Long-Term Outcome of Antireflux Surgery in Patients With Barrett’s Esophagus

Abstract

Objective

To assess the long-term outcome of antireflux surgery in patients with Barrett’s esophagus.

Summary Background Data

The prevalence of Barrett’s esophagus is increasing, and its treatment is problematic. Antireflux surgery has the potential to stop reflux and induce a quiescent mucosa. Its long-term outcome, however, has recently been challenged with reports of poor control of reflux and the inability to prevent progression to cancer.

Methods

The outcome of antireflux surgery was studied in 97 patients with Barrett’s esophagus. Follow-up was complete in 88% (85/97) at a median of 5 years. Fifty-nine had long-segment and 26 short-segment Barrett’s. Patients with intestinal metaplasia of the cardia were excluded. Fifty patients underwent a laparoscopic procedure, 20 a transthoracic procedure, and 3 abdominal Nissen operations. Nine had a Collis-Belsey procedure and three had other partial wraps. Outcome measures included relief of reflux symptoms (all), patients’ perception of the result (all), upper endoscopy and histology (n = 79), and postoperative 24-hour pH monitoring (n = 21).

Results

At a median follow-up of 5 years, reflux symptoms were absent in 67 of 85 patients (79%). Eighteen (20%) developed recurrent symptoms; four had returned to taking daily acid-suppression medication. Seven patients underwent a secondary repair and were asymptomatic, increasing the eventual successful outcome to 87%. Recurrent symptoms were most common in patients undergoing Collis-Belsey (33%) and laparoscopic Nissen (26%) procedures and least common after a transthoracic Nissen operation (5%). The results of postoperative 24-hour pH monitoring were normal in 17 of 21 (81%). Recurrent hiatal hernias were detected in 17 of 79 patients studied; 6 were asymptomatic. Seventy-seven percent of the patients considered themselves cured, 22% considered their condition to be improved, and 97% were satisfied. Low-grade dysplasia regressed to nondysplastic Barrett’s in 7 of 16 (44%), and intestinal metaplasia regressed to cardiac mucosa in 9 of 63 (14%). Low-grade dysplasia developed in 4 of 63 (6%) patients. No patient developed high-grade dysplasia or cancer in 410 patient-years of follow-up.

Conclusions

After antireflux surgery, most patients with Barrett’s enjoy long-lasting relief of reflux symptoms, and nearly all patients consider themselves cured or improved. Mild symptoms recur in one fifth. Importantly, dysplasia regressed in nearly half of the patients in whom it was present before surgery, intestinal metaplasia disappeared in 14% of patients, and high-grade dysplasia and adenocarcinoma were prevented in all.

In 1950, Norman Barrett described the condition that bears his name. ¹ He incorrectly believed that he was observing a congenitally short esophagus and an intrathoracic stomach. Phillip Allison, in 1953, carefully examined seven esophagectomy specimens and conclusively showed that it was indeed the tubular esophagus lined with columnar epithelium. ² Barrett’s esophagus is now known to be an acquired abnormality; it is defined as a visible segment of esophageal columnar epithelium containing specialized intestinal metaplasia and occurs in 15% to 20% of patients with gastroesophageal reflux disease. ^3,4 Its increasing prevalence during the past decade and its relationship to adenocarcinoma of the esophagus have made it a significant public health problem. ^5,6

The treatment of patients with Barrett’s esophagus, particularly those with long segments, is difficult. Because it represents severe gastroesophageal reflux disease, is usually associated with large hiatal hernias and a shortened esophagus, and is of a premalignant nature, attempts at long-term success are frustrating. Acid-suppression medication is increasingly recognized to be inadequate, ^7,8 and ablative therapies remain difficult, complicated, and investigational. ^9,10 This leaves antireflux surgery as the best treatment option, provided that long-term success can be shown. Antireflux surgery has the potential to provide long-lasting symptom and reflux control and even halt progression to malignancy. Its ability to do so over the long term is compromised by the severe anatomic and physiologic defects and has been poorly studied.

