Barrett’s Esophagus

Alessandro RepiciDigestive Endoscopy Unit

IRCCS Istituto Clinico HumanitasMilano

goblets = Barrett‘s

no goblets = no Barrett‘s

Spechler SJ 2000

Definition of Barrett

Barrett‘s Definition

USA: specialized intestinal Metaplasia

UK/Japan: all columnar metaplasia

Europe: specialized intestinal Metaplasia

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

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

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

Risk of progression may be lower than previously thought

EAC incidence in NDBE

3.3 per 1000 patient years

Desai Gut 2012

Mortality in BE

Sikkema Clin Gastro Hepatology 2010

Key Features for the Endoscopic Recognition of Barrett’s Esophagus

Locate gastro-oesophageal junction

Recognise the squamocolumnar junction

Describe extent consistently

Endoscopic recognition of the columnar lined esophagus

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

• 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

X

X

X

X

X

XX

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 2011Curvers WL, Eur J Gastro Hep 2008; Abrams JA, Clin Gastro Hep 2009, Wani S, Gastroenterology 2011

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

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

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

- 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 2008Sharma P; IMAGE 2012

“look longer, biopsy less”

“look 2 minutes x cm of Barrett” !!!

Retroversion

Examination in inflation & deflation

Where is the dysplasia?

Pech et.al. Endoscopy 2007;39:588-593Kariawasan et.al. GIE 2012;75:938-44

New endoscopic modalities to detect early cancer in BE

CHROMOENDOSCOPYAUTOFLUORESENCE

ENDOSCOPYCONFOCAL

ENDOMICROSCOPY

OPTICAL COHERENCE TOMOGRAPHY

HIGH RESOLUTION MICRO ENDOSCOPY

ENDOCYTOOSCOPY

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%

Disadvantages of Chromoendoscopy

• Operator-dependant

• Labor-intensive

• Requires the use of dyes

• Spraying catheters

• Unequal distribution of dye

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

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

110 LGD pts reviewed 110 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/Ca No HGD/Ca No HGD/Ca No HGD/Ca

Median FU of 42 monthsMedian FU of 42 monthsMedian FU of 42 monthsMedian FU of 42 months

Pouw et al, GIE 2010

How dangerous is “real” LGD?

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

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?

Radiofrequency energy ablation – HALO360 system

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

Human Esophagus

Muscularis Mucosae

Submucosa

Muscularis Propria

GG

Surgical Depth

PDT, APC & Cryo Depth?

Lamina PropriaEpithelium

Keys to Endotherapy:1.Uniform mucosal removal2.Controlled depth of ablation

RFA Depth

EMR/ESD Depth

Focal ablation – HALO90 system

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

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

– .........

DEFINITION OF HGD AND EARLY CANCER DEFINITION OF HGD AND EARLY CANCER ON BARRETT’S ESOPHAGUSON BARRETT’S ESOPHAGUS

High-grade dysplasia exhibits more severe cytologic atypia and greater architecturalcomplexity 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 morecrowded, separated only by thin strands of fibrovascular tissue.

A 42y old male with IM Ca on BE

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

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

T1 m1-sm1 Esophageal Adenocarcinoma: a very low risk of lymphatic dissemination

Westerterp M, Virchows Arch, 2005

*

* Diameter of Node+: 12 mm

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

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

AGA Medical Position Statement

Recommend endoscopic therapy rather than surveillance for confirmed HGD

Recommend EMR in patients withvisible lesions

Strong recommendation

Strong recommendation

Gastroenterology March 2011

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

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

Staging of early neoplastic lesionsStaging of early neoplastic lesions

• Mucosal/submucosal Mucosal/submucosal

• Isolated lesion/multifocal lesionsIsolated lesion/multifocal lesions

• Nodes involvementNodes involvement

• Distant metastasisDistant metastasis

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

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

Accuracy of EUS in early EC

Proportion of correct results

EUSAccuracy

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%

EUS performance in EC: overstaging and understaging

Pech O, Endoscopy, 2010

Reasons for poor EUS performance

• Microscopic definition of disease

• Hiatal ernia

• No water assistance

• Duplication of muscolaris mucosae

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.

Endoscopic Resection Techniques

• Standard snare resection

• Cap assisted resection

• Band-ligator assisted

• Submucosal dissection

CAP-ASSISTED

WITH BAND-LIGATOR

ER-cap techniqueER-cap technique

Multi-Band Mucosectomy (DuetteR)

How to chose the right approach

• Location

• Extension of the targeted area

• Presence of visible nodules

4 bleeding10033539Conio

None75472318Mino-Kenudson

Not reported100452340Larghi

1 bleeding993550115Peck

2 stenosis100243428May

1 bleeding100131317Buttar

None100171525Nijhawan

1 bleeding97141235Ell

ComplicationsCompleteb Response

Recurrencea

%

F-up (mo)

# Patients

Authors

aMetachronous/recurrent lesionsbEnd 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)

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

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, performing performing 20 endoscopic resections may not be 20 endoscopic resections may not be sufficient to reach sufficient to reach the peak of the learning curve in endoscopic resection

Van Vilsterein FGI, et al Endoscopy 2012

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

• “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

Combine endoscopic resection & Combine endoscopic resection & ablationablation

The buried BE glands beneath squamous The 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

Endotherapy vs SurgeryThis Cochrane review has indicated that there are

no randomised control trials to compare managementoptions 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 histopathology3)Assessing which patients are fit or unfit for surgery

4)At least 5 years survival

Cochrane Database Syst Rev Apr 2009

Prasad A et al Gastroenterology 2009

Retrospective analysis of 178 patients treated by Endoscopy (132) or Surgery 46