurs, and repetitive bathing of the squamous mu-cosa at the gastroesophageal junction with gastric juiceinduces the development of cardiac-type columnar mucosa.Recently, we reported that most of the patients being eval-uated for symptoms of gastroesophageal reflux had cardiacmucosa juxtaposed between esophageal squamous and gas-tric fundic mucosa.28 Further, the cardiac epithelium almostalways had histologic evidence of inflammation unrelated toeither Helicobacter pyloriinfection or mucosal pathologyelsewhere in the stomach. Instead, the presence of inflamedcardiac mucosa, or carditis, correlated closely with objec-tive markers of GERD, including an incompetent LES,increased esophageal acid exposure on 24-hour pH moni-toring, a hiatal hernia, and erosive esophagitis. We sug-gested that carditis may represent the earliest manifestationof reflux disease, and that with continued reflux there mightbe a creeping columnarization of the squamous epitheliumwithin the LES, a progressive loss of sphincter competency,and ultimately explosion of the disease into the body of theesophagus.28

Step 2: Extension of Columnar MucosaProximally Into the Distal Esophagus

Exposure of the squamous esophageal mucosa to gastricjuice in persons without prior surgery is most likely to occurpostprandially, when the stomach is distended and the distalesophageal sphincter is taken up by the enlarging fundus.29

Csendes et al30 have demonstrated that with increasingseverity of gastroesophageal reflux, the squamocolumnarjunction progressively shifts or creeps proximally, resultingin a gradual increase in the length of cardiac-type columnarmucosa within the esophagus. In addition, studies using24-hour pH monitoring have shown that as acid exposureincreases, the length of columnar mucosa within the esoph-agus steadily and significantly increases as well (Fig. 4).31

The importance of this progressive increase in the lengthof cardiac-type columnar mucosa in the esophagus withincreasing severity of GERD lies in the direct correlationbetween the length of cardiac mucosa and the likelihood offinding an area of intestinal metaplasia. We found that theprevalence of any intestinalization within cardiac mucosaincreased from 12% when cardiac mucosa was limited tothe gastroesophageal junction, to 50% with less than 3 cm,and nearly 100% with 3 cm or more of cardiac mucosa (Fig.5). Spechler et al32 reported similar findings. They notedthat 36% of patients with a 1- to 2-cm columnar segment inthe esophagus had intestinal metaplasia, and this increasedto 93% of patients when the columnar segment was 3 cm inlength or more.


Step 3: Intestinalization of Cardiac Mucosa

The primary importance of inflamed cardiac mucosa isthat it seems to represent the only mucosal type that canprogress to intestinal metaplasia.26 Intestinalization of thecardiac mucosa occurs when hypertrophic cardiac mucouscells develop acid rather than neutral mucin and, mostimportantly, goblet cells appear. Once intestinalized, thecardiac mucosa seems to have an increased ability to with-stand damage by refluxed gastric juice, because there com-monly is little or no inflammation present on biopsy. How-ever, the development of intestinal metaplasia withincardiac mucosa is considered a detrimental or progressivechange, because this mucosa is capable of further progres-sion to epithelial dysplasia and adenocarcinoma. Availableevidence would suggest that cardiac mucosa itself is benign,and that it is only with the development of intestinal meta-plasia that the mucosa becomes premalignant.26

The specific cellular event that induces a change fromcardiac mucosa to intestinalized cardiac mucosa is un-known. Current theories support a second insult, perhapsfrom noxious luminal contents. Data from our esophageallaboratory on patients with short lengths of columnar mu-cosa in the esophagus suggests that compared with patientswithout intestinal metaplasia, those with intestinal metapla-sia tend to have a longer duration of symptoms (5 vs. 10years) and a greater frequency of abnormal exposure torefluxed bilirubin, as determined by Bilitec probe(Medtronic Functional Diagnostics, Shoreview, MN) mon-itoring for 24 hours. The frequency of abnormal acid expo-sure by 24-hour pH monitoring was similar between groups(DeMeester TR, unpublished data).

It is also unclear whether the development of intestinalmetaplasia represents a phenotypic change secondary to theinduction of genes, or a mutational event within the colum-nar cells. Mendes de Almeida et al33 have demonstratedbiochemically that both cardiac mucosa and intestinal meta-plasia express sucrase-isomaltase and crypt cell antigen, two

small intestine marker proteins; however, in that study onlythree patients with cardiac mucosa were evaluated. Re-cently, Griffel et al34 have shown that the murine antibodyDAS-1, which stains specialized columnar mucosa, reactspositively with cardiac mucosa, and that on repeat biopsieshistologic evidence of intestinalization later developed insix of the seven patients. If true, these findings wouldsuggest that biochemically cardiac mucosa and intestinalmetaplasia are similar, and that cardiac mucosa is the pre-cursor of intestinalized columnar epithelium, or Barrett’s.

Fitzgerald et al35 have recently suggested that the dynam-ics of acid exposure may effect columnar cell proliferationand differentiation. Using cultured human Barrett’s biopsyspecimens, they demonstrated that continuous exposure toacidic media at pH 3.5 resulted in increased villin expres-sion (a marker for epithelial cell differentiation) and re-duced cell proliferation. In contrast, villin expression wasnot detected when the culture medium was made moreacidic (pH , 2.5). A dramatic increase in proliferationoccurred when the Barrett’s tissue was exposed to a short(1-hour) pulse of acidic medium (pH 3.5) followed by areturn to neutral pH. Consequently, alterations in luminalpH and the pattern of exposure may lead to altered growthproperties and may contribute to the molecular and struc-tural heterogeneity seen in the esophageal mucosa of pa-tients with Barrett’s.

Intestinal Metaplasia of the Cardia

One unresolved issue is whether intestinal metaplasialimited to the region of the gastroesophageal junction de-velops in response to the same stimuli that produce tradi-tional, or long-segment, Barrett’s esophagus. Recently, wereviewed 411 patients with cardiac mucosa either at the

Figure 5. The prevalence of intestinal metaplasia in cardiac-type mu-cosa of varying extents: limited to the gastroesophageal (GE) junctionand involving short (,3 cm) and long ($3 cm) segments of the esoph-ageal body. (Reproduced with permission from Oberg S, DeMeesterTR, Peters JH, et al. The extent of Barrett’s esophagus depends on thestatus of the lower esophageal sphincter and the degree of esophagealacid exposure. J Thorac Cardiovasc Surg 1999; 117:572–580.)

