Barrett’s Esophagus: Model of Neoplastic Progression

Human cancer progression is characterized by clonal expansion of cells with accumulated genetic errors. Invasive carcinomas contain all the genetic errors that were acquired during neoplastic progression and then continue to accumulate further abnormalities, leading to tumor heterogeneity. Many investigations of human cancer have given valuable insights in genetic abnormalities important for tumor biology. Early events responsible for neoplastic progression, however, are often impossible to investigate in invasive cancers because the premalignant tissue in which the tumors develop are often overgrown and the premalignant conditions cannot be studied in vivo because they are either not detected owing to lack of symptoms or are removed before cancer develops. Unlike many other premalignant conditions Barretts esophagus is often associated with symptoms leading to diagnosis at an early stage before cancer develops, and the premalignant epithelium is seldom removed at an early stage of cancer progression. Furthermore, in patients who present with invasive carcinoma the tumor is often surrounded by premalignant epithelium, which is available for further investigations. Therefore Barretts esophagus is an excellent model in which to study the early events of neoplastic progression. It may not only contribute to a better understanding of the neoplastic process but also provide a base for safer assessment of cancer risk during surveillance for early detection of esophageal adenocarcinoma.     

Barrett’s Esophagus: A Review of the Literature

Barrett’s esophagus (BE) is the premalignant lesion of esophageal adenocarcinoma (EAC) defined as specialized intestinal metaplasia of the tubular esophagus that results from chronic gastroesophageal reflux. Which patients are at risk of having BE and which are at further risk of developing EAC has yet to be fully established. Many aspects of the management of BE have changed considerably in the past 5 years alone. The aim of this review is to define the critical elements necessary to effectively manage individuals with BE. The general prevalence of BE is estimated at 1.6–3% and follows a demographic distribution similar to EAC. Both short-segment (<3 cm) and long-segment (≥3 cm) BE confer a significant risk for EAC that is increased by the development of dysplasia. The treatment for flat high-grade dysplasia is endoscopic radiofrequency ablation therapy. The benefits of ablation for non-dysplastic BE and BE with low-grade dysplasia have yet to be validated. By understanding the intricacies of the development, screening, surveillance, and treatment of BE, new insights will be gained into the prevention and early detection of EAC that may ultimately lead to a reduction in morbidity and mortality in this patient population.     

Surgical Treatment of Barrett’s Esophagus: 1980-2003

Barretts esophagus is a complication of long-standing gastroesophageal reflux and can be a premalignant condition. The goals of surgical treatment, which were well summarized by DeMeester, have been increased and more detailed by us. They consist of (1) controlling symptoms of gastroesophageal reflux disease; (2) abolishing acid and duodenal reflux into the esophagus; (3) preventing or eliminating the development of complications; (4) preventing extension of or an increase in the length of intestinal metaplasia; (5) inducing regression of intestinal metaplasia to the cardiac mucosa; and (6) preventing progression to dysplasia, thereby inducing regression of low-grade dysplasia and avoiding the appearance of an adenocarcinoma. We have reviewed 25 articles in the English-language literature published from 1980 to 2003 dealing specifically with the surgical treatment of Barretts esophagus. In most of these papers too few patients were included, the follow-up was less than 60 months, and the clinical success deteriorated with time. Acid reflux persists after surgery in nearly 35% of Barretts esophagus patients; and at 10 years after surgery duodenal reflux is present in 95%. Peptic ulcer, stricture, and erosive esophagitis are present in 15% to 30% late after surgery, and in 16% there is progression of the intestinal metaplasia. There is the appearance of low-grade dysplasia in 6.0% and adenocarcinoma in 3.4%, and there is regression of low-grade dysplasia in 45.0%. These results challenge the arguments supporting antireflux surgery for patients with Barretts esophagus: The clinical results are not optimal, no long-lasting effect has been demonstrated, and it does not prevent the appearance of dysplasia or adenocarcinoma. An excellent alternative is acid suppression and a duodenal diversion procedure, which has had 91% clinical success for more than 5 years. This regimen has almost eliminated acid and duodenal reflux, and there has been no progression to dysplasia or adenocarcinoma. Moreover, in 60% of the patients with low-grade dysplasia, regression to nondysplastic mucosa has occurred.     

