Joint hospital surgical grandround 16/7/2016 Cheung Hing Fong Barrett’s esophagus 12+3 minute Look for  FU OGD 2009before the dx, BE/ hiatus hernia/ regular surveillance biopsy Obese patient Joint hospital surgical grandround 16/7/2016 Cheung Hing Fong

Content Case presentation Prevalence Updated management Summary dysplastic, BE nodularity and adenocarcinoma Summary

54/M Cerebral palsy reflux esophagitis dx in 2000 on long term PPI developed increased symptom in 2014 2000: reflux esophagitits OGD 2009: hiatus hernia

OGD 2014 SCJ at 30cm; OGJ at 38cm; diaphragmatic hiatus at 46cm huge hiatus hernia 8cm Prague C8M8 Barrett esophagus a 1.2cm raised nodule at 34cm from incisor biopsy: adenocarcinoma

Endoscopic images HN150102463

Progress EUS: 1.2cm tumour involving mucosa and submucosa, MP preserved; no gross perioesophageal LN CT: no distant met Ivor Lewis esophagectomy histology: moderately differentiated ADENOCARCINOMA, with background barrett's esophagus invades into submucosa, T1bN0 no lymphovascular permeation

Can this Barrett associated early adenocarcinoma be treated endoscopically without surgery? this T1bN0 tumour, esophagectomy with LN clearance is generally preferred ESD is requiring to ascertain the depth of SM invasion For T1b SM1 cancer, reported outcome of highly selected patient are encouraging Manner H , Pech O , Heldmann Y et al. Effi cacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion . Clin Gastroenterol Hepatol 2013

Prague criteria Circumferential (C) and maximal (M) length

Prevalence of Barrett’s esophagus in Asia Endoscopic BE7.8% Histological confirmed BE1.3% Pooled prevalence of dysplasia among histological confirmed BE low grade dysplasia6.9% high grade dysplasia3% adenocarcinoma2% Trend of increased prevalence from 1991 to 2014, especially in Eastern Asian Countries Seiji Shiota,et al Clin Gastroenterol Hepatol. 2015 Nov ;13(11):1907-18

Risk of progression to adenocarcinoma based on dysplasia Non-dysplastic BE: 0.33% per year Low grade dysplasia: 0.5% per year High grade dysplasia: 7-19% per year

Endoscopic surveillance for dysplastic BE Important for detection of dysplasia/ neoplasia Seattle protocol 4 quadrant bx every 1cm interval starting from the top of the gastric folds up to the most proximal extent of the BE mucosal abnormality sampled separately Chart/ pic Reid BJ et al. Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia. Am J Gastroenterology 2000

Use of image enhanced endoscopy

Use of image enhanced endoscopy RCT NBI targeted biopsy compared with high definition white light endoscopy random biopsy no difference in detection of intestinal metaplasia NBI detected a higher proportion of areas with dysplasia (30% vs 21%, p=0.01) Sharma P , Hawes RH , Bansal A et al. Standard endoscopy with random biopsies vs. narrow band imaging targeted biopsies in Barrett's oeso phagus: a prospective, international, randomised controlled trial . Gut 2013 ; 62 : 15 – 21. Acg p11 Sharma P et al. Standard endoscopy with random biopsies vs. narrow band imaging targeted biopsies in Barrett's oesophagus: a prospective, international, randomised controlled trial . Gut 2013

Risk stratification of Barrett’s surveillance Loss of SOX2 and aberrant p53 expression increased the risk of neoplastic progression Improve risk stratification of Barrett’s surveillance ACG p 11 Role of endoscopic therapy as part of multimodality treatment in adenocarcinoma van Olphen S et al. SOX2 as a novel marker to predict neoplastic progression in Barrett’s esophagus. Am J Gastroenterol 2015

Radiofrequency ablation (RFA) the preferred endoscopic eradication therapy for biopsy confirmed dysplastic BE (both low and high grade dysplasia) application of bipolar electrical energy to the mucosal surfaces ablation deep to epithelium and muscularis mucosa without injury to submucosa after several weeks to months, the exposed submucosal surface resurfaces with a “neosquamous” epithelium HALO circumferential(360) and focal ablation(90) bipolar RF electrode Shaheen NJ et al. ACG clinical guideline: Diagnosis and management of Barrett's esophagus. Am J Gastroenterol 2015

RFA for dysplastic BE High efficacy Durable Eradication rate: 90% for LGD, 81% for HGD Durable Dysplasia remained eradicated in 85% and intestinal metaplasia remained eradicated in 75% of patients after 3 year without maintenance RFA Shaheen NJ et al. Durability of radiofrequency ablation in Barrett's esophagus with dysplasia.Gastroenterology 2011

