Gastrolearning II modulo/11a lezione L'esofago di Barrett Dott. A. Repici - Istituto Clinico Humanitas, Milano

1. Barrett’s Esophagus
Alessandro Repici
Digestive Endoscopy Unit
IRCCS Istituto Clinico Humanitas
Milano

2. goblets = Barrett‘s
no goblets = no Barrett‘s
Spechler SJ 2000
Definition of Barrett

3. Barrett‘s Definition
USA: specialized intestinal Metaplasia
UK/Japan: all columnar metaplasia
Europe: specialized intestinal Metaplasia

7. 481 000 new cases (3.8% of the total) oesophageal cancer estimated in 2008
The sixth most common cause of death from cancer with 406 000 deaths
(5.4% of the total).
More than 75% of the cases in developing countries are squamous
More than 60% of the cases in western countries are adenoca
280 000 new cases of LGD and HGD BE are expected in 2012

8. Incidence of BE is increasing in men under
60 years
BE/1000 scop
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
1996 1997 1998 1999 2000 2001 2002 2003
Man <60
Man >60
Vrouw <60
Vrouw >60
van Soest et al. Gut 2005

9. EAC : lethal, rapidly rising incidence
J Natl Cancer Inst, June 2005
Relative incidence of Esophageal
AdenoCa/other malignancies
Disease specific incidence rates/
mortality of Esophageal AdenoCa

10. Risk of progression may be lower
than previously thought
EAC incidence in NDBE
3.3 per 1000 patient years
Desai Gut 2012

11. Mortality in BE
Sikkema Clin Gastro Hepatology 2010

12. Key Features for the Endoscopic
Recognition of Barrett’s Esophagus
Locate gastro-oesophageal
junction
Recognise the squamocolumnar
junction
Describe extent
consistently

13. Endoscopic recognition of the
columnar lined esophagus

14. Endoscopic BE: Prague C&M Criteria
• Based on –
Circumference and
Maximum extent
• Patient with 5 cm
long Barrett’s, distal
2 cm circumferential
and proximal 3 cm in
form of a tongue
Barrett’s: C2M5
C2
M5
Sharma P et al, Gastroenterology 2006

15. • Endoscopic surveillance using white-light endoscopy (WLE)
• Random 4-quadrant biopsies of every 1 to 2 cm of the BE
segment (Seattle protocol)
• Targeted biopsies of any endoscopically visible
lesions
Bennett C, Vakil N, Bergman J, et al.
Consensus statements for management of Barrett’s dysplasia and early-stage esophageal
adenocarcinoma, based on a Delphi process. Gastroenterology 2012;143:336–46

16. X
X
X
X
X
X
X
X
X
X
X X
Seattle Protocol
2cm
2cm
Disadvantages:
-Time consuming
-Risk of bleeding
-Poor adherence
-Costs for the health care
BSG guidelines 2005; Wang KK, AmJG 2008; Spechler SJ, Gastro 2011
Curvers WL, Eur J Gastro Hep 2008;
Abrams JA, Clin Gastro Hep 2009, Wani S, Gastroenterology 2011

17. Praga & Seattle protocol
• Praga classification adopted in less 40%
• Seattle protocol adherence <50%
• Correct sampling and collection of specimens
35%
• High Res/Def scope used randomly
• Only those centers with research interest in BE
showed excellent compliance
Sharma P, DDW 2012

18. Barrett’s Inspection Time (BIT)
Longer BIT led to more HGD/EAC detection (p=0.001) despite
no difference in BE length (p=0.10)
Gupta N et al. GIE 2012

19. What look for and how
• Mucosal irregularities/nodulesMucosal irregularities/nodules
– Acetic acid
– Methylene blue
– Electronic chromoendoscopy
• Pit patternPit pattern
– Methylene blue and electronic chromo
• Vascular patternVascular pattern
– Electronic chromoendoscopy

20. - Sedation
- Esophagus should be carefully cleaned
- Scope gradually withdrawn in inflated fashion
- Esophagus should gradually be deflated to reveal any
irregularities maybe stretched out during inflation
- Special attention at area between 12 and 6 o’clock
- Inspect in retroflexed position when hiatal hernia
Careful and dedicated technique
Curvers WL; Endoscopy 2008
Sharma P; IMAGE 2012
 “look longer, biopsy less”
 “look 2 minutes x cm of Barrett” !!!