Figure 4. Correlation between acid exposure as determined by 24-hour pH monitoring and the length of cardiac-type columnar epitheliumwithout intestinal metaplasia in the esophagus. The length of cardiacmucosa was measured from the endoscopic gastroesophageal junc-tion to the site of the highest biopsy showing cardiac-type columnarepithelium on histologic examination.


gastroesophageal junction or extending up into the esopha-gus, and found that overall 35% of patients had intestinalmetaplasia. When only the patients with intestinal metapla-sia were compared, we noted that the length of intestinalmetaplasia was inversely correlated with LES pressure andoverall length and directly correlated with the percentage oftime spent at less than pH 4 on 24-hour esophageal pHmonitoring.36 Our interpretation of this data is that bothintestinal metaplasia limited to the gastroesophageal junc-tion (CIM) and Barrett’s are related through the commondenominator of cardiac mucosa, and that CIM, Barrett’s,and cardiac mucosa are all linked to gastroesophageal re-flux. Others, including Goldblum et al,37 have publishedtheir opinion that intestinal metaplasia of the gastroesoph-ageal junction is related toH. pylori infection and intestinalmetaplasia in the stomach. One problem is that they failedto distinguish clearly between gastric fundic and cardiacmucosa, as evidenced by the histologic finding of parietalcells on several “cardiac” biopsy specimens. Further, theirstudy was flawed in that it lacked a reliable control group ofpatients, because 7% of the nonreflux “control” patientswere found to have esophagitis on endoscopy. CertainlyH.pylori infection and intestinalization of the stomach arepresent in some patients with intestinal metaplasia of thegastroesophageal junction. However, the intestinal metapla-sia related toH. pylori infection in these patients is oftendiffuse throughout the stomach. Intestinal metaplasia lim-ited to the gastroesophageal junction does not appear relatedto eitherH. pylori infection or intestinal metaplasia of thestomach.28,38,39

Location of Intestinal Metaplasia Withina Columnar-Lined Esophagus

Interestingly, as first described in the report by Paull etal,8 when intestinal metaplasia is found within cardiac mu-cosa, it is always present at the most proximal portion of thecolumnar mucosa at the squamocolumnar junction. Al-though intestinal metaplasia may involve the entire colum-nar segment, often an area of cardiac mucosa without in-testinal metaplasia is found distally near the gastro-esophageal junction. Morales et al40 and others have usedthis finding to suggest that CIM and Barrett’s are not re-lated, or at least that CIM is not the precursor of Barrett’s.41

Instead, we propose that this observation supports the con-cept that intestinalization of cardiac mucosa and prolifera-tion of Barrett’s occur as a consequence of the compositionand pH of the refluxed juice and the pulsatile or continuousnature of the exposure. Extrapolating from the work ofFitzgerald et al,35 it is conceivable that because the proximalportion of the columnar segment is the area furthest awayfrom the stomach, it is the area most likely to be exposed ina more continuous manner to a pH of 3.5 or greater due tothe mixing of refluxed gastric juice and saliva. This wouldstimulate increased cellular differentiation and less prolif-eration, creating the opportunity for the development of

intestinal metaplasia. If CIM and Barrett’s represent twounrelated conditions, each caused by different factors, thenin some patients the two conditions should exist simulta-neously—in other words, there should be some patientswith intestinal metaplasia at both the proximal and distalends of a segment of columnar epithelium, with cardiacmucosa in between. This does not occur. Rather, patientseither have intestinal metaplasia throughout the entirelength of the columnar epithelium, or it is confined to theproximal end of the columnar segment, and cardiac mucosawithout goblet cells is found distally.

Time Interval From Columnar toIntestinalized Columnar Mucosa

There is increasing evidence, particularly from follow-upstudies in children, that cardiac-type columnar mucosa de-velops within the esophagus initially, and with time intes-tinalization may occur. In a series of 11 children aged 1.1 to13.3 years (average 5.9 years) with symptoms of gastro-esophageal reflux and a columnar-lined esophagus, Cooperet al42 found that only 1 child had intestinal metaplasia onbiopsy. In older children, Hassall et al43 and Hoeffel et al44

reported the presence of intestinal metaplasia within a co-lumnar-lined esophagus, and in two patients (ages 11 and16), adenocarcinoma was found within the Barrett’s. Qual-man et al45 followed up 28 pediatric and 38 adult patientswith a columnar-lined esophagus and noted that comparedwith the pediatric patients, the percentage of adult patientswith goblet cells and intestinal metaplasia was significantlyincreased. The youngest patient with goblet cells in theirreport was a 5-year-old with intestinal metaplasia foundonly at the gastroesophageal junction. They also describedone 10-year-old patient with a columnar-lined esophaguswithout intestinal metaplasia who was followed up withserial endoscopies and biopsies; at age 15, goblet cellsdeveloped in this patient.

Another source for information about the time intervalfrom cardiac mucosa to intestinalized columnar epitheliumare reports documenting follow-up on patients after esoph-agectomy with gastric pull-up reconstruction. In a review of17 patients who had undergone partial esophagectomy withintrathoracic esophagogastrostomy, Hamilton and Yard-ley46 noted that columnar mucosa had developed above theesophagogastric anastomosis in 10 of the 17 patients. Theynoted that cardiac-type columnar mucosa without gobletcells could be found as soon as 2 months after surgery in anarea that had previously been histologically shown to besquamous epithelium. In two patients, intestinal metaplasiawas found within the cardiac mucosa at the squamousjunction at 76 and 106 months after surgery.

These findings would suggest that cardiac mucosa is theprecursor of intestinal metaplasia, and that the process ofintestinalization occurs sequentially over a period of at least5 years. In contrast to this stepwise extension theory is thecommon belief that Barrett’s develops rapidly and to its full


extent with little subsequent change. This concept is basedlargely on a study by Cameron et al47 in which 21 patientswith 3 cm or more of intestinal metaplasia were followed upfor a mean of 7.3 years. At the end of follow-up, the lengthof Barrett’s was not significantly different from what it hadbeen initially, and the mean length of Barrett’s was similarin all age groups. However, we contend that patients withlong segments of Barrett’s uniformly have profound defectsin LES function, and further deterioration would not beexpected. Consequently, the fact that the length of Barrett’sdid not change in their study is not surprising. Importantfuture studies documenting the natural history of short-segment Barrett’s and intestinal metaplasia limited to thecardia should help clarify this issue.

METAPLASIA, DYSPLASIA,CARCINOMA SEQUENCE

The development of intestinal metaplasia within cardiacmucosa heralds the onset of a mucosal change that ulti-mately may lead to the development of esophageal adeno-carcinoma. Consequently, the term “benign Barrett’s” is anoxymoron. With continued inflammation and irritation ofthe metaplastic intestinal epithelium, some patients willprogress through low-grade dysplasia, high-grade dysplasia,and subsequently invasive adenocarcinoma. It is unknownwhether the movement toward cancer is due to mitogenesissecondary to chronic mucosal injury, or mutagenesis as aconsequence of exposure to a mutagen. One theory is thatbile salts in their unionized state act as mutagens, andstudies are underway to investigate this possibility. In ourlaboratory, cell culture studies indicate that repetitive shortexposure of cells to bile salts at a pH of 5 to 7 increases themutation frequency without altering the growth curve of thecultured cells (DeMeester TR, unpublished data). If bilesalts are demonstrated to contribute to the development ofmalignancy, then early intervention with an antireflux pro-cedure should be encouraged. The precise risk of develop-ing adenocarcinoma in patients with Barrett’s esophagus isunknown; however, it likely is 0.2% to 2.1% per year for apatient without dysplasia, which is an incidence 30 to 125times that of the general population.48 A common estimateis that there will be one cancer found for each 100 patient-years of follow-up. This increased incidence of cancer is therationale for enrolling all patients with Barrett’s esophagusin a surveillance program, and heightening the surveillancein patients with low-grade dysplasia.

