Barret Esophagus

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Barrett-Ösophagus (Endobrachyösophagus)

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• Das Auftreten einer Schleimhautmetaplasie im distalen Ösophagus ist eine Komplikation der Refluxkrankheit.
• Differenziertes Plattenepithel ist durch differenziertes Zylinderepithel ersetzt worden.
• Dieser Selbstschutz der Speiseröhre führt zwar einerseits zu einer größeren Unempfindlichkeit gegenüber saurem oder alkalischem Refluat, birgt aber in der Folge die
• Gefahr einer Dysplasieentstehung und eines sich daraus entwickelnden Karzinoms.

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Pathogenese

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• Die Erstbeschreibung der heute als intestinale Metaplasie bezeichneten potentiellen Präkanzerose geht auf Untersuchungen des amerikanischen Chirurgen Norman Barrett aus dem Jahre 1950 zurück.
• einer langjährigen Refluxösophagitis und weiteren prädisponierenden Faktoren wie ausgeprägtem duodenogastralem Reflux und alkalischem Refluatanteil der Barrett-Ösophagus als eine präkanzerotisch einzustufende Erkrankung entwickeln kann.
• Dabei wird die Häufigkeit einer Epithelmetaplasie mit 10% aller Refluxkranken angenommen.
• Eine andere Theorie geht davon aus, dass es insgesamt drei Formen der Refluxkrankheit gibt:
• die symptomatische ohne endoskopischen Nachweis einer erosiven Ösophagitis,
• die klassische mit einer erosiven Schleimhautalteration und
• die Barrett-Mukosa.
• weder eine medikamentöse noch eine operative Therapie die maligne Entartung verhindern kann.
• Daher ist für diese Patienten ein endoskopisches Überwachungsprogramm mit möglichst genauer histopathologischer Differenzierung der Barrett-Schleimhaut in Metaplasie oder intraepitheliale Neoplasie (ein neoplastischer Prozess im Epithel oberhalb einer intakten Basalmembran) von besonderer Bedeutung.

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Therapie

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• Behandlung der Symptome im Vordergrund.
• intestinalen Metaplasie das Risiko der Karzinomentwicklung etwa 3% beträgt,
• intraepithelialen Neoplasie mit hochgradiger Dysplasie um das 10fache erhöht ist.
Empfehlungen für die Praxis:
• Patienten mit intestinaler Metaplasie können im Abstand von 3 Jahren kontrollendoskopiert werden.
• Beim Nachweis einer intraepithelialen Neoplasie mit niedrigem Dysplasiegrad ist zunächst eine halbjährliche Kontrolle mit Biopsie empfohlen.
• Wenn der Dysplasiegrad unverändert bestehen bleibt, können die Untersuchungsintervalle auf 12 Monate ausgedehnt werden.
• Bei Nachweis hochgradiger Dysplasien ist die histopathologische Diagnose durch ein Referenzzentrum zu bestätigen.
• Danach muss mit dem Patienten über eine operative Intervention in Form einer (limitierten) Resektion des Ösophagus gesprochen werden, da bei etwa jedem 5. Patienten in diesem Stadium bereits ein (Früh-)Karzinom besteht.
• Eine Alternative zur Resektion scheint sich durch eine endoskopisch durchführbare lokale Mukosaresektion zu entwickeln.
• Ziel dieses Verfahrens ist die vollständige Ausschälung der Barrett-Schleimhaut im distalen Ösophagus.

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INTRODUCTION

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Barrett's esophagus is the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus.
The condition develops as a consequence of chronic gastroesophageal reflux disease (GERD), and predisposes to the development of adenocarcinoma of the esophagus.

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EPIDEMIOLOGY

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• Barrett's esophagus can affect children, it rarely occurs before the age of five
• Barrett's esophagus is an acquired condition, not a congenital one.
• The male to female ratio is approximately 2:1
• Estimates of the frequency of Barrett's esophagus in the general population have varied widely ranging from 0.9 to more than 20 percent
• Familial aggregation of Barrett's esophagus has been described
• The overall reliability of endoscopy with biopsy for detection of specialized intestinal metaplasia in Barrett's esophagus is approximately 80 percent.