21. Retroversion

22. Examination in inflation & deflation

23. Where is the dysplasia?
Pech et.al. Endoscopy 2007;39:588-593Kariawasan et.al. GIE 2012;75:938-44

24. New endoscopic modalities to
detect early cancer in BE
CHROMOENDOSCOPY
AUTOFLUORESENCE
ENDOSCOPY
CONFOCAL
ENDOMICROSCOPY
OPTICAL COHERENCE
TOMOGRAPHY
HIGH RESOLUTION
MICRO ENDOSCOPY
ENDOCYTOOSCOPY

25. Acetic Acid
• Fortun: APT 2005-15% pts had histologic
upgrade with acetic acid
• Pohl: Endoscopy 2007—sensitivity 87% PV
39%
• Curvers: Gastro 2008—no increased yield of
AA over HRE
• Longcroft-Wheaton: CGH 2010-specificity
80% sensitivity : 95%
• Pohl: AJG 2010: Sensitivity 97% specificity
66%

26. Disadvantages of Chromoendoscopy
• Operator-dependant
• Labor-intensive
• Requires the use of dyes
• Spraying catheters
• Unequal distribution of dye

28. The pathway to BE cancer
Low Grade Dysplasia
High Grade Dysplasia
Intramucosal cancer
→ Architectural changes
→ Architectural changes
Cellular changes
→ Architectural changes
Cellular changes
Macroscopic changes

29. How dangerous is LGD?
• Low grade dysplasia has 3 - 6% 5yr cancer risk
• Grading dysplasia is difficult for pathologists
• Is low-grade always low-grade?
• Amsterdam Gut Club Barrett registry
– More than 3000 pts in 16 hospitals
– 110 LGD cases diagnosed between ’00-’06

30. 110 LGD pts reviewed110 LGD pts reviewed
by 2 expert pathologistsby 2 expert pathologists
87 pts NDBE87 pts NDBE
(80%)(80%)
13 pts Indef13 pts Indef
(12%)(12%)
10 pts LGD10 pts LGD
(8%)(8%)
60% HGD/Ca60% HGD/Ca60% HGD/Ca60% HGD/CaNo HGD/CaNo HGD/Ca No HGD/CaNo HGD/Ca
Median FU of 42 monthsMedian FU of 42 monthsMedian FU of 42 monthsMedian FU of 42 months
Pouw et al, GIE 2010

31. How dangerous is “real” LGD?

32. Treatment is related to different factors
• Grade/Stage of BE neoplasia
• Endoscopic morphology (flat vs nodular lesion)
• Extension of the neoplasia (multifocal vs single dysplatic area)
• Site of the BE
• Extension of the BE
• Previous treatments

33. Ideal treatment for LGD (& NDBE)
• Safe (<1% SAE’s for LGD, <0,1 for NDBE)
• Effective (reducing cancer risk)
• Minimally invasive
• Obviating need for future surveillance
• Not more expensive than ??? yrs of surveillance
• EMR? MBM? PDT? RFA? Cryo?

34. magnified
electrode
Controlled ablation depth by:Controlled ablation depth by:
• Bipolar balloon based electrodeBipolar balloon based electrode
• Fixed energy densityFixed energy density
• Fixed powerFixed power
• Automated RF deliveryAutomated RF delivery

35. Human Esophagus
Muscularis Mucosae
Submucosa
Muscularis Propria
GG
Surgical
Depth
PDT, APC &
Cryo Depth?
Lamina Propria
Epithelium
Keys to Endotherapy:
1.Uniform mucosal
removal
2.Controlled depth of
ablation
RFA Depth
EMR/ESD
Depth

36. Focal ablation – HALO90
system

37. A Randomized, Multicenter, Sham Controlled Trial of RF Ablation
• 128 patients with BE and dysplasia (LGD/HGD)
• Mean BE length 5 cm; 12 month follow up
IM Eradication
(n=127)
LGD Eradication
(n=64)
HGD Eradication
(n=63)
2%
23%
19%
77%
*
90%
* 81%
*
Patients
%
0
10
20
30
40
50
60
70
80
90
100
SHAM
RFA
p<0.001
Shaheen N et al. NEJM 2009

39. How effective is RFA?
• RFA extensively studied for HGD and early ca
• Often combination of mucosectomy with RFA
• RFA has excellent results in expert hands
• RFA is only a small part of patient care
– High quality endoscopy (team + equipment)
– Expert pathology
– Counselling
– .........