Radiofrequency ablation (RFA) good safety profile Stricture risk(1-6%) Bleeding and perforation rare appear not to interfere with subsequent endoscopic resection for residual lesions less submucosal scarring possible to resect residual Barrett’s mucosa after multiple RFA without the need for submucosal lifting using the ligate-and-cut technique

Low grade dysplasia previous controversy RCT: decreased risk of progression to HGD or adenocarcinoma over 3 year FU Alternative: yearly endoscopic surveillance ACG P11 Phoa KN et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA 2014

Recurrence and disease progression after RFA intestinal metaplasia recurrence-13% progression to cancer occurred in 0.2% of patients during treatment and in 0.7% of those after complete eradication of dysplasia and intestinal metaplasia (CEIM)  intensive endoscopic surveillance needed Orman ES, Li N, Shaheen NJ. Efficacy and durability of radiofrequency ablation for Barrett's Esophagus: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013

Endoscopic resection (ER) Endoscopic visible nodularity in BE EMR as the initial diagnostic and therapeutic maneuver Histological diagnosis Degree of dysplasia/ adenocarcinoma For adenocarcinoma Depth of invasion Risk for lymph node metastasis Complications of EMR: bleeding, stricture, perforation under EUS guidance to ensure SM not involved Bleeding occurs in 0 to 46 percent of cases (depending in part on how it is defined) and can usually be managed easily with endoscopic methods [9,58,60,61,67,80,82]. Perforation has been reported with an estimated incidence <1 to 5 percent Strictures have been reported in 2 to 88 percent of patients undergoing ER for BE [65,77-80,83,84]. The size/length of the mucosal defect and the degree of circumferential involvement by the BE predict stricture formation [79,83,85]. In a study of 73 patients who underwent ER for BE with high-grade dysplasia or intramucosal carcinoma, symptomatic strictures developed in 25 percent. Strictures were more common if the BE involved more than 50 percent of the esophageal circumference (odds ratio [OR] 4.2, 95% CI 1.3-14). There was a trend toward tobacco use also increasing the risk (OR 3.3, 95% CI 0.93-12). Strictures arising after ER usually resolve with dilation [83]. Shaheen NJ et al. ACG clinical guideline: Diagnosis and management of Barrett's esophagus. Am J Gastroenterol 2015

Classification of early esophageal cancer Classification of the depth of superficial esophageal cancer T1a confined to MM T1b SM tumour, breach MM T2 breach MP T1b tumour subclassification SM1 – Penetrates the shallowest one-third of the submucosa (<500 microns) SM2 – Penetrates into the intermediate one-third of the submucosa SM3 – Penetrates the deepest one-third of the submucosa Shimada H et al. Prediction of lymph node status in patients with superficial esophageal carcinoma: analysis of 160 surgically resected cancers. Am J Surg 2006

Prevalence of LN metastasis for early adenocarcinoma Mucosal CA (T1a): 0% Submucosal CA (T1b) SM1 6% SM2 23% SM3 58%

Risk stratification for early esophageal adenocarcinoma Lymphovascular invasion and poor tumour differentiation are significant poor prognostic factors Favorable histology for EMR well and moderately differentiated tumour without LVI Risk stratification for early esophageal adenocarcinoma: analysis of lymphatic spread and prognostic factors. Ann Surg Oncol. 2010

Management of BE associated adenocarcinoma T1a with favorable histology EMR, followed by mucosal eradication therapy T1b (SM1, SM2, and SM3 tumors)  esophagectomy with LN clearance is generally preferred Lesions with superficial submucosal invasion (T1b SM1) conflicting data regarding the likelihood of lymph node invasion for high risk patient, endoscopic therapy can be considered as an alternative especially for CA with favorable histology especially for well-differentiated tumors and tumour with no lymphovascular invasion

Endoscopic therapy for early adenocarcinoma--Limitation of EMR Contraindications for EMR Submucosal invasion detected by EUS Failure of submucosal lifting Lesion larger than 2cm require piecemeal resection Increased risk of recurrence and perforation

Endoscopic submucosal dissection (ESD) Allow enbloc resection of large lesions Higher R0 resection rate No difference in complete remission from neoplasia at 3 months Terheggen G et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett's neoplasia. Gut 2016 Lower risk of local recurrence Guo HM et al. Endoscopic submucosal dissection vs endoscopic mucosal resection for superficial esophageal cancer. World J Gastroenterol. 2014