PATIENTS AND METHODS

Study Population

The study population consisted of 97 consecutive patients with symptomatic Barrett’s esophagus who underwent primary antireflux surgery between 1991 and 1998. Follow-up was complete in 85 patients (86%); 2 patients died of unrelated causes. Patients were identified as having Barrett’s esophagus by the presence of specialized intestinal metaplasia in a columnar-lined esophagus. Patients with nonvisible, histologically evident intestinal metaplasia in biopsy samples at the gastroesophageal junction were excluded, as were patients with high-grade dysplasia or invasive carcinoma. The extent of Barrett’s esophagus was defined as the distance from the top of the gastric rugal folds to the location of the highest point of the squamocolumnar junction. There were 66 male patients and 19 female patients with a median age of 46 years (range 15–76). All patients underwent preoperative assessment with videoesophagraphy, standard esophageal manometry, 24-hour pH monitoring, and upper endoscopy with biopsy. Stricture ulcer and esophagitis were noted. Preoperative evaluation included a detailed symptom questionnaire focused on foregut symptoms.

Assessment of Symptoms and Objective Measures of Outcome

Symptomatic outcome was divided into both a physician and a patient assessment. A physician other than the responsible surgeon assessed the symptomatic outcome by telephone interview and completion of a standardized questionnaire. The severity of symptoms typical of gastroesophageal reflux disease (i.e., heartburn, regurgitation, and dysphagia) was assessed and graded in a standardized fashion. Further symptom assessment included the presence of chest or epigastric pain, cough, dumping, diarrhea, and choking.

The outcome was considered excellent in asymptomatic patients; good when reflux symptoms were relieved but minor gastrointestinal symptoms, such as bloating or diarrhea, remained; fair when some reflux symptoms remained but were improved and/or there was a need for occasional drug therapy; and poor when symptoms required daily medications or a second antireflux procedure was performed.

Patients were asked to make their own assessment of the outcome by judging whether they were cured, improved, or worsened by the procedure and whether they would undergo surgery again under the same circumstances.

Objective measures of outcome included the presence or absence of hiatal hernia on endoscopy, regression or progression of intestinal metaplasia or low-grade dysplasia on histology, and postoperative 24-hour pH studies in 21 patients.

Upper Endoscopy and Histology

All patients underwent upper endoscopy with biopsy before surgery and were enrolled in an annual surveillance program. At endoscopy, the gastroesophageal junction was defined as the level where the gastric rugal folds ended and the tubular esophagus began. A columnar-lined esophagus was identified when the squamocolumnar junction or any part of its circumference extended above the gastroesophageal junction. Patients with an irregular squamocolumnar junction had biopsy samples obtained from the tongues of the glandular mucosa extending into the esophagus. In patients whose squamocolumnar junction was separated from the gastroesophageal junction, four-quadrant biopsy samples were obtained every 2 cm of the columnar-lined segment.

The presence of intestinal metaplasia and dysplasia was assessed by standard histologic criteria. The condition was considered to have regressed or progressed if two consecutive biopsy samples taken more than 6 months apart showed the same change in the mucosal characteristic in question. Recurrent hiatal hernias were identified endoscopically by the appearance of the fundoplication above the separated diaphragmatic crura on retroflex view of the cardia (Fig. 1).

Figure 1. Endoscopic photograph of recurrent hiatal hernia.

Esophageal Function Studies

Standard esophageal motility studies were performed after an overnight fast. Lower esophageal sphincter resting pressure was measured at the respiratory inversion point as previously described. The resting pressure, overall length, and abdominal length were calculated from the mean of five recordings. A structurally defective sphincter was defined by a resting pressure of less than 6 mm Hg, overall sphincter length of less than 2 cm, abdominal length of less than 1 cm, or a combination of these. Esophageal pH monitoring was performed using a standard electrode (Medtronic Functional Diagnostics, Minneapolis, MN) placed 5 cm above the upper border of the manometrically defined lower esophageal sphincter. Patients with an esophageal pH of less than 4 for more than 4.4% of the recording time were classified as having abnormal esophageal acid exposure. The overall esophageal acid exposure was expressed as a composite acid score of more than 14.7. Medications known to affect gastrointestinal motility or acid secretion were discontinued 3 days before testing, except for proton pump inhibitors, which were discontinued at least 2 weeks earlier.

