Barrett s Esophagus: Old Dog, New Tricks Stuart Jon Spechler, M.D. Chief, Division of Gastroenterology, VA North Texas Healthcare System; Co-Director, Esophageal Diseases Center, Professor of Medicine, Berta M. and Cecil O. Patterson Chair in Gastroenterology, UT Southwestern Medical Center Consultant: Takeda Disclosures Stratified Squamous Epithelium Metaplastic Columnar Epithelium Barrett s Esophagus The condition in which a metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus Affects 5.6% of adult Americans AGA Medical Position Statement. Gastroenterology 2011;140:1084. Barrett s Metaplasia Esophageal Adenocarcinoma 1
Metaplasia One type of adult tissue replaces another Response to chronic tissue injury Esophageal mucosal damage can heal through: Regeneration of squamous epithelium Columnar metaplasia GERD Reflux Esophagitis Mucosal Damage Stratified Squamous Epithelium (Normal Esophagus) Intestinal Metaplasia (Barrett s Esophagus) Pathogenesis of Barrett s Metaplasia Potential Progenitor Cells for Columnar Metaplasia Mature squamous cells change into columnar cells Transdifferentiation involves individual differentiated cells Immature progenitor cells Can produce and maintain multiple different cell types - Progenitor cells native to esophagus - Basal cells of squamous epithelium - Cells in submucosal gland ducts - Progenitor cells in proximal stomach - Gastric cardia - Embryonic-type cells at GEJ - Progenitor cells from bone marrow Must involve reflux-related reprogramming of the expression of developmental transcription factors Squamous Epithelium Goblet Cells Intestinal Metaplasia 2
Barrett s Esophagus Goblet Cells Intestinal Metaplasia No Goblet Cells Cardiac Mucosa British Society of Gastroenterology Definition of Barrett s Esophagus 2014 An esophagus in which any portion of the normal distal squamous epithelial lining has been replaced by metaplastic columnar epithelium, which is clearly visible endoscopically ( 1 cm) above the GOJ and confirmed histopathologically from oesophageal biopsies. Includes cardiac mucosa Fitzgerald RC et al. Gut 2014;63:7-42. Can be metaplastic, acquired as a result of reflux Expresses molecular markers of intestinal differentiation (e.g. villin, CDX2) Exhibits DNA content abnormalities similar to intestinal metaplasia Frequently found next to esophageal adenocarcinomas One study suggests cancer risk is similar to that for intestinal metaplasia Kelty CJ. Scand J Gastroenterol 2007;42:1271. Cardiac Mucosa 3
Estimates of cancer risk in Barrett s based on studies that included patients with intestinal metaplasia either primarily or exclusively Goblet cell unlikely to be cell of origin for adenocarcinoma, but goblet cell a good marker for malignant predisposition Intestinal Metaplasia (with goblet cells) Most studies suggest cancer risk for cardiac mucosa alone is minimal Westerhoff M. Clin Gastroenterol Hepatol 2012;10:1232. Disagreement on Histological Criteria for Barrett s Esophagus Should Barrett s esophagus be defined as... a histological curiosity? (a mucosal metaplasia irrespective of its clinical importance) a medical condition? (a mucosal metaplasia that predisposes to cancer) Barrett s Esophagus Conceptual Definition 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 Diagnostic Criterion Intestinal metaplasia (with goblet cells) in the esophagus AGA Medical Position Statement. Gastroenterology 2011;140:1084. Risk Factors for Barrett s Esophagus and Esophageal Adenocarcinoma Chronic GERD Heartburn, hiatal hernia Age >50 years Uncommon in children Male sex White race Less common in African-Americans, Uncommon in Asians Obesity Intra-abdominal fat distribution 4
AGA Medical Position Statement on Endoscopic Screening for Barrett s Esophagus We recommend against screening the general population with GERD for Barrett s esophagus. In patients with multiple risk factors associated with esophageal adenocarcinoma, we suggest screening for Barrett s esophagus. Norman Barrett Chronic GERD, hiatal hernia, age 50, male gender, white race, elevated BMI, intra-abdominal body fat distribution Spechler et al. Gastroenterology 2011;140:1084. U.S. Incidence of Esophageal Adenocarcinoma Has Been Rising Incidence per 1,000,000 30 25 20 15 10 Incidence Time Trend 25.6 per million 2006 5 3.6 per million 1973 0 1975 1980 1985 1990 1995 2000 2005 Pohl H. Cancer Epidemiol Biomarkers Prev 2010;19:1468. Estimates of Cancer Risk for Individual Patients with Non-Dysplastic Barrett s Have Been Falling 1990s Estimate: 1% per year 1 in 100 patients per year Drewitz. Am J Gastroenterol 1997;92:212. 