Although intestinal metaplasia is itself a premalignantcondition, the development of high-grade dysplasia is asso-ciated with a significantly increased risk for adenocarci-noma. Several reports have correlated the progression ofdysplasia within Barrett’s with other cellular and genomicalterations, including mutations of the tumor suppressorgene p53, aneuploidy, and loss of the Y chromosome.49–52

Importantly, any focus of intestinal metaplasia is capable ofundergoing dysplastic change and ultimately becoming an

invasive adenocarcinoma. Cameron and Carpenter53 havedemonstrated that areas of dysplasia and cancer within longsegments of intestinal metaplasia are often small andpatchy, and that microscopic areas of different grades ofdysplasia are often dispersed throughout the Barrett’s. Theysuggested that dysplasia develops simultaneously in manyareas and ultimately becomes confluent rather than spread-ing progressively outward from one site. In addition, theynoted that cancers developed throughout the length of theintestinal metaplasia, including distally near the stomach.This is in contrast to prior reports indicating that the cancersalways occur near the squamocolumnar junction at theproximal extent of the Barrett’s. This is likely a conse-quence of imprecision in the use of the term Barrett’s. Asnoted above, if intestinal metaplasia is present in a segmentof columnar epithelium, it is always at the proximal end ofthe columnar segment. It may extend distally to involvemost or all of the columnar segment, but it may be limitedto the area near the squamocolumnar junction. Becauseavailable evidence suggests that adenocarcinoma occursonly within areas of intestinal metaplasia, it is likely that inthese prior reports the intestinal metaplasia was limited tothe proximal portion of the columnar-lined distal esopha-gus.

DIAGNOSIS

When performing an esophagogastroduodenoscopy, theendoscopist should carefully note the location of the gas-troesophageal and squamocolumnar junctions as well as thecrura. Barrett’s esophagus should be suspected when thegastroesophageal junction is located distal to the squamo-columnar junction, or when there are pink tongues of gas-tric-like mucosa extending up into the esophagus above analigned gastroesophageal and squamocolumnar junction.Precise determination of the gastroesophageal junction canbe difficult in these patients because frequently a hiatalhernia is present, and as a group patients with Barrett’s havea very low LES pressure.13 Identification of the proximalmargin of the gastric folds with the stomach and esophagusdeflated facilitates localization of the gastroesophagealjunction.54

Because both erosive esophagitis and erythema of theesophagus may be confused visually with Barrett’s, confir-mation of the diagnosis requires histologic identification ofgoblet cells within a columnar mucosa devoid of parietalcells. To maximize the likelihood of identifying intestinalmetaplasia, multiple biopsy samples should be taken at theproximal extent of the columnar mucosa, just below thesquamocolumnar junction, where intestinal metaplasia, ifpresent, will always be found.8 If there is endoscopic sus-picion of Barrett’s, the endoscopist should ascertain thelength of involved esophagus and carefully examine themucosa for any suspicious lesions. Biopsies of all mucosalabnormalities should be performed; in addition, once adiagnosis of Barrett’s is established, biopsies should be


obtained at 1- to 2-cm intervals throughout the length of themetaplastic mucosa to evaluate for the presence of dyspla-sia.

Patients with intestinal metaplasia limited to the cardia donot have an endoscopically visible area of columnar epithe-lium within the esophagus. Thus, diagnosing CIM requiresthat biopsy samples be taken from a normal-appearing gas-troesophageal junction. A combination of circumferentialantegrade biopsies as well as biopsies taken with the esoph-agoscope retroflexed in the stomach will most reliably iden-tify CIM. These biopsies, in our opinion, should be astandard part of the endoscopic evaluation of all patientssuspected of having GERD.

TREATMENT

Surveillance Endoscopy

The rationale for endoscopic surveillance in patients withBarrett’s is straightforward: to detect progression of diseasetoward cancer, and to allow early intervention while cure isstill likely. Predicated on this rationale is the concept thatthe surveillance will be frequent enough that rarely, if ever,does the disease progress beyond an early, curable stageduring the surveillance interval, and that once disease pro-gression is detected, an intervention is performed. Contin-ued surveillance despite disease progression may help clar-ify the natural history of the disease but does little to benefitthe patient. Controversy exists, however, about the point atwhich there has been sufficient progression to warrant in-tervention, and what intervention should be done.

Provenzale et al48 used a Markov model of decisionanalysis to demonstrate that aggressive endoscopic surveil-lance combined with esophagectomy for high-grade dyspla-sia would markedly reduce the incidence of cancer in pa-tients with Barrett’s esophagus and would increase bothoverall and quality-adjusted life expectancy. The predic-tions of the model have now been verified in several clinicalseries. We and others have reported that patients with ade-nocarcinoma detected within a surveillance program presentat an earlier stage and have a significantly improved long-term survival after esophagectomy compared with patientswho present de novo with symptoms.55,56

The cost effectiveness of surveillance endoscopy for Bar-rett’s has recently been compared with mammography forthe detection of breast cancer (Table 2).57 The cost percancer detected and the cost per patient cured were similar,but the cost per life-year saved was dramatically lower forsurveillance endoscopy in Barrett’s patients than mammog-raphy in women. This likely is because outside of a surveil-lance program, esophageal cancer often presents in an ad-vanced stage, and the clinical course is rapidly fatal. Incontrast, the lag time between mammographic and palpabledetection of breast cancer is shorter, and the clinical coursewith breast cancer is often protracted.

The recommended frequency for endoscopic surveillance

in patients with Barrett’s is based on available data aboutthe likelihood and rapidity of progression. Important factorsinclude the length of intestinal metaplasia and whetherdysplasia is present. In longer segments of intestinal meta-plasia, there is more mucosa at risk for progression, andpatients with low-grade dysplasia have already moved astep closer to cancer. We advise our patients with any lengthof intestinal metaplasia within the esophagus to have yearlyendoscopy, and we increase the frequency to every 3 to 6months for patients with dysplasia. Sampliner and the Prac-tice Parameters Committee of the American College ofGastroenterology13 have recently suggested that surveil-lance may be extended to every 2 to 3 years in Barrett’spatients lacking dysplasia on systematic biopsy at two en-doscopies. For patients with low-grade dysplasia, they rec-ommend that surveillance endoscopy be performed at6-month intervals for the first year, and subsequently doneyearly if there has been no change.