Procedure Selection

The primary antireflux procedure was selected based on hiatal hernia size, esophageal motility, presence of obesity, and previous abdominal surgery. In general, laparoscopic Nissen fundoplications were performed in patients with hiatal hernias less than 5 cm long and normal esophageal motility. The procedure routinely included division of the short gastric vessels and crural closure. Patients with extensive previous abdominal surgery who otherwise met the criteria for a laparoscopic Nissen procedure were operated on by laparotomy. Those with hernias greater than 5 cm and those who were obese were approached transthoracically to allow full esophageal mobilization. A Collis gastroplasty was added if the fully mobilized esophagus could not be placed tension-free below the crural closure, and used in combination with a Belsey partial fundoplication. A transabdominal partial fundoplication was selected in the presence of poor motility (contraction amplitudes <20 mm Hg or >50% simultaneous contractions, or both) and a hernia measuring less than 5 cm.

Statistical Analysis

Values are expressed as medians and interquartile ranges (IQR) unless otherwise stated. The Fisher exact test was used to compare proportions between individual groups. Comparisons of proportions between more than two groups were performed using the chi-square test. The Kruskal-Wallis test was used to compare continuous data between more than two groups, and the Mann-Whitney test was used to compare continuous data between individual groups. P < .05 was accepted as significant.

RESULTS

Symptomatic Outcome

Characteristics of the patient population are shown in Table 1 and the physician’s assessment of outcome is shown in Table 2. At a median follow-up of 5 years, reflux symptoms were absent in 67 of the 85 patients (79%). Ninety-nine percent of the patients considered themselves cured (77%) or improved (22%), and 97% were satisfied with the procedure (Table 3). Eighteen patients (21%) developed recurrent symptoms. Of these, only four had returned to taking daily acid-suppression medication. Recurrent heartburn was the most common reason for symptomatic failure, occurring in 15 patients. The heartburn was usually intermittent and did not require regular medication use, as evidenced by the fact that 8 of the 15 considered themselves cured. Seven patients underwent a secondary repair and are asymptomatic, increasing the eventual successful outcome to 87%. Tables 4 and 5 show the effect of disease severity and procedure selection on recurrence. The presence of long-segment Barrett’s or complications such as an ulcer or stricture did not significantly affect the outcome. Recurrent symptoms were most common in patients undergoing Collis-Belsey (33%) and laparoscopic Nissen procedures (26%) and were least common after a transthoracic Nissen procedure (5%).

Table 1. PATIENT CHARACTERISTICS (n = 85)

Table 2. PHYSICIANS’ ASSESSMENT OF OUTCOME (n = 85)

Table 3. PATIENTS’ PERCEPTION OF OUTCOME (n = 85)

Table 4. EFFECT OF DISEASE SEVERITY ON RECURRENT SYMPTOMS

Table 5. EFFECT OF PROCEDURE ON RECURRENCE

Anatomic Evidence of Hernia Recurrence

Recurrent hiatal hernias were detected endoscopically in 16 of the 79 patients undergoing surveillance endoscopy (20%; see Fig. 1). Nine had a laparoscopic fundoplication, four had a Collis gastroplasty and Belsey partial fundoplication, and three had a transthoracic Nissen procedure. Six of these were small asymptomatic hernias. Of the 16 patients with recurrent hernia, 8 were studied with ambulatory pH monitoring, 4 were pH positive and underwent repeat fundoplication, and the other 4 had normal studies and consider themselves cured. Table 6 shows the association between various risk factors and recurrent hernia. Statistically significant associations were found between hernia recurrence and the length of the Barrett’s segment and severity of acid reflux (DeMeester score and the percentage of time pH < 4).