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CLINICAL FEATURES

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• The specialized intestinal columnar metaplasia typical of Barrett's esophagus causes no symptoms.
• Most patients are seen initially for symptoms of associated GERD, such as heartburn, regurgitation, and dysphagia.
• GERD associated with long-segment Barrett's esophagus frequently is complicated by
• esophageal ulceration,
• stricture, and
• hemorrhage
• patients with a peptic stricture have a higher prevalence of Barrett's esophagus than those without strictures.

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DIAGNOSTIC CRITERIA

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— Endoscopic examination generally is required to diagnose Barrett's esophagus.
Two criteria must be fulfilled:
• The endoscopist must document that columnar epithelium lines the distal esophagus.
• Histologic examination of biopsy specimens from that columnar epithelium must reveal intestinal metaplasia.
• Columnar epithelium has a reddish color and velvet-like texture on endoscopic examination, whereas squamous epithelium has a pale, glossy appearance

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Intestinal metaplasia at the GEJ and in the gastric cardia

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Medical societies recommend endoscopic cancer surveillance routinely for patients with Barrett's esophagus, but not for patients with intestinal metaplasia in the stomach.

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Differences between long- and short-segment Barrett's

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• prevalence of short-segment Barrett's esophagus is substantially higher than long-segment Barrett's esophagus.
• The degree and mechanism of acid exposure in patients with short- and long-segment Barrett's esophagus suggest that patients who develop long-segment Barrett's were predisposed to more severe reflux:
• Patients with long-segment Barrett's tend to have upright and supine reflux in contrast to those with short-segment Barrett's who have predominantly upright reflux
• Proximal esophageal acid exposure is more common in patients with long-segment Barrett's
• Compared with patients with long-segment Barrett's, those with short-segments tend to have higher LES pressures and increased distal esophageal peristaltic amplitudes

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Dysplasia and adenocarcinoma in short-segment Barrett's

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• patients with short-segment Barrett's have a lower incidence of dysplasia since less mucosa is involved (6 to 8 versus 15 to 24 percent in long-segment Barrett's)
• risk of adenocarcinoma has been estimated to be 2 to 15 times higher in patients with long-segment Barrett's.
• patients with short- and long-segment Barrett's esophagus presently are managed similarly.

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SCREENING PATIENTS FOR BARRETT'S ESOPHAGUS

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• patients with GERD symptoms should be screened endoscopically for Barrett's esophagus
• long-segment Barrett's esophagus can be found in 3 to 5 percent of patients who have endoscopy for chronic GERD symptoms, whereas
• 10 to 15 percent have short-segment Barrett's esophagus
• patients with GERD symptoms are at increased risk for esophageal adenocarcinoma:
• screening should not be performed in men younger than 50 years or in women of any age, regardless of the frequency of GERD symptoms,
• screening may be appropriate in men over the age of 60 years with weekly GERD.

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Guidelines

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American Gastroenterological Association
screening patients with multiple risk factors associated with esophageal adenocarcinoma for Barrett's esophagus. Risk factors considered by the AGA include:
• Age 50 years or older
• Male sex
• White race
• Chronic GERD
• Hiatal hernia
• Elevated body mass index
• Intra-abdominal distribution of body fat
The AGA recommends against screening the general population with GERD.
American College of Gastroenterology
"If the patient's history is typical for uncomplicated GERD, an initial trial of empirical therapy [including lifestyle modification] is appropriate. Patients in whom empiric therapy is unsuccessful or who have symptoms suggesting complicated disease should have further diagnostic testing [ie, endoscopy]."
Symptoms that might suggest complicated disease requiring early endoscopic evaluation include anorexia, weight loss, dysphagia, odynophagia, bleeding, and signs of systemic illness.

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Alternate screening methods

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• capsule sponge (Cytosponge, Surepath; BD Diagnostics, Durham, NC) combined with an immunohistochemical biomarker (trefoil factor 3)
• The patient ingests a gelatin capsule that is attached to a string and contains a compressed mesh.