Medical Therapy of Barrett’s

There are three goals for treating patients with Barrett’sesophagus: stop reflux, promote or induce healing or regres-sion of the metaplastic epithelium such that the risk mucosa(intestinal metaplasia) is eliminated, and halt progression todysplasia and cancer. Most patients with Barrett’s aretreated medically; however, adequate medical therapy isdifficult because of the degree of impairment of the LES andthe poor esophageal body motility frequently present inpatients with Barrett’s. This is likely the reason why theleast controlled symptom in patients with Barrett’s receiv-ing medical treatment is regurgitation.58 Medical treatmentoptions are limited to dietary and lifestyle modifications,promotility agents, and acid-suppression therapy. Recently,Sampliner and the Practice Parameters Committee of theAmerican College of Gastroenterology13 stated that “thegoal of therapy of Barrett’s esophagus should be the controlof the symptoms of GERD” and that “symptom relief is anappropriate endpoint for the therapy of Barrett’s esopha-

Table 2. COMPARISON OF COST OFSURVEILLANCE MAMMOGRAPHY FOR

BREAST CANCER TO COST OFSURVEILLANCE ENDOSCOPY FOR

PATIENTS WITH BARRETT’S ESOPHAGUS

Breast Cancer/Mammography

Barrett’s Esophagus/EGD

Cost per cancerdetected

$54,513 $37,928

Cost per cure $83,292 $83,340Cost per life-year saved $57,926 $ 4,151

EGD, esophagogastroduodenoscopy.Data from reference 57.


gus.” However, this viewpoint flies in the face of logic.Gastroesophageal reflux causes both Barrett’s and esopha-geal cancer. Symptoms are not part of the pathophysiologyof the disease; rather, they are merely the variably expressedbyproduct of reflux. Many patients with Barrett’s have fewor no reflux symptoms, probably as a consequence of analtered sensitivity of the metaplastic epithelium to refluxedacid. Consequently, the eradication of symptoms, if present,cannot be equated with elimination of reflux. Katzka andCastell59 demonstrated that standard-dose omeprazole (20mg/day) fails to suppress acid sufficiently to keep gastric pHneutral for a full 24 hours in patients with Barrett’s. Further,increasing the dose of omeprazole until all symptoms werealleviated was an unreliable measure of effective therapy,because 80% of patients studied with 24-hour pH monitor-ing still had abnormal distal esophageal acid exposure.Sampliner likewise found that high-dose proton pump in-hibitor administration (lanisoprazole, 60 mg/day) failed tonormalize the 24-hour pH test in more than one third ofpatients with Barrett’s tested while receiving therapy.58

Consequently, for medical therapy to achieve the first ofthe three goals of treatment for patients with Barrett’s,prevention of reflux, the medical therapy will have to beaggressive and not guided by symptoms. Most patientsrequire a minimum of twice-daily omeprazole. All patientsshould be tested while receiving acid-suppression therapywith 24-hour pH monitoring, and as suggested by Castell etal,60 the majority are likely to demonstrate night-time acidbreakthrough and will need an evening dose of an H2

receptor antagonist in addition to the twice-daily protonpump inhibitor. Lastly, given the concern about creatingunionized, lipophilic bile salts, it may be that the endpointof acid suppression in these patients needs to be a gastric pHof 7 rather than just a pH of more than 4.25 In the finalanalysis, incomplete therapy may prove to be worse than notherapy.

The second and third goals of therapy in patients withBarrett’s are to eliminate the risk mucosa (i.e., intestinalmetaplasia) and to prevent progression to dysplasia andcancer. Medical therapy has not been shown to achieveeither of these goals reliably. Several reports have con-cluded that medical therapy does not cause regression ofintestinal metaplasia.61–63This may be different in patientswith short-segment Barrett’s. Weston et al64 have describedthe loss of goblet cells from lengths of intestinal metaplasialess than 2 cm in 32% of patients treated medically for 1 to3 years. In contrast, only 2 of 29 patients (7%) with lengthsof intestinal metaplasia 3 cm or more had loss of gobletcells.

With respect to the efficacy of medical therapy in pre-venting progression of Barrett’s to dysplasia and cancer,there is speculation that prolonged and perhaps inadequateacid suppression may actually promote the development ofBarrett’s and the complications of Barrett’s.25 Lagergren etal65 recently reported that the risk of esophageal adenocar-cinoma was increased nearly eightfold among persons in

whom heartburn, regurgitation, or both occurred at leastonce a week compared with persons without these symp-toms. Interestingly, they noted that the risk of esophagealadenocarcinoma was three times higher among patients whoused medication for symptoms of reflux compared withthose who did not use acid suppression medications. Others,including Ortiz et al62 and Hameeteman et al,66 have alsolinked medical therapy for Barrett’s esophagus with pro-gression to dysplasia and adenocarcinoma. In the study byHameeteman et al from the Netherlands, 50 patients with acolumnar-lined esophagus were treated medically and fol-lowed up from 1.5 to 14 years (mean 5.2 years). Of these 50patients, initially only 34 had intestinal metaplasia on bi-opsy of the columnar mucosa. At the completion of thestudy, 37 patients had intestinal metaplasia, indicating thatBarrett’s developed in 3 patients during the 5-year studyperiod. In addition, at the start of the study, six patients hadlow-grade dysplasia and one patient had high-grade dyspla-sia. By the end of the 5-year study period, 10 patients hadlow-grade dysplasia, 3 had high-grade dysplasia, and 5 hadadenocarcinoma.66 Similarly, Sharma et al67 followed 32medically treated patients with short-segment Barrett’s(mean length 1.5 cm) for a mean of 36.9 months and founda 5.7% annual incidence of progression to dysplasia. Duringthe 98 patient-years of follow-up in their series, high-gradedysplasia developed in two patients, and one of these pa-tients progressed to cancer. Recall that the expected rate ofcancer is 1 per 100 patient-years of follow-up. All patientsin the study by Sharma et al were treated with omeprazole,ranitidine, and/or promotility agents. They commented thatmost patients developed dysplasia while taking acid-sup-pression medication, and they concluded that medical treat-ment does not prevent the development of dysplasia.