Table 6. MULTIVARIATE ANALYSIS OF THE ASSOCIATION BETWEEN VARIOUS RISK FACTORS AND OUTCOME

LES, Lower esophageal sphincter.

Bold type indicates a significant association.

Postoperative 24-Hour pH Studies and Endoscopic Surveillance

Postoperative 24-hour pH studies were obtained in 21 patients and are compared with the preoperative values in Figure 2. The percentage of time the esophagus was exposed to a pH less than 4 decreased from a median of 11 ± 4.2 before surgery to 0 ± 1.3 after surgery (P = .004). In 17 of these studies the results were normal (83%), including 12 that were 0. Four were abnormal at 6.9%, 8.3%, 16.5%, and 19.3% pH less than 4; all were symptomatic.

Figure 2. Percentage of time pH was less than 4, plotted as individual preoperative and postoperative values in 24 patients.

Endoscopic surveillance was performed in 79 patients. Nineteen percent of the patients exhibited some form of histologic regression (Table 7). Low-grade dysplasia regressed to nondysplastic Barrett’s in 7 of 16 (44%), and intestinal metaplasia was lost, regressing to cardiac mucosa, in 9 of 63 (14%). Low-grade dysplasia developed in 4 of 63 (6%) patients. No patient developed high-grade dysplasia or cancer in 410 patient-years of follow-up.

Table 7. ENDOSCOPIC SURVEILLANCE; DYSPLASIA REGRESSION AND/OR PROGRESSION (n = 79)

DISCUSSION

There are four aims of therapy for patients with Barrett’s esophagus, and they should be the same for both surgical and nonsurgical treatment: provide long-term relief of symptoms; allow healing of reflux-induced esophageal mucosal injury, including stricture formation; prevent progression to more advanced mucosal injury or dysplastic changes; and induce regression of dysplastic to nondysplastic Barrett’s or of intestinalized to nonintestinalized columnar epithelium.

Our data document several important observations. First, control of reflux symptoms occurs in nearly 80% of patients with Barrett’s esophagus 5 years after antireflux surgery, and up to 87% if secondary procedures are taken into account. Second, a successful antireflux procedure can result in histologic regression of both dysplastic and metaplastic epithelium in a substantial number of patients. The latter may obviate the need for ablative therapy. Finally, successful antireflux surgery may, in fact, prevent the development of adenocarcinoma. Although proof of the latter awaits prospective trials, the absence of esophageal adenocarcinoma in more than 400 patient-years of follow-up certainly supports this possibility.

Surprisingly few studies have focused on the symptomatic outcome after antireflux surgery in patients with Barrett’s esophagus. Those that are available after open antireflux surgery document excellent to good results in 72% to 95% of patients at 5 years after surgery. ^11–14 Several have compared medical and surgical therapy. Attwood et al, ¹⁵ in a prospective but nonrandomized study, reported on 45 patients undergoing either medical or surgical treatment of Barrett’s esophagus. Symptoms of heartburn or dysphagia recurred in 88% of patients treated with medical therapy alone and in 21% after antireflux surgery. Ongoing mucosal injury, largely the development of an esophageal stricture, occurred in 38% of medically treated and 16% of surgically treated patients (P < .05) during the 3-year follow-up period. Ortiz et al ¹⁶ reported a prospective randomized comparison of medical and surgical therapy in 59 patients with Barrett’s esophagus. Twenty-seven patients were treated with either histamine-2 blockade or proton pump inhibitors and 32 with antireflux surgery. Symptomatic improvement occurred in the majority of patients in both groups, 85% receiving medical therapy and 89% after antireflux surgery. Taken together, these studies document the ability of antireflux surgery to achieve two of the four aims of therapy outlined above: it provides long-term symptomatic relief and is more conducive to healing of reflux-induced esophageal mucosal injury.

