04/07/2013

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Detection and Treatment of Upper GI Dysplasia

Kenneth K. Wang, MDVan Cleve Professor of Gastroenterology 

ResearchDirector Advanced Endoscopy Group

Mayo Clinic, Rochester, MN

Aims

• Understand terminology regarding lesion description

• Identification of dysplastic tissue on magnification

• Describe the new imaging devices

• Understand the application of radiofrequency ablation

• Describe the role of cryotherapy for dysplasia

Case 1

• A 59 year old white male was found to have Barrett’s esophagus after an investigation for anemia 3 years ago

• The segment is described as C3M4

• On surveillance biopsy, a 4 mm lesion described as a Paris IIa lesion is seen with Sano Classification IIIb mucosal appearance

• Biopsies showed adenocarcinoma, moderately differentiated

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What Will You Absolutely Need for this Procedure ?

1. A high resolution white light endoscope

2. A endoscope with high resolution as well as narrow band imaging and autofluorescence

Best Imaging

• Careful observation: Time spent examination

– Polyps

– Dysplasia in Barrett’s

• High resolution white light endoscopy

• Describe lesions carefully

What Does Paris IIa Mean ?

1. A flat lesion that has no noticeable borders that are elevated or depressed beyond 2 mm

2. A  lesion that is elevated but less than the width of a closed biopsy forceps

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Paris Classification

Paris Classification: Is

Is : >2.5mm(sessile) 2.5 mm

Biopsy forceps

Paris Classification:: IIa +IIc

IIa+c : Elevated at the edges  And depressed centrally

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Modified Sano’s classification

Endoscopic View

How Would You Image this Cancer ?

1. Wide field imaging: NBI, chromoendoscopy

2. Point imaging

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Techniques

• Wide Field Imaging

– Low Tech: Chromoendoscopy

– Higher Tech: Narrow Band Imaging, Autofluorescence Imaging

– Highest Tech: Volume Laser Endomicrosocpy

• Point Imaging:

– High Tech: Confocal laser endomicroscopy, optical coherence tomography

– Spectroscopic techniques

Indigo Carmine 0.2%, 60 cc

Non-dysplastic Barrett’s oesophagus

Regular mucosal pattern

Regular vascular pattern

High-grade Dysplasia

Irregular mucosal pattern

Irregular vascular pattern

Abnormal blood vessels

Kara et al. Gastrointest. Endosc, 2006Yamashina, Dig Endosc. 25 Suppl 2:173-6, 2013

Narrow Band Imaging

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Narrow Band Imaging for DysplasiaStudy Pt #

(HGD/Total)

Sensitivity Specificity

Sharma

2006

7 / 51 100% 98.7%

Kara

(AFI+NBI)

2006

14 / 20 96% 93%

Sharma

2013

14/113 53%* 100%

Giachino(AFI+NBI)

2013

14/42 71% 46%

* For dysplasia

Would You Apply Confocal Laser Endomicroscopy ?

1. Yes

2. No

Probe‐Based Confocal Laser Endomicroscopy

Confocal laser probe

– passed through anyendoscope

Laser scanning unit

– frame rate of 12 images/sec 

Control and acquisition software

– real‐time image reconstruction

IV  Fluorescein  Contrast

Mauna Kea Technologies-Cellvizio

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Endoscopic MicroscopySystems

Confocal

Endoscope

Confocal

Probe

Instrument Dedicated Endoscope

Probe via

any Endoscope

Contrast IV: Fluorescein

Topical: acriflavin, cresyl violet

IV: Fluorescein

Magnification 700-1000x 750x

Image depth 250 microns 70 microns

Resolution 1 micron 1.2 microns

Frame Rate 0.8/sec 12/sec

Schema of Endomicroscopy250µm

7µm

Optical Resolution, lateral 1µm5 ml fluorescein (10% )

Acriflavine 0.05%

Miami Classification

Non dysplastic BE ‐ Uniform villiform architecture‐ Columnar cells (block arrow)‐ Dark “goblet” cells (thin arrow)

Dysplastic BE‐ Villiform structures‐ Dark, irregularly thickened epithelialborders (arrow)

‐ Dilated irregular vessels (block arrow)

Wallace MB et al Endoscopy 2011

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Miami Classification

Adenocarcinoma‐ Disorganized/loss of villiform structure and crypts

‐ Dark columnar cells (thin arrow)‐ Dilated irregular vessels (block arrow)

Accuracy of pCLE for High Grade Dysplasia

• 296 biopsy sites from 38 patients– 95 used to establish criteria (testing set)– 201 used to validate criteria– Images read blinded by 2 MD

per bx per patient

• Sensitivity 80% 58%• Specificity 94% 75%• PPV 44%• NPV 99% 92%

• Kappa 0.6 (“good” agreement)