Antireflux Surgery for Barrett’s

Some of the problems and concerns associated with med-ical therapy for Barrett’s include issues about patient com-pliance, the safety of long-term high-dose acid-suppressiontherapy, and the prompt return of symptoms after drugwithdrawal. In contrast, antireflux surgery restores LESfunction and abolishes reflux of gastric contents into theesophagus. Consequently, an antireflux operation ends therepetitive injury to both the metaplastic and normal esoph-ageal mucosa. Randomized clinical studies have confirmedsuperior control of reflux after antireflux surgery comparedwith medical therapy, and antireflux surgery has beenproven safe, effective, and durable.62,68 In addition, manypatients are candidates for a minimally invasive laparo-scopic approach associated with a short hospital stay andrapid recovery. We therefore favor the performance of anantireflux procedure in patients with Barrett’s.

There have been conflicting reports about whether intes-tinal metaplasia regresses after antireflux surgery. Brand etal, in 1980,69 described complete regression in 4 of 10patients with Barrett’s who underwent fundoplication. Sub-


sequently, most reports have demonstrated that althoughsome regression of the length of Barrett’s is common,complete regression occurs only rarely. Review of the En-glish language literature since 1977 documents follow-upon 340 patients after antireflux surgery.10,62,69–77Completeregression occurred in only 13 patients; in 256 of the 340patients (74%), the Barrett’s epithelium remained un-changed (Fig. 6). Thus, the available literature would sug-gest that regression of traditional Barrett’s cannot reliablybe predicted or anticipated after antireflux surgery.

In contrast to the unreliable regression of traditional or3-cm segments of Barrett’s, we recently demonstrated that73% of patients with intestinal metaplasia at the gastro-esophageal junction had complete regression after antirefluxsurgery.78 By comparison, only 4% of patients with anendoscopically visible segment of Barrett’s had loss ofintestinal metaplasia after an antireflux procedure. Many ofthese patients demonstrated the development of squamousislands or a shorter length of Barrett’s, but in our opinionregression should be considered only when there has beencomplete loss of the mucosa at risk for malignant degener-ation. Recently, Low et al79 also reported complete regres-sion of Barrett’s esophagus after antireflux surgery. In theirreport, loss of intestinal metaplasia occurred in 2 of 14patients followed up for a mean of 25 months after surgery.

Perhaps of greater importance is the issue of progressionof Barrett’s to dysplasia or cancer after surgical treatment ofreflux disease. Compared with medical therapy, antirefluxsurgery is associated with a reduced incidence of dysplasiaand adenocarcinoma. McCallum et al80 prospectively fol-lowed 181 patients with Barrett’s. Twenty-nine had antire-flux surgery; the remaining 152 were treated medically.After a mean follow-up of 62 months in the surgical groupand 49 months in the medical group, there was a significantdifference in the incidence of dysplasia and adenocarci-noma. Dysplasia was found in 3.4% of the surgical groupand 19.7% in the medical group. No patient in the surgicallytreated group developed adenocarcinoma of the esophagus,

compared with two medically treated patients. They con-cluded that compared with medical therapy, an antirefluxoperation in patients with Barrett’s was significantly asso-ciated with the prevention of dysplasia and cancer. Simi-larly, Katz et al81 followed 102 patients with Barrett’s for amean of 4.8 years. By 3 years, dysplasia had developed inapproximately 8% of the medically treated patients. In con-trast, patients treated by antireflux surgery had a signifi-cantly reduced risk of developing dysplasia (P 5 .03).

One factor complicating any analysis of progression ofBarrett’s after antireflux surgery is that the cellular andgenetic alterations leading to the development of dysplasiaand adenocarcinoma may have already occurred before per-formance of the antireflux procedure. It has been estimatedto take up to 6 years for adenocarcinoma to develop withinBarrett’s with low-grade dysplasia, and thus some cancers,particularly those that present during the first few postop-erative years, probably do not represent progression ofdisease after surgery. McDonald et al77 made this point in astudy from the Mayo Clinic. They found invasive adeno-carcinoma in two patients and carcinoma in situ in onepatient during surveillance after antireflux surgery, but theynoted that carcinoma did not develop in any patient after 39months despite a median follow-up of 6.5 years and amaximum follow-up of 18.2 years.

Review of the English language literature since 1975revealed 11 series and a total of 346 patients with Barrett’sfollowed after fundoplication.10,62,69–71,73–75,77,80,82Pa-tients were found to have esophageal adenocarcinoma afterantireflux surgery in only 7 of the 11 reports. Apart fromthese series, four isolated reports were found describingadenocarcinoma developing in patients with Barrett’s afteran antireflux operation.9,83–85 Although the length of fol-low-up was not always available, 11 of the 19 cancers(58%) developed within 3 years of fundoplication, and 15(79%) developed within 5 years of fundoplication. Theremaining four cancers developed from 5 to 10 years afterfundoplication, but in each case the patient had recurrentreflux on the basis of symptoms or positive 24-hour pHmonitoring (Fig. 7). Thus, a functioning fundoplicationseems to provide protection from progression of Barrett’s toadenocarcinoma.

Mucosal Ablation

Theoretically, the ideal treatment for a patient with Bar-rett’s esophagus is one that will restore the normal squa-mous mucosa and eliminate the cancer risk associated withintestinal metaplasia. Currently, neither medical nor surgi-cal therapy reliably offers this in patients with lengths ofintestinal metaplasia of 3 cm or more. However, severalexperimental techniques for mucosal ablation show prom-ise. Investigational techniques include the use of laser,photodynamic therapy (PDT), multipolar electrocoagula-tion, and the ultrasonic aspirator. In animal and limitedclinical trials, some of these techniques have successfully

Figure 6. Review of the English language literature identified 11 seriesin which patients with Barrett’s were followed up after antireflux surgery.A total of 340 patients were followed up for an overall mean of 4.4 years(range 1–18 years). Most patients (74%) did not have any change in theirBarrett’s with follow-up. Regression occurred in 17% of patients, pro-gression in 9%.


produced ablation of the columnar mucosa and subsequentsquamous reepithelialization.

Elimination of gastroesophageal reflux is critical to suc-cessful squamous reepithelialization after mucosal ablationof Barrett’s. Persistent or recurrent areas of intestinal meta-plasia plague most series of mucosal ablation in patientstaking proton pump inhibitors. In contrast, Salo et al86

recently reported successful ablation of Barrett’s using Nd:YAG laser after antireflux surgery. They followed up 11patients for a mean of 26 months after the last laser treat-ment and noted complete squamous regeneration in allpatients. There was no residual metaplastic epithelium ex-cept in two patients with persistent intestinal metaplasia atthe gastroesophageal junction.

One problem with ablation for Barrett’s is that in mostpatients the intestinal metaplasia is circumferential, andoften involves a large surface area. Many of the ablationtechniques suffer from an imprecise control of the depth ofinjury, and when applied circumferentially have a high rateof stricture formation. In a review by Overholt et al,87

esophageal strictures developed in 34% of patients treatedwith PDT. PDT eradicated Barrett’s in 8% of patients, butthis increased to 43% with the addition of Nd:YAG laserablation. In 23% of patients treated with PDT for adenocar-cinoma in Barrett’s the malignancy persisted, and in bothpatients who underwent surgical resection, lymph node me-

tastases were found. Three patients died during treatment(3%). Biopsies showed no evidence of subsquamous glan-dular mucosa in 98% of patients; however, in 2% of patientsareas of Barrett’s with high-grade dysplasia were foundbelow squamous mucosa, and in one patient a subsquamousadenocarcinoma was found 6 months after PDT treatment.