In contrast, Csendes et al ¹¹ suggested that the long-term results of antireflux surgery in patients with Barrett’s esophagus might not be as good as previously thought. They reviewed their long-term results with “classic” antireflux surgery in 152 patients with both complicated and uncomplicated Barrett’s esophagus. Fifty-four percent of those with uncomplicated Barrett’s and 64% of those with Barrett’s complicated by stricture or ulceration were classified as failures when symptoms were assessed 8 years after surgery. Although this report challenges the long-term results of antireflux surgery in patients with Barrett’s esophagus, it suffers from the fact that 85% of the patients were treated with a Hill repair, and these data should not be extrapolated to patients undergoing Nissen fundoplication.

Predictors of Recurrence

Our data suggest a relatively high percentage of recurrent symptoms in patients with Barrett’s esophagus after laparoscopic repair. Others have assessed the outcome of laparoscopic Nissen fundoplication in patients with Barrett’s esophagus at 1 to 3 years after surgery. Farrell et al ¹⁷ reported symptomatic outcome in 50 patients with both long- and short-segment Barrett’s esophagus. Mean scores for heartburn, regurgitation, and dysphagia all improved dramatically after the Nissen procedure. Importantly, there was no significant decrement in symptom scores when 1-year results were compared with 2- to 5-year results. They did find a nearly three times higher prevalence of “anatomical” failures requiring reoperation in patients with Barrett’s esophagus compared with non-Barrett’s patients with gastroesophageal reflux disease. Chen et al ¹⁸ reported the outcome of 45 patients with Barrett’s esophagus undergoing Collis-Nissen procedures. The mean follow-up was 36 months. Reflux symptoms were relieved in all patients, although 10 of 44 patients had positive results on postoperative pH studies. They concluded that Collis-Nissen procedures provided control of reflux symptoms in patients with Barrett’s esophagus.

Patients with Barrett’s esophagus generally have severe gastroesophageal reflux disease, with its attendant sequelae such as large hiatal hernia, ¹⁹ stricture, shortened esophagus, and poor motility. ²⁰ These anatomic and physiologic features make successful antireflux surgery, particularly when approached laparoscopically, a challenge in this population. It may be that the use of a transthoracic approach improved our overall results because it allowed a more complete esophageal mobilization, the capacity to assess esophageal length, and excellent exposure for closure of the hiatal defect. Our policy of selecting patients with the most limited disease for a laparoscopic approach and the most advanced disease for a transthoracic approach may have prevented identifying the difference in outcome among the procedures.

Regression and Prevention of Progression

The common belief that Barrett’s epithelium cannot be reversed is probably false. We recently reported that after antireflux surgery, loss of intestinal metaplasia was rare in patients with visible Barrett’s esophagus but occurred in 73% of patients with intestinal metaplasia of the cardia. ²¹ This suggested that the metaplastic process may indeed be reversible if reflux-induced injury is eliminated early in its process. Antireflux surgery was also associated with regression of dysplasia in 70% of patients with cardia intestinal metaplasia and low-grade dysplasia before surgery. These data have recently been confirmed by the University of Washington group. ²² Fourteen patients with short-segment Barrett’s esophagus were followed up for a mean of 25 months after antireflux surgery. Two of 14 (14%) had no evidence of intestinal metaplasia on repeated postoperative biopsies, and four regressed from low-grade dysplasia to nondysplastic Barrett’s. The finding that nearly 20% of patients in this study developed some form of regression further supports the fact that antireflux surgery promotes regression in a substantial minority of patients with Barrett’s esophagus.