40. DEFINITION OF HGD AND EARLY CANCERDEFINITION OF HGD AND EARLY CANCER
ON BARRETT’S ESOPHAGUSON BARRETT’S ESOPHAGUS
High-grade dysplasia exhibits more severe
cytologic atypia and greater architectural
complexity than does low-grade, but the cutoff
between low-grade and high-grade dysplasia is
difficult to define.
In high grade dysplasia the neoplastic glands
are irregularly shaped and are more
crowded, separated only by thin strands of
fibrovascular tissue.

41. A 42y old male with IM Ca on BE

42. How much frequent is HGD on flat Barrett?
• 150 cases of nodular lesions or focal abnormalities
• 143 flat mucosa
• Flat lesions were associated with a reduced risk of
HGD or invasive cancer

44. Incidence of lymph node metastasesIncidence of lymph node metastases
Level of infiltrationLevel of infiltration Lymph node (N)Lymph node (N)
IM esophagusIM esophagus (Adenoca)(Adenoca) 0.3-0.5%0.3-0.5%
IM esophagus (SCC)IM esophagus (SCC) 8%8%
Sm1 (Adenoca)Sm1 (Adenoca) 2%2%
Sm1 (SCC)Sm1 (SCC) 10-14%10-14%
Endoscopic management of BE: rationaleEndoscopic management of BE: rationale

45. T1 m1-sm1 Esophageal Adenocarcinoma: a
very low risk of lymphatic dissemination
Westerterp M, Virchows Arch, 2005
*
* Diameter of Node+: 12 mm

46. Prevalence of T1b carcinoma at
esophagectomy for HGD-IMC
• Retrospective study, 60 pts. with HGD or IMC at biopsy.
• Pts. with endoscopic evidence of mass and with EUS evidence
of sm invasion were excluded
Wang V.S., Gastrointestinal Endoscopy, 2009

47. Muscolaris
mucosae
The Paris Endoscopic Classification of Superficial Neoplastic Lesions
Gastrointest Endosc 2003
Cut-off limit
500 µ
m
sm
mp
Barrett’s Esophagus
ENDOSCOPY SURGERY
sm1sm1

48. AGA Medical Position Statement
Recommend endoscopic therapy rather than
surveillance for confirmed HGD
Recommend EMR in patients with
visible lesions
Strong recommendation
Strong recommendation
Gastroenterology March 2011

49. The pathway to BE cancer
Low Grade Dysplasia
High Grade Dysplasia
Intramucosal cancer
→ Surveillance or
Radiofrequency
→ EMR or
Radiofrequency or
Combination of ER and RF
→ EMR or
ESD or
Radiofrequency or
Combination of ER and RF or
Surgery

50. Endoscopic approach for early EC is the most
effective and less expensive option:
a decision analysis model
The position of the threshold is
determined by 5-year survival rate
after endoscpic therapy among N+
pts: 10%, 20%, 25%
Pohl H., Gastrointestinal Endoscopy , 2009

51. Staging of early neoplastic lesionsStaging of early neoplastic lesions
• Mucosal/submucosalMucosal/submucosal
• Isolated lesion/multifocal lesionsIsolated lesion/multifocal lesions
• Nodes involvementNodes involvement
• Distant metastasisDistant metastasis

52. Staging dysplasia/early neoplasiadysplasia/early neoplasia in BE
• HD/HR Endoscopy
• Chromoendoscopy and Electronic Chromoendoscopy
• Radial EUS
• HF miniprobes EUS
• Linear EUS with FNA for nodes
Mucosal Resection may be considered a strategic staging modality

53. EC staging by EUS in 266 pts. who had
esophagectomy without induction-CT
• EUS erroneously classified T3-T4 in 42 pts (16%)
• EUS is insesitive for N+, but with high specificity
• EUS is completely insensitive for M+
Gregory Zuccaro, Am J Gastroenterol, 2005

54. Accuracy of EUS in early EC
Proportion of correct
results
EUS
Accuracy
Mucosal
Invasion
Sub-Mucosal
Invasion
Chemaly, Endoscopy 2008 62 13 75/102 73.5 %
May , Gut 2004 62 12 74/93 79.6%
Larghi, GIE 2005 9 NA 9/15 60.0%

55. EUS performance in EC:
overstaging and understaging
Pech O, Endoscopy, 2010

56. Reasons for poor EUS performance
• Microscopic definition of disease
• Hiatal ernia
• No water assistance
• Duplication of muscolaris mucosae

58. Endoscopic Resection (ER)
• ER allows for histological correlation, enabling optimal
selection of patients for endoscopic treatment.
• However, after focal ER for early Barrett neoplasia,
metachronous lesions are observed in 30% during follow-up.