The most promising ablation technique uses the CavitronUltrasonic Surgical Aspirator (CUSA; Valley Lab, Boulder,CO) device to remove the mucosa without violating themuscularis mucosa. Animal studies have demonstrated thatstrictures are not produced if the muscularis mucosa is keptintact.88 In addition, the entire area of intestinal metaplasiacan be eradicated at a single setting, and rather than de-stroying the mucosal cells, with this technique the aspiratedcells are available for cytologic review. When combinedwith an antireflux procedure, this technique is likely to bethe most reliable method to ablate Barrett’s and allowsquamous regeneration. Refinements in the different tech-niques and careful clinical evaluation of the completeness ofablation, long-term complication rates, and impact on pro-gression of Barrett’s to dysplasia and cancer with each ofthe techniques should be forthcoming in the near future.

Barrett’s With Low-Grade Dysplasia

Identification of low-grade dysplasia on biopsies from apatient with Barrett’s is of concern because it may representprogression of disease along a continuum that ends withadenocarcinoma of the esophagus. Patients who are found tohave low-grade dysplasia on the basis of a random biopsyshould undergo repeat endoscopy with systematic four-quadrant biopsies every 1 to 2 cm throughout the length ofthe Barrett’s segment to rule out high-grade dysplasia orcancer. In addition, any abnormal-appearing area within thecolumnar segment should be carefully biopsied. Because ofthe potential for confusion between inflammatory atypia andlow-grade dysplasia, patients who have not been treated forreflux should receive a 3-month course of intensive acid-suppression therapy with 40 mg omeprazole twice a day.These patients should then undergo repeat endoscopy andbiopsy. If low-grade dysplasia is again identified, thesepatients should undergo an antireflux operation followed byendoscopic surveillance. In our series of 60 patients withintestinal metaplasia of the esophagus or esophagogastricjunction, we found that preoperative low-grade dysplasiawas present in 10 patients. In 7 of the 10, the low-gradedysplasia reverted to Barrett’s without dysplasia after anantireflux procedure.78 Similarly, Low et al79 noted that 4 oftheir 14 patients had low-grade dysplasia, and in all 4patients it regressed to Barrett’s without dysplasia aftersurgery. If the low-grade dysplasia persists after antirefluxsurgery, consideration should be given to mucosal ablationwith the ultrasonic aspirator. Further, patients with low-grade dysplasia should be under frequent surveillance, be-cause progression to high-grade dysplasia and cancer canoccur quickly.

Figure 7. Review of the English language literature identified 11 seriesin which patients with Barrett’s were followed up after antireflux surgery.In 4 of the 11 series, adenocarcinoma developed in no patients duringthe follow-up period. A total of 346 patients were followed up and 12cancers occurred. Seven additional cases of adenocarcinoma devel-oping in Barrett’s esophagus after an antireflux procedure were found inother reports. Thus, a total of 19 adenocarcinomas that occurred afteran antireflux procedure were found in the literature. Each case of canceris plotted on the time line at the point where it occurred. Time is markedin 5-year segments, with 0 the time of the antireflux procedure. Note themaximum as well as the mean or median follow-up for each of the 11series. Despite the long follow-up in these series, most cancers areclustered between 0 and 5 years after the antireflux procedure. Thesecancers probably occurred as a consequence of cellular and geneticalterations that took place before the fundoplication. For each of thecancers occurring after 5 years, there was evidence either by the recur-rence of reflux symptoms or a positive 24-hour pH test that the fundo-plication had failed.


Barrett’s With High-Grade Dysplasia

Optimal treatment for patients with Barrett’s and high-grade dysplasia remains controversial. The major issues are:

1. What is the likelihood that adenocarcinoma will de-velop in a patient with high-grade dysplasia, and overwhat time interval does this typically occur?

2. What is our ability with current technology to detecta focus of adenocarcinoma within Barrett’s esopha-gus with high-grade dysplasia—and the corollary,how likely is it that no cancer is present if theendoscopy and biopsies show no cancer?

3. What are the treatment options for high-grade dys-plasia, and what outcomes are associated with each?

Issue 1

Progression to adenocarcinoma was reported to occur in26% of 58 patients with high-grade dysplasia followed for amedian of 24 months by Levine et al from Seattle.89 How-ever, they excluded 12 patients found to have adenocarci-noma on an early rebiopsy after initially diagnosing onlyhigh-grade dysplasia. Inclusion of these patients would in-crease the frequency of progression to 39% in this group ofpatients followed up for 2 years. Similarly, Schnell et al90

reported progression to adenocarcinoma in 8 of 42 patients(19%) with high-grade dysplasia. The median length offollow-up was not specified; however, it was noted that fiveof the eight patients who progressed to carcinoma did sowithin 1 year. The literature would suggest that although thetime required to progress from high-grade dysplasia tocancer is variable, most cancers develop within 3 years, andoften the cancer is found within several months of initiallyfinding high-grade dysplasia. Williamson et al91 reportedthat five patients with Barrett’s and high-grade dysplasiaprogressed to cancer at intervals of 2, 2, 5, 6, and 8 monthsafter developing high-grade dysplasia.

Issue 2

Currently, the only way to detect a focus of adenocarci-noma within Barrett’s esophagus is by histologic examina-tion of a biopsy specimen, but differentiation between high-grade dysplasia and carcinoma is difficult and requires anexperienced pathologist. Efforts are underway to identifymarkers that can indicate which patients with high-gradedysplasia are likely to progress rapidly to cancer. Examplesof studied markers include DNA content abnormalities suchas increased G2/tetraploid fractions, aneuploid cell popula-tions, or both; mutations of the p53 tumor suppressor gene;c-erbB-2 oncogene overexpression; increased expression ofepidermal growth factor receptor and transforming growthfactor-alpha; decreased activity of glutathione S-transferase;p16 promoter hypermethylation; and increased expressionof inducible nitric oxide synthase and cyclooxygenase-2.92–95As yet, no clear correlation has been established thatallows any of these to be clinically useful in assigning riskof progression to an individual patient.