There is also a growing body of evidence to suggest that fundoplication may protect against dysplasia and invasive malignancy. Four recent studies have shown that effective antireflux surgery may have an impact on the natural history of Barrett’s esophagus. The first such evidence came from an analysis of longitudinal follow-up of patients with Barrett’s esophagus in the registry of the American College of Gastroenterologists. ²³ All patients had nondysplastic quiescent Barrett’s at initial endoscopy. One hundred nineteen patients received medical treatment and 42 underwent antireflux surgery. Surveillance endoscopy was performed annually. Ten of 119 patients in the medically treated group (19.7%) and 2 of 42 (3.4%) in the surgical group developed dysplasia. A retrospective review of 118 patients with Barrett’s esophagus undergoing antireflux surgery at the Mayo Clinic between 1960 and 1990 revealed three cancers occurring during an 18.5-year follow-up period. ²⁴ All were found within the first 3 years after surgery. The fact that the development of adenocarcinoma was clustered in the early years after antireflux surgery and was not randomly dispersed throughout the follow-up period strongly suggests that antireflux surgery altered the natural history of the disease, particularly given the fact that once dysplasia has developed, prospective studies show that carcinoma ensues in an average of 3 years. The occurrence of all observed cancers in the first few years suggests that the “point of no return” in the dysplasia-to-cancer sequence had already occurred before surgery.

Further evidence that antireflux surgery may alter the natural history of Barrett’s esophagus was reported by Katz et al. ²⁵ This Veterans Administration outcomes group retrospectively reviewed 102 patients undergoing annual surveillance for Barrett’s esophagus from 1970 to 1994, for a total of 563 patient-years of follow-up. All specimens with any degree of dysplasia were blinded and rereviewed. Nineteen patients developed new-onset low-grade dysplasia, four high-grade dysplasia, and three adenocarcinoma. Antireflux surgery (n = 15) was associated with a significantly decreased risk of the development of dysplasia, the presence of which persisted in a multivariate analysis taking into account covariables such as age, sex, and smoking. None of the 15 patients in this study developed dysplasia or cancer after antireflux surgery. Finally, in the only prospective randomized study, Ortiz et al ¹⁶ reported that dysplasia developed in 6 of 27 (22%) patients receiving medical treatment and in only 1 of 32 (2.3%) patients at a median of 5 years after antireflux surgery. This patient was shown to have an ineffective fundoplication with 24-hour pH monitoring. Each of these authors concluded that there is a critical need for future trials exploring the role of antireflux surgery in protecting against the development of dysplasia in patients with Barrett’s esophagus.

In summary, antireflux surgery provides long-term control of reflux symptoms that is comparable or better than medical therapy, and it alters the natural history of Barrett’s epithelium by inducing regression in up to 20% of the patients and preventing the development of dysplasia and carcinoma in nearly all. These accomplishments are associated with a higher-than-expected incidence of recurrent hernia, which was associated with longer segments of Barrett’s metaplasia and severe esophageal acid exposure. Surgical therapy for advanced Barrett’s needs to take into account this tendency for recurrence in advanced disease and should encourage surgical therapy at an earlier stage of the disease, when factors associated with failure are less common.

Discussion

Dr. Gerald M. Fried (Montreal, Quebec, Canada): Dr. Peters, that was an outstanding presentation. We all recognize that the treatment of gastroesophageal reflux disease should be directed at improving quality of life and altering the natural history of the disease. Patients with Barrett’s metaplasia are a sub-group of patients with reflux disease in whom the natural history of the disease includes, in some people, progression from metaplasia to dysplasia to adenocarcinoma.

The specific goal of therapy for GERD is to diminish the exposure of the esophageal mucosa to acid and duodenal contents. This would seem to be particularly important in patients with Barrett’s metaplasia. How do we measure the effectiveness of our therapy? Clearly, the relief or improvement in reflux symptoms does not always equate with control of reflux as measured objectively. I have a few questions for you.

Should all patients be followed either on medical therapy or after surgery for Barrett’s esophagus and undergo periodic 24-hour pH studies to ensure control of their acid reflux? And if so, how frequently would you recommend this?

Did patients with Barrett’s esophagus have a greater likelihood of recurrent symptoms after surgery than patients with symptomatic reflux but without Barrett’s esophagus in your series?