59. Endoscopic Resection Techniques
• Standard snare resection
• Cap assisted resection
• Band-ligator assisted
• Submucosal dissection

60. CAP-ASSISTED
WITH BAND-LIGATOR

61. ER-cap techniqueER-cap technique

62. Multi-Band Mucosectomy (DuetteR
)

63. How to chose the right approach
• Location
• Extension of the targeted area
• Presence of visible nodules

64. 4 bleeding10033539Conio
None75472318Mino-
Kenudson
Not reported100452340Larghi
1 bleeding993550115Peck
2 stenosis100243428May
1 bleeding100131317Buttar
None100171525Nijhawan
1 bleeding97141235Ell
ComplicationsCompleteb
Response
Recurrencea
%
F-up
(mo)
#
Patients
Authors
a
Metachronous/recurrent lesions
b
End of f-up after multimodality (EMR-APC-PDT) treatment
Larghi et al., Gastrointest Endosc Clin N Am 2007
EMR for HGD or IMC (visible lesions)

65. Randomized, controlled trial in tertiary-care and community-care centers.
Piecemeal ER was performed by using ER-cap (n 42) or MBM (n 42).
Outcome Measurements: Safety, efficacy, procedure time, costs.
Results: Procedure time (34 vs 50 minutes; P .02) and costs (€240 vs €322; P .01) were
significantly less with MBM compared with ER-cap. MBM resulted in smaller resection
specimens than ER-cap (18 13 mm vs 20 15 mm; P .01).
Maximum thicknesses of specimens and resected submucosa were not significantly
different.
There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-
cap, 1 with MBM
Rouw PE, GIE 2011

66. In this intense, structured training program, the first 120 esophageal endoscopic resections performed by
six participants were associated with a 5.0% perforation rate5.0% perforation rate.
Although perforations were adequately managed, performingperforming 20 endoscopic resections may not be20 endoscopic resections may not be
sufficient to reachsufficient to reach the peak of the learning curve in endoscopic resection
Van Vilsterein FGI, et al Endoscopy 2012

67. EMR of early cancer and high-grade dysplasia
at distal esophagus and GEJ
• 1120 ERs in 6 years (680 pts)
• Mortality 0
• Major complications 1.1% (13 patients)
Perforation 1
Bleeding 10 (epinephrine, clip)
Stenosis 8 (bougienage)
• 5-yr survival rate 79%
Ell C, UEGW 2010

68. • “Low-risk”: sm1, type I/II, no vascular or lymphatic
involvement, well or moderately differentiated
• 21 patients: 19 treated by endoscopy
• Complete remission obtained in 95% (18/19) over 5.3
months
• ER is associated with favorable outcomes even in case of
“low-risk” submucosal Barrett Cancer.
Manner H et al AJG 2008

69. Combine endoscopic resection & ablationCombine endoscopic resection & ablation

70. The buried BE glands beneath squamousThe buried BE glands beneath squamous
epitheliumepithelium
A total of 47 patients’ initial mucosectomy
slides were reviewed
Buried BE underneath the squamous resection
margin was identified in 13/47 patients (28%)
The linear distance of the Barrett’s epithelium
from the resection’s squamous margin ranged
from 0.8 to 5.6 mm (mean 2.3 mm and
median 1.9 mm).
Histopathology revealed nondysplastic buried
BE in 3 patients, HGD in 9 patients, and
IMC in 1 patient.
Chenneat J et al GIE 2010

71. Endotherapy vs Surgery
This Cochrane review has indicated that there are
no randomised control trials to compare management
options in this vital area, therefore trials should be
undertaken as a matter of urgency
The problems with such randomised methods are:
1)Standardising surgery and endotherapy
2)Standardising histopathology
3)Assessing which patients are fit or unfit for surgery
4)At least 5 years survival
Cochrane Database Syst Rev Apr 2009

72. Prasad A et al Gastroenterology 2009
Retrospective analysis of 178 patients treated by Endoscopy (132)
or Surgery 46