Cons of ESD Higher risk of perforation and stricture Longer procedure time

European Society of Gastrointestinal Endoscopy guideline 2015 EMR should be preferred for resection of mucosal cancer ESD may be considered in selected cases lesions larger than 1.5cm poorly lifting tumors lesions at risk for submucosal invasion

Can the patient treated endoscopically without surgery? T1bN0 tumour Esophagectomy with LN clearance is preferred For consideration of endoscopic therapy ESDdepth of SM invasion and histological feature For T1b SM1 cancer, reported outcome of endoscopic treatment in highly selected patient are encouraging Manner H et al. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low risk sm1 invasion. Clin Gastroenterol Hepatol 2013 macroscopically polypoid or flat histologic pattern of sm1 invasion good-to-moderate differentiation [G1/2] no invasion into lymph vessels or veins

Summary RFA is currently the preferred endoscopic eradication therapy for dysplastic BE EMR serves as the initial diagnostic and therapeutic maneuver of nodular BE Management of BE associated adenocarcinoma depends on the depth of invasion and histological features Pictures Animation Colour and text adjustment Practice Time distribution Questions being asked

Diagnostic criteria Extension of salmon coloured mucosa into tubular esophagus >=1cm proximal to the OGJ with biopsy confirmed intestinal metaplasia Asia pacific consensus and US histology confirmation required Intestinal metaplasia globet cell on bx of esophageal mucosa (from squamous to columnar epithelium) Medscapeasia pacific consensus +/- picture of globet cell OGD view

Surgery for dysplastic BE Anti-reflux surgery Limited role in the prevention of adenocarcinoma one relatively small randomized trial showed no difference in progression outcomes meta-analyses revealed conflicting results Indication control of reflux symptom despite optimised medical therapy Esophagectomy HGD with no durable eradication Esophagectomy HGD with no durable eradication

Endoscopic surveillance after endoscopic eradication therapy 4 quadrant biopsy every cm thought the extent of previous BE, GEJ and cardia to check for complete eradicaton of intestinal metaplasia and dysplasia (CEIM) surveillance interval after CEIM HGD/ intramucosal carcinoma: Q3month in first year  Q6month in second year yearly LGD: Q6month in first year yearly

Photodynamic therapy light-sensitizing drug injected stimulated by exposing the BE portion of the esophagus to light of a specific wavelength cytotoxicity resulted most commonly used photosensitizer in the United States is porfimer sodium (Photofrin, Pinnacle Biologics Inc)

RFA PDT Pros High efficacy, eradication rate: 90% for LGD, 81% for HGD 93% for LGD and 77% for HGD Cons No tissue pathology Risk Chest pain Stricture(1-6%) Bleeding and perforation rare High stricture rate (up to 30%) Photosensitivity (up to 26%) Perforation rare Comparison between RFA and PDT and EMR RFA perforation usually happen during insertion or removal of ablation catheter EMR: under EUS guidance to ensure SM not involved Combined with RFA for ablation of remaining BE after EMR of the nodular component RFA+fundoplication Buried gland foci of BE either left behind or developed below the epithelialized squamous layer After systemic injection, the photosensitizer is absorbed by most tissues, but for reasons not yet clearly understood, it is selectively retained at a higher concentration by neoplastic tissue. Approximately 48 hours after injection, the ratio of photosensitizer in neoplastic tissue compared with non-neoplastic tissue is approximately 2:1 [11]. However, residual photosensitizer may remain in the skin for up to 30 days rendering the patient sensitive to ambient sunlight and even strong indoor lighting. Thus, patients should be warned to avoid direct sunlight for four weeks after injection. For endoscopic applications, the light is transmitted via a quartz optical fiber passed through the accessory channel of an endoscope. The tip of the diffusing fibers is provided in several lengths to better match the length of the lesion being treated. For treatment of Barrett's esophagus with high-grade dysplasia, most operators recommend a power of 400 mW/cm fiber for a total light energy dose of approximately 200 J/cm fiber. Balloon diffusers have been made of a cylindrical diffuser fiber located in the center of a balloon. The advantage of this system over the diffusing fiber alone is that the balloon allows for a more homogeneous light application by flattening mucosal folds and permits a more central positioning of the fiber within the lumen [10].

Importance of expert pathologists Interpreting EMR specimens of Barrett's neoplasia may be more difficult tissue architecture differs from the layered architecture in squamous mucosa  more difficult to discern a clear transition between wall layers severe inflammation due to the reflux disease EMR involved use of electrocoagulation, the resection margins may have coagulation artifacts the deep and especially the lateral resection margins may have coagulation artifacts

Vagal sparing esophagectomy significantly reduced incidence overall infectious complications postoperative dumping and diarrhea less weight loss