High-Energy Laser Therapy of Barrett’s Esophagus: Preliminary Results

We present the preliminary results obtained by our research group utilizing Nd:YAG and diode lasers to treat Barretts esophagus (BE). A total of 15 patients with BE (mean age 58 years) underwent endoscopic laser therapy: 11 with intestinal metaplasia, 2 with low-grade dysplasia, and 2 with high-grade dysplasia. The mean length of BE was 4 cm (range 1–12 cm). Six of these patients also underwent antireflux surgery, and nine were prescribed acid-suppressive medication. Endoscopic Nd:YAG laser treatment was carried out from 1997 to 1999; thereafter, diode laser was employed. The mean follow-up of these patients after the first laser session was 28 months. Patients underwent a mean of 6.5 laser sessions (range 3–17 sessions), with no apparent complications. The mean energy per session was 1705 JJ. Only six of these patients (40%) showed complete endoscopic and histologic remission, but a mean of 77% (SD 23.8%) of the total metaplastic tissue in all these patients was ablated. The percentage of healed mucosa was higher in patients with short-segment BE (92%) (p < 0.05) and in subjects treated by two or more laser sessions per centimeter of BE length (89%) (p < 0.05). All four patients with dysplasia showed histologic regression to nondysplastic BE or to squamous epithelium, without recurrence during a mean follow-up of 30 months. The patients who underwent antireflux surgery and those prescribed pharmacologic treatment had similar results. Nd:YAG and diode laser treatment of BE is a safe, effective procedure; it required two sessions per centimeter of metaplasia; and it achieved complete regression of the dysplasia. Further studies are necessary to quantify its effect on cancer incidence.     

Prevention of Adenocarcinoma by Reversing Barrett’s Esophagus with Mucosal Ablation

The ultimate goal of therapy in patients with Barretts esophagus (BE) is to reduce the risk of developing adenocarcinoma of the esophagus. Neither pharmacologic nor surgical therapy has been documented to reduce this risk. There is preliminary evidence that many forms of mucosal ablation combined with acid reduction therapy result in restitution of normal squamous epithelium in patients with BE. Acid reduction can be accomplished with high-dose proton pump inhibitor therapy or antireflux surgery. Endoscopic ablation can be accomplished with photodynamic therapy, laser, multipolar electrocoagulation, a heater probe, and argon plasma coagulation. These techniques require further study so the complication rates can be compared. The success of reversing BE must be evaluated in a standard way utilizing large-capacity biopsy forceps through a therapeutic endoscope. Ideally, patients at high risk of developing adenocarcinoma of the esophagus can be treated with ablation therapy and followed to document a reduction in the development of adenocarcinoma of the esophagus. A validated biomarker would help select high risk patients appropriate for reversal therapy. Currently, patients who are at prohibitive risk for surgery or who refuse surgery are candidates for combination therapy including mucosal ablation to reverse their BE. This therapy offers the promise of less morbidity and greater quality of life than resection.     

Barrett’s Esophagus: Environmental Influences in the Progression of Dysplasia

Barretts esophagus (BE) is composed of multiple lineages including Paneth cells and endocrine cells in addition to gastric and intestinal cells. Although the origin of the BE stem cell is a matter of conjecture, the stem cells are clearly multipotent, and therefore the phenotype is restricted by genomic imprinting (termed restricted potency). Recent evidence suggests that the microenvironment may select various lineages. In this regard the proportion of gastric and specialized intestinal metaplastic cells has been attributed to the composition of the refluxate, acid or bile, respectively. Experimental evidence also implicates specific xenobiotics in this process, including bile acids. In particular we discuss the potential biologic roles of bile acids in epithelial adaptation from in vivo and in vitro models.     

Prevalence of Barrett’s Esophagus in Bariatric Patients Undergoing Sleeve Gastrectomy

Background

The appearance and incidence of gastroesophageal reflux after sleeve gastrectomy is not yet resolved, and there is an important controversy in the literature. No publications regarding the appearance of Barrett’s esophagus after sleeve gastrectomy are present in the current literature.

Purpose

The purpose of this paper was to report the incidence of Barrett’s esophagus in patients submitted to sleeve.

Material and Methods

Two hundred thirty-one patients are included in this study who were submitted to sleeve gastrectomy for morbid obesity. None had Barrett’s esophagus. Postoperative upper endoscopy control was routinely performed 1 month after surgery and 1 year after the operation, all completed the follow-up in the first year, 188 in the second year, 123 in the third year, 108 in the fifth year, and 66 patients over 5 years after surgery.

Results

Among 231 patients operated on and followed clinically, reflux symptoms were detected in 57 (23.2 %). Erosive esophagitis was found in 38 patients (15.5 %), and histological examination confirmed Barrett’s esophagus in 3/231 cases (1.2 %) with presence of intestinal metaplasia.

Conclusion

Bariatric surgeons should be aware of the association of gastroesophageal reflux (GER) disease and obesity. Appropriate bariatric surgery should be indicated in order to prevent the occurrence of esophagitis and Barrett’s esophagus.