Did regression of dysplasia or metaplasia only occur in patients with complete resolution of symptoms and documented reduction of acid reflux on pH testing? Or was regression independent of the measures of effective treatment?

Finally, the rate of recurrent symptoms after laparoscopic Nissen fundoplication in your series was about 26% at a median of five years. How soon after the surgery did their symptoms usually recur? Was the operation not effective from early on or was it not durable on long-term follow-up?

Presenter Dr. Jeffrey H. Peters (Los Angeles, California): Thank you, Dr. Fried, for your excellent and insightful questions and comments.

The question of the outcome of therapy in patients with Barrett’s esophagus is a significant one and one that is being bantered about right now both in the medical and surgical communities; that is specifically, should we change the outcome measure from purely symptom-based to one which measures the control of esophageal acid reflux? I would agree with your premise that we should change, particularly as increasing numbers of studies show that we may be able to alter the natural history of the metaplasia, dysplasia, and cancer sequence.

Yes, we have moved toward routine pH testing in patients with visible segments of Barrett’s epithelium. I can’t tell you the precise interval. My bias would be somewhere between one and three years. I can tell you that I have watched a few patients go from negative pH studies to positive pH studies over the years. One of the patients was redone because his pH study turned positive. I do think the outcome measure should change.

Is there a greater likelihood of recurrent symptoms in the population with Barrett’s? I think the answer to that is probably yes. There are increasing numbers of papers that suggest that this is true, including those from Dr. Hunter Jamieson and others in the audience. It is a more difficult population of patients. When you throw patients with short segment Barrett’s into the equation it may be a little bit different, but the severe physiologic and anatomic defects do make a difference in the long-term outcome. It also probably makes a difference in the application of laparoscopic fundoplication. I do think the incident of recurrent hernias and recurrent symptoms is higher in Barrett’s patients when done laparoscopically. Whether we know this well enough now to exclude patients with Barrett’s from the laparoscopic approach, I don’t think we do.

There was no significant trend in the time to recurrence. I didn’t show you that data, but the recurrence was pretty much equal over the five years, it did not cluster in the early years or in the late years.

Dr. John G. Hunter (Atlanta, Georgia): This magnificent paper makes four points, and I have four questions to follow.

The salient points were that outcomes of antireflux surgery in patients with Barrett’s esophagus were not as good as those seen in patients with uncomplicated disease, that patients with Barrett’s esophagus were more likely to need second operations than those with uncomplicated disease, but that successful antireflux surgery prevented progression to high grade dysplasia and neoplasia. Additionally, 20% of patients had histologic regression of intestinal metaplasia. We have made nearly identical observations in a similar size population followed for five years, and these data will be presented at the SSAT meeting next month in Atlanta.

The four questions relate to histologic regression:

Does the length of Barrett’s esophagus matter in determining the likelihood of histologic regression?

Does the duration of follow-up influence the likelihood of regression? We have found more histologic regression in those patients with the longest follow-up.

Lars Lundell, looking at this issue of follow-up pH study, has said that patients who develop pH failure generally develop recurrent reflux symptoms. Were the patients who were pH positive in your follow-up studies symptomatic? And were those the same patients who progressed histologically?

And lastly, does the type of operation influence the histologic outcome? Why do you shy away from my favorite operation in the patient with advanced esophageal disease and esophageal shortening, the Collis-Nissen, which couples the advantage of reestablishing esophageal length with creation of the best antireflux valve?

Dr. Jeffrey H. Peters: Thank you, Dr. Hunter, for your very insightful questions.

Does the length of a Barrett’s effect regression? It probably does, although I don’t know that we have a preponderance of evidence yet. Steve DeMeester before this Association two years ago, presented a paper showing that cardia-intestinal metaplasia, that is non-visible Barrett’s segments has 70% regression. The data is beginning to sort out that short segment Barrett’s esophagus has about a 20 to 40% likelihood of regression. 80% of those that regressed in our population had short segment Barrett’s. So it probably will relate to the length of the Barrett’s segment, although I don’t think we have quite enough data to say that dogmatically yet.