Pohl, H et al. Gut 2008;57:1648‐1653

pCLE for BE Surveillance – Interobserver Agreement

• Blinded review of pCLE videos by 11 experts in BE imaging• 40 videos (20 – 30 sec)• Criteria proposed by Pohl et al• Training set (20 videos – 10 HGD/EC and 10 no IEN)• Validation set ( 20 videos – 11 HGD/EC and 9 no IEN)

pCLE ExperiencedObservers (N = 4)

pCLE Inexperienced observer (N = 7)

Sensitivity 91% 87%

Specificity 100% 94%

Accuracy 95% 90%

Agreement 92% 82%

Kappa (95% CI) 0.83 (0.64 – 1.00) 0.64  (0.48 – 0.80)

Wallace MB et al. Gastrointest Endosc 2010

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pCLE versus eCLE for Dysplasia Classification

• 16 eCLE stacks (depth imaging) compared with video pCLE

Leggett, DDW 2013

100% 100%

94%

75%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

eCLE pCLE

Dysplasia Detection Rate Diagnostic Accuracy

Volumetric Laser Endomicroscopy

Volumetric Laser Endomicroscopy

Mucosa

Submucosa

Muscularis mucosa

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Volumetric Laser Endomicroscopy

• Detection of dysplasia in 22 EMR specimens

• VLE versus eCLE

75

80

85

90

95

100Dysplasia Detection Rate (%

)

VLE                      CLE

Leggett, DDW 2013

Molecular Probes

Images

• In vitro imaging with peptide• Rapid binding• Specific binding to Barrett’s flat dysplasia (C. 

Piraka, DDW 2013)

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Light-tissue interactionsLight-tissue interactions

ScatteringScattering

ReflectionReflection Incident lightIncident light

FluorescenceFluorescence

Absorption

Low‐Coherence Enhanced Backscattering Spectroscopy

Clin Cancer Res. 2009 May 1;15(9):3110-7

LEBS

• Nanoscale disruptions in cells nearby cancers  (Cancer Res. 2009 Jul 1;69(13):5357‐63)

• Sensitivity of 100%, specificity of 80%, and AUC= 0.895 for colon polyps (rectal biopsy) (Cancer Res. 2009 May 15;69(10):4476‐83)

• AUC for colon polyps using microvascular markers was 0.82 in 157 patients with 17 advanced adenomas (Roy, DDW 2013)

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Advanced Technology

“One Should Use New Therapy Quickly While It Still Works”

Sir William Osler

Case 2

• 72 year old white male with 3 year history of abdominal pain, unresponsive to PPI

• Pain is epigastric, appears to be relieved with eating

• No weight loss

Endoscopy

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Should We Perform Surveillance ?

1. Yes

2. No

Gastric Cancer• Male predominant disease 1.6:1

• 21,320 will be diagnosed in 2012 in US– 10,540 will die (49%)

• Decreasing over last decades (1.5% per decade)

SEER database, seer.cancer.gov

Pathway to Gastric Cancer

Correa, Cancer Res 1992, 52(24):6735‐40.

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Detection of Intestinal Metaplasia with Methylene Blue

• Methylene blue with magnification can identify patterns associated with metaplastictissue (Dinis‐Ribeiro et al, Gastrointestinal Endoscopy  57:498–504, 2003)

Round tubular pattern, IM Irregular pattern

Indigo Carmine

• Indigo carmine has been shown to enhance detection of depressed and flat gastric lesions (Kawahara, Digestive Endoscopy 21:14–19, 2009)

• Intraobserver agreement between observers of pit patterns using indigo carmine is excellent (kappa=0.86) (Dinis‐Ribeiro Gastrointest Endosc

57:498–504, 2003)

• Detect the presence of intestinal metaplasia in the gastric cardia (Guelrud, Amer J Gastro 97, 584–589, 2002)

NBI Classification Mucosa of Gastric Polyps

Omori et al. BMC Gastroenterology 2012, 12:17 

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NBI Classification of Capillary Pattern Gastric Polyps

Classification of Gastric PolypsPolyp Classification Fundic gland Hyperplastic Adenoma

Small round pattern ++++ + +

Prolonged pattern ‐ +++ +

Villous or ridged + +++ +++

Honeycomb ++++ + ‐

Dense vascular ‐ ++++ +

Core vascular + + +++

Fine network,unclear

‐ ‐ +

Indigo Carmine

• Type 1 patterns, regular = normal gastric mucosa

• Type 2: Round pits and villi = intestinal metaplasia

• Type 3 = Loss of pattern, dysplasia

Dinis‐Ribeiro Gastrointest Endosc 57:498–504, 2003

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Indigo Carmine (0.4%) and Surface Enhancement

Endoscope Confocal Laser Endomicroscopy

• N=31 males

• Adenoma accuracy: 94%

• Adenocarcinoma: 95% 

Jeon, Gastrointestinal Endoscopy, 74:781‐783, 2011 

Intestinal metaplasia and gastric cancer.