The diagnosis of Barrett’s, dysplasia, and cancer contin-ues to rely on histologic evaluation of biopsy specimens.Most endoscopic biopsies are obtained randomly fromwithin Barrett’s in the sense that unless an ulcer or noduleis noted, the biopsies are taken from an area of Barrett’s thatlooks like any other area. It is important that the biopsies aretaken circumferentially at close intervals, but the impor-tance of using “jumbo” forceps and the number of biopsiesthat should be taken per linear 2 cm of esophagus continueto be debated. Given the typically large surface area ofBarrett’s, as well as the irregular distribution of dysplasticchanges, there is an inherent possibility of sampling error.Certainly taking multiple biopsy samples will reduce theerror rate; however, the only way to eliminate the possibilityof sampling error is to remove the entire mucosa. This factis reinforced by data suggesting that up to 60% of patientswho have an esophagectomy for high-grade dysplasia arefound on careful pathologic examination of the surgicalspecimen to have an unidentified focus of carcinoma despitenumerous preoperative biopsies that showed only high-grade dysplasia.55,96

Endoscopic ultrasound has been used in patients withhigh-grade dysplasia in an effort to detect areas of cancer.However, current ultrasound probes, especially the balloon-tipped probes, cannot provide sufficient detail to evaluatethe esophageal wall superficial to the muscularis propria.Cameron and Carpenter53 reported that endoscopic ultra-sound identified only one of four early invasive cancers andgave one false-positive result in nine patients without can-cer. In the future, it is hoped that new high-frequencyultrasound probes will be able to assess with accuracycancers limited to the mucosa and submucosa. Recently,endoscopic fluorescence techniques have been used to try toidentify areas of high-grade dysplasia or cancer withinBarrett’s based on the different autofluorescence spectra ofnormal versus metaplastic versus dysplastic tissue.97,98Theutility of these techniques remains to be determined.

Issue 3

Treatment options for patients with Barrett’s and high-grade dysplasia include continued endoscopic follow-up,some form of mucosal ablation, or resection of the esoph-agus. The main issue to focus on during the next severalyears is the outcome associated with the various treatmentsfor high-grade dysplasia. Important outcome measures in-clude the recurrence rate for intestinal metaplasia, dysplasia,and cancer, treatment-related complication and death rates,and patients’ satisfaction with lifestyle and ability to eat. Asmore data about these issues become available, physiciansand patients will have a better understanding of the pros andcons for each treatment option.

Currently one option is to repeat endoscopy and biopsy inpatients with high-grade dysplasia until a definitive diagno-sis of cancer is established. The obvious advantage of thistype of approach is that the patient is spared the potentialrisks of surgery until cancer is identified. This is balanced


by the need for repeat endoscopies with multiple biopsies ona frequent basis, and the real possibility of a sampling errorresulting in a missed focus of adenocarcinoma. An adeno-carcinoma that is missed and allowed to invade into thesubmucosa has a 50% likelihood of associated lymph nodemetastases.99 Unfortunately, in these patients the opportu-nity for cure will have been compromised and the benefitsof endoscopic surveillance potentially negated.

This concern is not theoretical. In the study by Hameete-man et al,66 five patients were found during surveillance toprogress to adenocarcinoma, and three underwent resection.All three had cancers that invaded into the muscularispropria. These are relatively advanced tumors, and our datawould suggest that 80% of tumors penetrating this depthinto the wall of the esophagus will have lymph node me-tastases.99 Likewise, in the series by Williamson et al,91 fivepatients progressed from high-grade dysplasia to adenocar-cinoma during endoscopic surveillance. All five patientsunderwent resection, and although four of the patients hadstage 1 tumors, one patient was found to have a stage 3tumor (T3 N1 M0). Thus, despite a policy of close endo-scopic surveillance, invasive cancer developed in five pa-tients and one had lymph node metastases. Perhaps this riskis warranted in older patients or those with multiple orsevere medical comorbidities, but in young fit patients it isnot justified.

A second approach is to ablate the metaplastic mucosa,including areas of high-grade dysplasia. As discussed pre-viously, techniques that have been used include PDT, elec-trocoagulation, laser, and argon beam coagulation. Long-term outcome after ablation by these techniques is not welldefined, and none of these techniques remove a specimen orallow evaluation of the margins of resection. Consequently,an area of invasive cancer might not only go unrecognized,but might be inadequately treated as well. Ferguson andNaunheim96 reviewed three published series involving atotal of 46 patients with high-grade dysplasia treated withPDT. During an average follow-up of less than 2 years,strictures requiring dilation developed in 46% of patients,41% had residual Barrett’s, and 9% had residual high-gradedysplasia. In a series of 100 patients treated with PDT plusNd:YAG laser reported by Overholt et al,87 residual Bar-rett’s was present in 57% of patients, and persistent ormetastatic adenocarcinoma was found in 23% of patientswith a pretreatment diagnosis of cancer. Dysplasia of anytype persisted in 18% of patients, whereas high-grade dys-plasia persisted in 10% of patients after treatment. Esoph-ageal strictures requiring dilatation developed in 34% ofpatients. These poor results suggest that PDT should not beconsidered first-line therapy for Barrett’s and high-gradedysplasia, but perhaps could be considered in patients whoare poor candidates for esophagectomy.

A third treatment option, and one that we endorse, isesophageal resection. Esophagectomy represents the stan-dard against which all other therapies must be compared foreradication of cancer. Ferguson and Naunheim96 reviewed

the English literature from 1990 to 1996 and analyzed theoutcome from 10 series totaling 110 patients who under-went esophagectomy for high-grade dysplasia. The deathrate was 2.6%, and the overall 5-year survival rate was 82%.All patients were thought before surgery to have only high-grade dysplasia; however, cancer was found in 56 of the 110patients (51%), and in 15 patients the tumors were stage IIaor higher.

We have recently reviewed our experience with high-grade dysplasia at the University of Southern California.100

Repeat biopsy in 23 patients referred for high-grade dyspla-sia demonstrated a focus of adenocarcinoma in 9 patients(39%). After esophagectomy, review of the specimen dem-onstrated an additional six cancers. Thus, of 23 patientsreferred for high-grade dysplasia, ultimately cancer wasfound in 15 (65%). Among 25 patients with adenocarci-noma in Barrett’s esophagus but no visible lesion, the tumorwas limited to the lamina propria (intramucosal) in 22(88%) but invaded into the submucosa in 3 patients (12%).Of the 25 patients with adenocarcinoma and no visiblelesion, 10 underwent en bloc esophagectomy with system-atic thoracic and abdominal lymphadenectomy. From these10 patients, a total of 370 lymph nodes were removed andanalyzed with both routine histology and immunohisto-chemical staining. Only a single node from one patient waspositive for metastatic cancer. Consequently, we concludedthat a routine lymph node dissection is unnecessary inpatients with high-grade dysplasia or invasive cancer in theabsence of an endoscopically visible lesion. However, giventhat in 12% of patients the cancer had invaded deeper thanthe mucosa, therapy directed purely at ablation of the mu-cosa is not adequate even in the absence of a visible lesion.