2000s Estimate: 0.5% per year 1 in 200 patients per year Shaheen. Gastroenterology 2000;119:333. 2015 Estimate: 0.25% per year 1 in 400 patients per year Endoscopic Surveillance Might Not Decrease Mortality from Esophageal Adenocarcinoma 8,272 pts. with Barrett s esophagus (BE) Surveillance 351 pts. endoscopy with esophageal within 3 adenocarcinoma years was NOT (EAC) associated with decreased risk of death from esophageal cancer 70 EAC in pts. with prior diagnosis of BE ( 6 months) (adjusted odds ratio 0.99; 95% CI 0.36-2.75) Cases 38 pts. with confirmed death from esophageal cancer 55% surveillance endoscopy performed within 3 years Controls 101 living Barrett s pts. matched for age, sex, follow-up duration 60% surveillance endoscopy performed within 3 years Corley DA. Gastroenterology 2013;145:312. 5
Do Proton Pump Inhibitors (PPIs) Prevent Cancer in Barrett s Esophagus? PPIs are the most effective medical treatment for reflux esophagitis Decrease gastric acid production Decrease acid reflux Heal reflux esophagitis Evidence that PPIs prevent carcinogenesis in Barrett s esophagus is indirect and not proven in controlled trials. PPIs Reduce the Risk of Neoplastic Progression in Barrett s Esophagus 540 Barrett s patients, median follow-up 5.2 years PPI Nonusers PPI use associated with 75% reduction in risk of neoplastic progression PPI Users Kastelein F. Clin Gastroenterol Hepatol 2013;11: 382-8. Norman Barrett Age 13 AGA Medical Position Statement on the Treatment of GERD in Barrett s Esophagus GERD therapy with medication effective to treat GERD symptoms and to heal reflux esophagitis is clearly indicated. Antireflux surgery is not more effective than medical therapy for prevention of cancer in Barrett s esophagus. We recommend against attempts to eliminate esophageal acid exposure (PPIs in doses >once daily or antireflux surgery) for cancer prevention. Spechler et al. Gastroenterology 2011;140:1084. AGA Medical Position Statement on Endoscopic Surveillance for Barrett s Esophagus We suggest that endoscopic surveillance [with biopsy] be performed in patients with Barrett s esophagus. Norman Barrett We suggest the following surveillance intervals: No dysplasia: 3-5 years Low-grade dysplasia: 6-12 months High-grade dysplasia in the absence of eradication therapy: 3 months Spechler et al. Gastroenterology 2011;140:1084. 6
The Cancer Risk for High-Grade Dysplasia in Barrett s is Sufficient to Warrant Intervention AGA Medical Position Statement on the Management of Barrett s Esophagus High Grade Dysplasia ~6% per year Cancer Rastogi. Gastrointest Endosc 2008;67:394. Spechler. Am J Gastroenterol 2005;100:927. AGA Medical Position Statement. Gastroenterology 2011;140:1084. Norman Barrett We recommend endoscopic eradication therapy rather than surveillance for treatment of patients with confirmed highgrade dysplasia in Barrett s esophagus. Spechler et al. Gastroenterology 2011;140:1084. Muscularis mucosae HGD T1 T2 Epithelium Lamina propria Basement membrane T1 T Staging of Esophageal Cancer T2 T3 T4 Muscularis mucosae None considered curable by endoscopic therapy. Drawing courtesy of Tom Rice Drawing courtesy of Tom Rice 7
HGD T1 T2 High Grade Dysplasia Intramucosal Carcinoma Muscularis mucosae T1a T1b T1b: LN mets >10% Potentially curable with endoscopic therapy Potentially metastatic Endoscopic therapy is appropriate for neoplasms confined to the mucosa. Drawing courtesy of Tom Rice Systematic Review: Risk of Lymph Node Metastases for High Grade Dysplasia (HGD) or Intramucosal Carcinoma (IMC) in Barrett s Esophagus Reviewed studies that included: - Patients who had esophagectomy for HGD or IMC and - Final surgical pathology results (lymph node status) Identified 70 relevant articles 1,874 patients who had esophagectomy for HGD (524 patients) or IMC (1,350 patients) Lymph node metastases in 26 of 1,874 patients (1.39%, 95% CI 0.86% - 1.92%) Dunbar K, Spechler S. Am J Gastroenterol 2012;107:850. Accurate T Staging Crucial to Determine if Curative Endoscopic Therapy Feasible High Grade Dysplasia, Intramucosal Carcinoma Lymph node metastases in 1%-2% Curative endoscopic therapy feasible Submucosal invasion Lymph node metastases in >10% Failure rate for endoscopic therapy unacceptable Endoscopic mucosal resection (EMR) the best procedure for T staging EMR is as much a staging procedure as it is a therapeutic procedure. If EMR shows submucosal invasion, then endoscopic therapy is not advised. 8