Goetz M , Kiesslich R Am J Physiol Gastrointest Liver Physiol 2010;298:G797-G806

©2010 by American Physiological Society

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Sampling Protocols

• Devries et al 2010: 12 non‐targeted biopsies and additional biopsies of any lesions– Primarily found in incisura

– Second most common antrum

– Third was less curve

• A protocol of 7 biopsies found 97% of IM/dysplasia– 3 antrum

– 1 incisura

– 3 body (1 greater, 2 lesser curve)

Management of BE

Resect the Neoplastic Lesion

Eradicate the Remaining BE

Manage Complications and Recurrences

EMR Changes Diagnosis in Visible and Flat Dysplasia

• Multicenter US study

• 148 patients with HGD/ Cancer

• 24% without visible lesions

10%

31%

41% 40%43%

0%

10%

20%

30%

40%

50%

Upstaging Downstaging OverallChange

Visible lesionspresent

Visible lesionsabsent

Wani S et al. DDS 2013

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RadiofrequencyEradication

CircumferentialFocal

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

Shaheen N et al. NEJM 2009

6.0%3.6% 2.4%1.7% 3.6%

0.9%0%

20%

40%

60%

80%

100%

Any RFA Procedure Primary RFAProcedure

Secondary RFAProcedure

% Incidenceper Patient

% Incidenceper Procedure

Stricture Occurrence

• 5 Strictures in 84 patients

– 5 of 84 patients (6.0%)

– 5 of 297 cases (1.7%)

• All strictures resolved with mean of 2 dilations

• All patients now complete response for IM (CR‐IM)

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Eradication of all BE by EMR

• 49 patients with HGD/ Cancer

• Average length: 3.2 cms

• 106 EMR procedures

Chennat J et al. Am J Gastroenterol 2009

ESD vs EMR

EMR‐Cap ESD p

En‐bloc resection None (1‐11 pieces) 96% <0.0001

Surface resected (mm2) 1488 (185‐3194) 2453 (600‐5400) <0.01

Proc time (min) 61 (20‐130) 154 (64‐334) <0.001

Device costs (€) 264 (60‐515) 486 (247‐1019) <0.001

Deprez et al. GIE 2010

R0 24%

CE Neoplasia 100% 100% NS

CE‐IM 84 84 NS

Perforations 1 2

Strictures 20% 44%

• 50 patients (25 each with ESD and EMR)• HGD 25; Cancer 25• Average extent: C2M5

Cryotherapy HGD

• N=98 with HGD

• 333 treatments cryotherapy

• Complications

– Strictures 3%

– Pain 2%

– No perforations

Gastrointest Endosc 2010;71:680‐5N=60, completed Rx

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PDT

Absolute Risk Reduction: 45% versus 69%Number Needed to Treat Versus RFA: 1.5 versus 2.2

Strictures versus RFA: 36% versus 6%

Endoscope

Fiber OpticGuide

High‐GradeDysplasia

LaserLight

CenteringBalloon

Long term RFA results

86

95 96

77

93 91

0

25

50

75

100

1 year 2 years 3 years

Dysplasia

Barrett's

Recurrence Rates

Study Patient Number Recurrence %

Pech 2008 337 21.5%

Baddredine 2010 172 17%

Shaheen 2010 99 25%

Gupta 2013 592 16%

Ginsberg 2013 156 42%

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What Else Determines Ablation Success

37 BE patients underwent RFA

Complete eradication60% (n=22)

Incomplete eradication 40% (n=15)

PredictorsBE lengthHernia

Frequency of reflux

Krishnan K et al. Gastroenterology 2012

Post Ablation Follow up

• Every 3 months X 4

• 6 months x 2

• Then yearly

Barrett’s Esophagus Treatment Algorithm

Barrett’s Esophagus with dysplasia

Mucosal Abnormality: EMR

Flat Mucosa, No Cancer

Ablative Therapy

Cancer found, Assess Margins, lymphovascularinvasion, Differentiation, 

Ulceration

Flat Mucosa

Ablative Therapy

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Summary• Describe Barrett’s esophagus lesions

carefully• Chromoendoscopy and narrow band

imaging can increase recognition of mucosal and vascular patterns

• pCLE and VLE have a role in further defining BE lesions

• Mucosal resection techniques can be used for any mucosal abnormalities

• Complete eradication of all BE should be performed using RFA

• Post-ablation requires careful vigilence