In contrast to the rarity of lymph node metastases inpatients with cancer and no visible lesion, we found that55% of patients with high-grade dysplasia and a biopsyshowing cancer in the setting of a visible mucosal irregu-larity such as an ulcer or nodule had lymph node metasta-ses.100 Further, in 75% of these patients the tumor hadinvaded into or beyond the submucosa. Therefore, the pres-ence of an endoscopically visible abnormality and a biopsyof cancer mandates esophagectomy with lymphadenectomy.

Obviously, when recommending esophagectomy, onemust balance the potential risks against the benefits ofcurative resection in patients with high-grade dysplasia.This requires that the procedure be done at a center that isexperienced with this type of surgery and has a low com-plication rate. In addition, it is important that the reconstruc-tion in these patients functions well and does not predisposethem to recurrence of Barrett’s. It is now recognized thatpatients with an intrathoracic anastomosis between theirstomach and residual esophagus are prone to have continuedreflux of gastric contents into the remaining esophagus. Thishas led to esophagitis and even the recurrence of Barrett’s.Because this is less likely to occur when the anastomosis isdone in the neck, we believe that a cervical esophagogastricanastomosis should be performed routinely. Reconstruction


with the colon does not lead to this problem, and we believethat long-term function of a colon graft is superior to that ofa gastric pull-up.

One technique we now use for high-grade dysplasia is avagal-sparing esophagectomy with colon interposition. Thisprocedure removes the esophagus by the minimally invasivetechnique of stripping and preserves the intact, innervatedstomach. The diseased esophagus is replaced with an iso-peristaltic left colon graft. The operation is very well toler-ated, and our early experience suggests that these patientshave excellent function of both their intact stomach andcolonic graft. In addition, they demonstrate few of the sideeffects potentially associated with a traditional esophagec-tomy, such as early satiety, dumping syndrome, or diarrhea.

SUMMARY

Since its description in the 1950s the definition of Bar-rett’s esophagus has evolved from the macroscopic visual-ization of gastric-like mucosa in the esophagus to the his-tologic identification of goblet cells confirming the presenceof intestinal metaplasia within a columnar-lined esophagus.The length of intestinal metaplasia necessary to be classifiedas Barrett’s and the relation between intestinal metaplasia ofthe esophagus and that limited to the cardia are beingevaluated. Meanwhile, the definition of Barrett’s has onceagain become ambiguous. Perhaps the best solution for nowis to use the term “Barrett’s esophagus” when there is anendoscopically visible area of columnar mucosa that onbiopsy demonstrates intestinal metaplasia. The term “intes-tinal metaplasia of the cardia” (CIM) should be used whenthere is a normal-appearing gastroesophageal junction onendoscopy, but biopsies taken at the gastroesophageal junc-tion demonstrate intestinal metaplasia within a columnarepithelium containing mucous cells but devoid of parietalcells.

There is evidence that cardiac mucosa is the commondenominator for CIM and Barrett’s and a prerequisite forintestinal metaplasia. Further, it appears that although car-diac epithelium is benign, any segment of intestinal meta-plasia can undergo dysplastic change and ultimately becomea focus of adenocarcinoma. It is logical to expect the degreeof risk for developing cancer to be proportional to theamount of intestinal metaplasia present; however, within apopulation, the low risk to any individual is balanced by therelative frequency of the process. Thus, given the largenumber of people in America with intestinal metaplasia ofthe cardia, even a small risk of progression to cancer willresult in a large number of patients with adenocarcinoma ofthe cardia. This is exactly what is occurring today, with theincidence of adenocarcinoma of the cardia and esophaguscurrently rising faster than that of any other cancer in theUnited States.

The major risk factor for adenocarcinoma of the esoph-agus is intestinal metaplasia, and intestinal metaplasia oc-curs as a consequence of GERD. Patients with Barrett’s

typically have severe GERD, with significant impairment ofboth LES function and esophageal body motility. Further,the composition of the refluxed gastric juice is different inpatients with Barrett’s and complicated Barrett’s esophagus.Patients who reflux both gastric and duodenal juice have ahigher prevalence of Barrett’s than do patients who refluxgastric juice alone, and among patients with Barrett’s asignificantly greater esophageal bilirubin exposure has beendemonstrated in those with dysplasia.

Reflux disease is difficult to control medically in patientswith Barrett’s, and symptoms are unreliable as a guide. Themost difficult symptom to control is regurgitation, and thereis concern that regurgitation and continued reflux of phar-macologically altered gastric contents, particularly bile ac-ids in their nonpolar form, may contribute to the develop-ment and progression of Barrett’s. Therefore, it is notsurprising that both medical therapy and failed antirefluxsurgery are both associated with progression of Barrett’s todysplasia and adenocarcinoma. In contrast, a functioningfundoplication appears to provide protection from progres-sion of Barrett’s. Intestinal metaplasia extending 3 cm ormore into the esophagus is unlikely to regress after antire-flux surgery; however, intestinal metaplasia limited to thegastroesophageal junction is perhaps more dynamic. Wefound that CIM regresses in 73% of patients after fundopli-cation. In addition, we found that low-grade dysplasia re-gressed in 70% of patients after an antireflux procedure.Antireflux surgery is safe, effective, and durable and oftencan be performed using minimally invasive techniques.Thus, antireflux surgery should be strongly considered inany patient with Barrett’s.

Patients with Barrett’s and high-grade dysplasia are atsubstantial risk for having a coexistent focus of adenocar-cinoma, and even with multiple biopsies there is the possi-bility of sampling error. Further, adenocarcinoma can de-velop rapidly in the setting of high-grade dysplasia, and ifthe cancer is allowed to invade into the submucosa, 50% ofthese patients will have lymphatic metastases, and the pur-pose of surveillance will potentially have been negated.Patients with intramucosal adenocarcinoma are unlikely tohave lymphatic metastases; however, current technologydoes not allow precise identification of the depth of wallpenetration superficial to the muscularis propria. Conse-quently, therapy directed only at the mucosa is potentiallyinadequate and should not be considered appropriate treat-ment for cancer. Instead, esophagectomy represents thestandard of care in these patients with a highly curable formof esophageal cancer.

Esophagectomy for adenocarcinoma of the esophagusshould be tailored to the patient and the known extent ofdisease. For high-grade dysplasia and invasive tumors with-out an endoscopically visible lesion, a vagal-sparing tech-nique with colon interposition provides an excellent func-tional outcome and removes the entire diseased organ.Patients with visible tumors are likely to have invasiondeeper than the mucosa or lymph node metastases. There-


fore, those who are physiologically fit should undergo enbloc esophagectomy with thoracic and abdominal lymphad-enectomy. In patients with extensive disease or those phys-iologically unfit, a palliative transhiatal resection or othernonsurgical palliative procedure may be appropriate.

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Columnar Mucosa and Intestinal Metaplasia of the Esophagus