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SUMMARY AND RECOMMENDATIONS

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• Barrett's esophagus is usually discovered during endoscopic examinations of middle-aged and older adults whose mean age at the time of diagnosis is approximately 55 years. The specialized intestinal columnar metaplasia typical of Barrett's esophagus causes no symptoms. Most patients are seen initially for symptoms of associated gastroesophageal reflux disease (GERD), such as heartburn, regurgitation, and dysphagia. (See'Epidemiology' above.)
• Two criteria must be fulfilled to make a diagnosis of Barrett's esophagus: (See 'Diagnostic criteria' above.)
• The endoscopist must document that columnar epithelium lines the distal esophagus.
• Histologic examination of biopsy specimens from that columnar epithelium must reveal specialized intestinal metaplasia. Some data suggest that gastric cardia-type epithelium in the esophagus also might predispose to cancer and thus might be considered "Barrett's esophagus," but most authorities still require the presence of specialized intestinal metaplasia for an unequivocal diagnosis.
• It has been proposed that patients with GERD symptoms should be screened endoscopically for Barrett's esophagus. We suggest that patients with at least weekly GERD symptoms that have been present for at least five years and who have multiple risk factors for esophageal adenocarcinoma undergo screening for Barrett's esophagus. However, the evidence supporting this recommendation is weak, and we feel that decisions on when to recommend endoscopic screening should be individualized. Factors known to increase the risk for Barrett's esophagus include white ethnicity, older age, obesity, and long duration of GERD symptoms. (See 'Screening patients for Barrett's esophagus' above.)
• The management of patients with Barrett's esophagus is discussed separately. (See "Management of Barrett's esophagus".)

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The management of patients with Barrett's esophagus involves three major components:

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• Treatment of the associated GERD
• Endoscopic surveillance to detect dysplasia
• Treatment of dysplasia

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TREATMENT OF GERD

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• initial therapy with a proton pump inhibitor (PPI), rather than incremental "step up" therapy based upon symptom response, for patients with Barrett's esophagus.
• In addition to controlling reflux symptoms, the goal of PPI therapy is to prevent cancer development.
• for patients with no GERD symptoms and no endoscopic signs of reflux esophagitis, the use of PPIs would be solely to reduce the risk of progression to dysplasia or cancer.
• we suggest the use of PPIs in such patients after a discussion of the potential risks and benefits.
• Antireflux surgery (fundoplication) is another option for controlling GERD in patients with Barrett's esophagus
• fundoplication does not appear to be more effective at preventing esophageal adenocarcinoma than medical therapy
• Does aggressive treatment of reflux prevent progression to cancer?
• Available data suggest, but do not prove, that aggressive antireflux therapy might also prevent cancer in these patients.
• Clinical studies
• Treatment of reflux sometimes results in limited regression of Barrett's esophagus.
• Aggressive antireflux therapy can cause partial regression of the specialized intestinal metaplasia in Barrett's esophagus
• Regression of Barrett's epithelium has also been observed with fundoplication , and some authorities have suggested that fundoplication might be more effective than antisecretory therapy for preventing cancer in Barrett's esophagus

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ENDOSCOPIC SURVEILLANCE

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• Influence of Barrett's esophagus on mortality
• annual cancer incidence in patients with Barrett's esophagus have ranged from 0.2 to 2.0 percent
• risk of developing esophageal cancer is increased at least 30-fold above that of the general population
• Evidence supporting surveillance
• endoscopic surveillance can detect curable dysplasia in Barrett's esophagus
• asymptomatic cancers discovered during surveillance are less advanced than those found in patients who present with cancer symptoms like dysphagia and weight loss
• Dysplasia as a marker of risk
• Cancers in this condition are judged to evolve through a sequence of genetic alterations that are associated with dysplastic changes of progressive severity.
• The following are our estimates of cancer risk for patients with Barrett's esophagus based upon available reports:
o For the general population of patients with Barrett's esophagus, the risk of esophageal adenocarcinoma is approximately 0.5 percent per year.
o For patients with high-grade dysplasia, the rate of cancer development is 5 to 8 percent per year.
o For patients with low-grade dysplasia, the risk of cancer is so poorly defined that it is not possible to provide a precise estimate.
• Presumably, the risk is greater than that of the general population of patients with Barrett's esophagus (0.5 percent per year) and less than that of patients with high-grade dysplasia (5 to 8 percent per year).
• Detecting dysplasia
• dysplastic areas can easily be missed because of biopsy sampling error.
• even when dysplasia is detected, foci of invasive cancer can be missed.
• esophagectomies because endoscopic examination revealed high-grade dysplasia in Barrett's esophagus with no apparent tumor mass, cancer (missed because of biopsy sampling error) was present in approximately 40 percent of resection specimens
• one meta-analysis of these studies found that only 13 percent of the resection specimens had invasive cancer,
• random biopsy sampling techniques have been used because dysplasia in Barrett's epithelium traditionally had been considered an endoscopically inconspicuous lesion.
• Molecular markers
• Promising molecular markers include abnormalities in p53 and cyclin D1 expression, and abnormal cellular DNA content
• Endoscopic techniques
• Long versus short segment
• risk of cancer for patients with short-segment Barrett's esophagus is less than that for patients with long-segment disease.