Radiofrequency Ablation (RFA) Radiofrequency Energy Generator Radiofrequency Ablation of Barrett s Esophagus Closely spaced electrodes Ablated Barrett s Metaplasia Randomized, Sham-Controlled Trial of Radiofrequency Ablation for Dysplasia in Barrett s Shaheen N et al. N Engl J Med 2009;360:2277-88. Radiofrequency Ablation of Dysplasia Prevents Neoplastic Progression at One Year % with Progression 3.6% 16.3% Progression of Neoplasia Radiofrequency ablation Sham ablation 9.3% 1.2% Progression to Cancer Shaheen. N Engl J Med 2009;360:2277-88. 9
Complications of Radiofrequency Ablation in 84 Patients 5 esophageal strictures (6%) 1 UGI Bleed (1%) 2 hospitalizations for chest pain (2%) Shaheen. N Engl J Med 2009;360:2277-88. Randomized Trial of RFA vs. Surveillance for Low- Grade Dysplasia (LGD) in Barrett s Esophagus 136 patients with LGD confirmed by expert pathologist Randomized to RFA (68 pts.) or surveillance (68 pts.) Progression to high-grade dysplasia or cancer at 3 years Data 1.5% & RFA Safety group Monitoring Board early termination: RFA 26.5% superior surveillance to surveillance group for preventing neoplastic progression 25% Potential risk of for progression patient safety issues (95% CI if trial 14.1-35.9%, continued P<.001) Progression to cancer at 3 years 1.5% RFA group 8.8% surveillance group 7.4% risk of cancer (95% CI 0-14.7%, P=.03) Phoa KN. JAMA 2014;311:1209. Randomized Trial of RFA vs. Surveillance for Low- Grade Dysplasia (LGD) in Barrett s Esophagus Issues Median 3 RFA sessions per patient 12% of RFA-treated patients developed strictures 28% of patients in surveillance group had no dysplasia detectable on follow-up No patient in surveillance group developed an unresectable tumor No patient in surveillance died of cancer Endoscopic Eradication Therapy for Mucosal Neoplasia in Barrett s Esophagus 2015 EMR of mucosal irregularities for staging and therapy Radiofrequency ablation of remaining Barrett s metaplasia to minimize metachronous neoplasia Phoa KN. JAMA 2014;311:1209. 10
Recurrent HGD/IMC Recurrence of Neoplasia and Metaplasia after Endoscopic Eradication of Mucosal Neoplasia 246 patients with HGD or IMC in Barrett s esophagus Completely eradicated intestinal metaplasia (IM) in 80% 1.00 0.75 0.50 0.25 0.00 Recurrence of Neoplasia after Complete Eradication of IM 25% HGD IMC 0 12 24 36 48 60 72 84 96 108 120 Follow-Up Months Recurrent IM 1.00 0.75 0.50 0.25 0.00 Recurrence of Metaplasia after Complete Eradication of IM 50% HGD IMC 0 12 24 36 48 Follow-Up Months Small AJ et al. Gastrointest Endosc 2015;81:1158-66. RFA for Non-Dysplastic Barrett s Esophagus? Generally requires several endoscopies for complete eradication Complication rate low, but not trivial Substantial rate of recurrence of metaplasia Efficacy in preventing cancer not established Does not eliminate need for surveillance Chronic GERD symptoms and 1 risk factor(s) for adenocarcinoma (Age>50, male, white, hiatal hernia, obesity, intra-abdominal body fat, smoking) No Barrett s No more screening on screening Consider screening endoscopy Barrett s esophagus No dysplasia Low-grade dysplasia High-grade dysplasia or intramucosal Ca Surveillance endoscopy every 3-5 yrs Spechler S, Souza R. N Engl J Med 2014;371:836. Have diagnosis confirmed by expert pathologist Low-grade dysplasia Surveillance endoscopy every 6-12 months or endoscopic eradication High-grade dysplasia or intramucosal Ca Endoscopic eradication AGA Medical Position Statement on the Management of Barrett s Esophagus Endoscopic eradication therapy is not suggested for the general population of patients with Barrett s esophagus in the absence of dysplasia. Norman Barrett RFA should be a therapeutic option for select individuals with non-dysplastic Barrett s esophagus who are judged to be at increased risk for progression to HGD or cancer. Specific criteria that identify this population have not been fully defined. Spechler et al. Gastroenterology 2011;140:1084. 11
Knowledge is knowing a tomato is a fruit. Wisdom is knowing not to put it in a fruit salad. 12