1. 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

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

3. 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

4. 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

5. Endoscopic images HN

7. 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

8. 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

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

10. 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 Nov ;13(11):

11. 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

12. 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

13. Use of image enhanced endoscopy

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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 ). There was a trend toward tobacco use also increasing the risk (OR 3.3, 95% CI ). 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

22. 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

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

24. 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

25. 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

26. 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

27. 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

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

29. 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

30. 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

31. 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

33. 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

34. 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

35. 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

36. 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)

37. 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].

38. 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

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