Does the rate of regression depend on the length of follow-up? I don’t know that I have that data from our experience but my bias would be that it probably does, and as we follow these patients longer, particularly if their esophageal acid exposure is controlled, we may see a higher rate of regression. Remember, these are all low-grade dysplasia at the time of operation and then they are re-biopsied up to a year or two later.

All the patients in our study who were pH positive post-op, interestingly enough, were symptomatic. The reverse, of course, is not true. All the patients who are symptomatic are not pH positive. Pretty much everyone has shown that. The fact that all of our patients who were pH positive were symptomatic may help clinically.

Finally, did the type of operation have any relationship to histologic regression? Again, I don’t know that we can answer that question from this data. That certainly is a very interesting question. I think it is likely going to fall to the efficacy of the operation to control esophageal acid exposure.

We have been moving a little bit away from the Collis procedure, swayed by our own data with outcomes that are less than ideal and others that have shown that there is a persistent prevalence of continued esophageal acid exposure in patients following a Collis. I don’t think we have the answer to the large hernia and short esophagus quite yet.

Dr. Carlos A. Pellegrini (Seattle, Washington): Findings published last year from the longitudinal study of the natural history of Barrett’s carried out as part of the ‘Seattle Barrett’s Project‘ (Rudolph et al Ann Int Medicine 2000:132:612) suggest that it is difficult to differentiate low-grade from no-dysplasia when it comes to its natural history. Indeed, the overall predictive value in terms of developing a cancer in patients with low-grade or no-dysplasia was the presence of DNA abnormalities (aneuploidy) or abnormal p53 genes. Did you determine DNA ploidy and p53 status in your patients, and were they altered by operation? Do you have any thoughts with regards to the difference between low-grade dysplasia and no-dysplasia? Can you really differentiate the two accurately?

Second, while I am happy that you found no cancer in your 408 patient/year follow-up, and no development of high-grade dysplasia, I am concerned about the message that readers may get from these data. In particular, I am talking about the need to continue endoscopic surveillance after operation in patients who have Barrett’s esophagus. It is possible that someone may infer from your data that, since there appears to be no risk of developing either high grade dysplasia or cancer, that there is no value to surveillance. Other studies, such as those by our new Honorary Member Dr. Jamieson, and by Dr. Csendes from Chile suggest that adenocarcinoma of the esophagus may develop several years after antireflux surgery in patients with Barrett’s. Can you expand on this?

Dr. Jeffrey H. Peters: Two very important points.

The first relates to the ambiguity of the phenotypic recognition of dysplasia. There is no doubt that there is some subjectivity in its interpretation. If you show a dysplastic slide to two different pathologists, even two different expert pathologists, you will find a 10 to 15% likelihood of discordant results. The question begs for a control group, without a doubt. I certainly hope that one day in the near future we can put together such a study with the appropriate control group so that we can answer that question.

You also point out the importance of other more objective measures, like the molecular markers. We and a number of other laboratories around the country are beginning to walk down that path. Clearly, we need such information. Our data is suggestive, but it certainly doesn’t end the question.

The same is true when we put up a slide showing there are no cancers or no dysplasias. I wouldn’t want the audience to take away the idea that patients should not be surveyed. Remember this is a retrospective study. And remember that there was a 20% failure within our group. If we recognize our own limitations, then I think we will realize the continued need for endoscopic surveillance. That doesn’t mean that we shouldn’t ask the question: Can we prevent cancers and can we prevent dysplasia? I think the evidence is increasing that we can, and that is a very important question.

Dr. Lawrence W. Way (San Francisco, California): What about high grade dysplasia?

Dr. Jeffrey H. Peters: High grade dysplasia ought to be removed. In every single patient? That is beyond my time commitment right now to answer that question, Dr. Way.