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TREATMENT OF HIGH-GRADE DYSPLASIA

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For patients with verified high-grade dysplasia (also called intraepithelial neoplasia) in Barrett's esophagus, there are generally four proposed management options:
• Esophagectomy
• Endoscopic therapies that ablate the neoplastic tissue
• Endoscopic mucosal resection
• Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.
• (AGA) recommended that patients with high-grade dysplasia within Barrett's esophagus undergo
• endoscopic eradication therapy with radiofrequency ablation,
• photodynamic therapy, or
• endoscopic mucosa resection.
Esophagectomy —With the development of efficacious endoscopic therapies, esophagectomy can now often be avoided.
• Endoscopic ablative therapies
• Radiofrequency ablation
• Photodynamic therapy
• Endoscopic spray cryotherapy
• Endoscopic mucosal resection
• Intensive endoscopic surveillance

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ENDOSCOPIC TREATMENT OF LOW-GRADE DYSPLASIA AND NONDYSPLASTIC BARRETT'S ESOPHAGUS

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multipolar electrocoagulation,
photodynamic therapy (PDT), and
radiofrequency ablation (RFA)

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CHEMOPREVENTION

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Epidemiological data suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), might protect against cancer in Barrett's esophagus

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American Gastroenterological Association

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• Screening for Barrett's esophagus is suggested in patients with multiple risk factors associated with esophageal adenocarcinoma (age 50 years or older, male sex, white race, chronic GERD, hiatal hernia, elevated body mass index, or intra-abdominal distribution of body fat).
• The AGA recommends against screening the general population with GERD for Barrett's esophagus.
• For patients with Barrett's esophagus, GERD therapy with medication effective to treat GERD symptoms and to heal reflux esophagitis is clearly indicated, as it is for patients without Barrett's esophagus.
• The diagnosis of dysplasia in Barrett's esophagus should be confirmed by at least one additional pathologist, preferably one who is an expert in esophageal histopathology.
• Endoscopic surveillance is suggested for patients with Barrett's esophagus using the following surveillance intervals:
• No dysplasia: 3 to 5 years
• Low-grade dysplasia: 6 to 12 months
• High-grade dysplasia in the absence of eradication therapy: 3 months
• The AGA recommends against the use of molecular biomarkers to confirm the histologic diagnosis of dysplasia or as a method of risk stratification for patients with Barrett's esophagus.
• Evidence to support the use of acid-reducing agents, specifically PPIs, in patients with Barrett's esophagus solely to reduce the risk of progression to dysplasia or cancer is indirect and has not been proven in a long-term controlled trial. The risks and potential benefit of long-term PPI therapy should be discussed carefully with patients with Barrett's esophagus in the context of their overall health status and medication use.
• For patients with Barrett's esophagus who are undergoing surveillance, the AGA recommends:
• Endoscopic evaluation using white light endoscopy
• Four-quadrant biopsy specimens be taken every 2 cm
• Specific biopsy specimens of any mucosal irregularities be submitted separately to the pathologist
• Four-quadrant biopsy specimens be obtained every 1 cm in patients with known or suspected dysplasia
• The AGA suggests against requiring chromoendoscopy or advanced imaging techniques for the routine surveillance of patients with Barrett's esophagus.
• The AGA recommends against attempts to eliminate esophageal acid exposure for the prevention of esophageal adenocarcinoma. Such attempts include proton pump inhibitor (PPI) administration in doses greater than once daily, esophageal pH monitoring to titrate PPI dosing, and antireflux surgery.
• The AGA suggests against the use of aspirin solely to prevent esophageal adenocarcinoma in the absence of other indications. However, it recommends screening patients to identify cardiovascular risk factors for which aspirin therapy is indicated.
• Endoscopic eradication therapy with radiofrequency ablation, photodynamic therapy, or endoscopic mucosal resection (EMR) rather than surveillance is recommended for treatment of patients with confirmed high-grade dysplasia within Barrett's esophagus.
• EMR is recommended for patients who have dysplasia in Barrett's esophagus associated with a visible mucosal irregularity to determine the T stage of the neoplasia.

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SUMMARY AND RECOMMENDATIONS

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• We suggest that patients with Barrett's esophagus have regular surveillance endoscopy to obtain esophageal biopsy specimens (Grade 2C).
• Gastroesophageal reflux should be treated prior to surveillance to minimize confusion caused by inflammation in the interpretation of dysplasia.
• we suggest that the first surveillance endoscopy be performed within one year of the index diagnosis of Barrett's esophagus if there is any question regarding the adequacy of biopsy sampling
• For patients with no dysplasia or endoscopic signs of neoplasia following adequate biopsy sampling, we suggest surveillance endoscopy at an interval of every three to five years (Grade 2C).
• If dysplasia is noted, we recommend that it be verified by consultation with a second pathologist with expertise in esophageal histopathology.
• For most patients with verified low-grade dysplasia after extensive biopsy sampling, we suggest surveillance endoscopy at intervals of 6 to 12 months (Grade 2C). Extensive biopsy sampling involves taking four-quadrant biopsies at intervals of no more than 1 cm throughout the columnar-lined esophagus.

Radiofrequency ablation may be an appropriate therapeutic alternative for verified low-grade dysplasia in selected cases if an experienced provider is available. (See 'Endoscopic treatment of low-grade dysplasia and nondysplastic Barrett's esophagus' above and "Radiofrequency ablation for Barrett's esophagus", section on 'Low-grade dysplasia'.)
• Esophagectomy is the only therapy for high-grade dysplasia that clearly removes all of the neoplastic epithelium, but it also has the highest rates of procedure-related mortality and long-term morbidity. On the other hand, endoscopic eradication therapy is available, has proven efficacy (although long-term data are not yet available), and is relatively safe. (See 'Esophagectomy' above and 'Endoscopic ablative therapies' above.)
• The choice of treatment for high-grade dysplasia and intramucosal cancer in Barrett's esophagus depends upon:
• The patient's age (eg, older patients with Barrett's esophagus are less likely to develop cancer due to their shorter life expectancy compared with younger patients)
• The patient's comorbidities
• The extent of dysplasia (short segments or Barrett's esophagus are easier to ablate than longer segments with multifocal dysplasia)
• Local expertise in surgery and endoscopy
• The patient's preferences with regard to undergoing surgery, undergoing repeated endoscopies, and accepting the possibility of recurrent neoplasia in the absence of esophagectomy
• For most patients with Barrett's esophagus and high-grade dysplasia who are fit to undergo endoscopy, we suggest endoscopic eradication therapy rather than esophagectomy or intensive endoscopic surveillance (Grade 2C). Endoscopic eradication therapy includes endoscopic mucosal resection for the removal and staging of visible lesions (if present), followed by radiofrequency ablation or photodynamic therapy to ablate the remaining metaplastic epithelium. (See 'Endoscopic mucosal resection' above and 'Endoscopic ablative therapies' above and 'American Gastroenterological Association' above.)

For younger patients with high-grade dysplasia, especially for those with long-segment Barrett's esophagus and multifocal dysplasia, esophagectomy is a reasonable alternative. After a thorough discussion with the younger patient of the risks and benefits of endoscopic eradication therapy and esophagectomy, the choice between the two should be based on patient preferences and the availability of skilled practitioners. For very elderly or infirm patients for whom invasive endoscopic procedures pose a substantial risk, intensive endoscopic surveillance is reasonable. (See'Esophagectomy' above and 'Intensive endoscopic surveillance' above.