Barrett’s EsophagusBarrett’s EsophagusEndoscopic DiagnosisEndoscopic Diagnosis

Alessandro RepiciAlessandro Repici

Dept of GastroenterologyDept of Gastroenterology

Molinette Hospital, TorinoMolinette Hospital, Torino

Historical notesHistorical notes

1906, Tileston1906, Tileston

1957, Barrett1957, Barrett

1975, Naef1975, Naef

“peptic ulcer of the esophagus” with a close resemblance of the mucous membrane to that found in the stomach

““The lower esophagus lined by columnarThe lower esophagus lined by columnar epithelium” (epithelium” (erroneously considered erroneously considered as congenital)as congenital)

“Columnar-lined oesophagus: an acquired lesion with malignant predisposition”

Which length?

Which metaplasia?

Barrett’s Esophagus: diagnostic issues

1998 A.C.G.: …”1998 A.C.G.: …”a change in the a change in the

esophageal epithelium of esophageal epithelium of any lengthany length

that can be recognized at endoscopy that can be recognized at endoscopy

and is confirmed to have and is confirmed to have intestinal intestinal

metaplasiametaplasia by biopsy by biopsy” ”

Presence of Goblet Cellsbecomes a “must”

A: Damage to the superficial compartments through acid or bile

B: Damage to the cellular layers and activation of toti- potential cells

Histomorphological changes in Barrett‘s esophagusHistomorphological changes in Barrett‘s esophagus

Development of areas with mucin secreting cells with resistance against acid and bile

Jankowski, AJP 1999

Histomorphological changes in Barrett‘s esophagusHistomorphological changes in Barrett‘s esophagus

>> 3 cm, Barrett 3 cm, Barrett

< 3 cm, < 3 cm, Short BarrettShort Barrett

Super Short BarrettSuper Short Barrett

AAJG 2000

Macroscopic classification

Easy to identify Long-segment Barrett

4

SCJ=„squamocolumnar junction“

OGJ=„oesophagogastric junction“

Correct definition of OGJ allows detection of shortsegments of Barrett’s esophagus

BE: ProgressionBE: Progression

BE (no dysplasia)BE (no dysplasia)

Low-grade dysplasiaLow-grade dysplasia

High-grade dysplasiaHigh-grade dysplasia

Esophageal adenocarcinomaEsophageal adenocarcinoma

Biomarkers in BEBiomarkers in BE Multiple genetic lesions occur during the neoplastic Multiple genetic lesions occur during the neoplastic

progression of BEprogression of BE

Biomarkers may be used for risk assessment of Biomarkers may be used for risk assessment of patients as well as intermediate endpoints in trialspatients as well as intermediate endpoints in trials

17p (p53) LOH and p16 abnormalities seem to 17p (p53) LOH and p16 abnormalities seem to predict progression to cancer in BE patientspredict progression to cancer in BE patients

No realiable markers of Cancer progressionNo realiable markers of Cancer progression are currently availableare currently available

Reid BJ, DDW 2001Reid BJ, DDW 2001

Wong DJ, DDW 2001Wong DJ, DDW 2001

Endoscopic diagnosis

• Surveillance

• Detection of dysplasia

• Staging of the disease

Endoscopic Surveillance of Endoscopic Surveillance of Barrett’s EsophagusBarrett’s Esophagus

Optimal endoscopic techniqueOptimal endoscopic technique• Biopsies of all mucosal abnormalities (ulcer, Biopsies of all mucosal abnormalities (ulcer,

nodule, plaque)nodule, plaque)• Four quadrant (jumbo) biopsies at 1 – 2 cm Four quadrant (jumbo) biopsies at 1 – 2 cm

intervalsintervals Recommended surveillance intervalsRecommended surveillance intervals

• No dysplasiaNo dysplasia 3 yrs after 2 EGD 3 yrs after 2 EGD• LGDLGD 6m for 1 yr, then 1yr6m for 1 yr, then 1yr• HGDHGD Confirm and resect vs. 3 mConfirm and resect vs. 3 m

LIMITATIONS OF SURVEILLANCE STRATEGYLIMITATIONS OF SURVEILLANCE STRATEGY

Cancer/Dysplasia -- multifocal and patchyCancer/Dysplasia -- multifocal and patchy ““Seattle Protocol” – cumbersome and tediousSeattle Protocol” – cumbersome and tedious

• Compliance is poorCompliance is poor Unsuspected Cancer -- up to 53% of HGDUnsuspected Cancer -- up to 53% of HGD Surveillance Intervals - poorly defined biologySurveillance Intervals - poorly defined biology Dilemma with HGD – variable interpretation Dilemma with HGD – variable interpretation

• surveillance vs. surgery?surveillance vs. surgery? Costly with unproven benefitCostly with unproven benefit

NEEDED TECHNIQUENEEDED TECHNIQUE

Highly sensitive to dysplasia – must Highly sensitive to dysplasia – must detect changes at a nuclear leveldetect changes at a nuclear level

High resolution but also able to scan High resolution but also able to scan wide area in real-timewide area in real-time

Specific – not affected by esophageal Specific – not affected by esophageal inflammationinflammation

High interobserver agreementHigh interobserver agreement Localize dysplastic area for biopsyLocalize dysplastic area for biopsy Cost not prohibitiveCost not prohibitive

Alternative Methods for SurveillanceAlternative Methods for Surveillance

Blind balloon cytology – sensitivity limitedBlind balloon cytology – sensitivity limited High Magnification EndoscopyHigh Magnification Endoscopy Confocal MicroscopyConfocal Microscopy Chromoendoscopy (methylene blue)Chromoendoscopy (methylene blue) Endoscopic Ultrasound (EUS)Endoscopic Ultrasound (EUS) Laser Induced FluorescenceLaser Induced Fluorescence Optical Coherence TomographyOptical Coherence Tomography Light Scattering SpectroscopyLight Scattering Spectroscopy Raman Spectroscopy Raman Spectroscopy

BE SURVEILLANCE --BLIND CYTOLOGYBE SURVEILLANCE --BLIND CYTOLOGY

AdvantagesAdvantages• Sample larger areaSample larger area• Quick and InexpensiveQuick and Inexpensive

DisadvantagesDisadvantages• Limited sensitivity (< 25% for LGD)Limited sensitivity (< 25% for LGD)

Future HopeFuture Hope• Molecular probesMolecular probes

ImmunostainsImmunostains FISHFISH

HIGH MAG – DETECTING BEHIGH MAG – DETECTING BE

Contrast AgentsContrast Agents• Acetic acidAcetic acid• Indigo carmineIndigo carmine• Methylene blueMethylene blue

Distinct morphology for IMDistinct morphology for IM High Sensitivity (> 95%) for IMHigh Sensitivity (> 95%) for IM Still inaccurate for LGD/HGDStill inaccurate for LGD/HGD

HIGH MAG – DETECTING DYSPLASIAHIGH MAG – DETECTING DYSPLASIA

Sharma et al. – 80 patientsSharma et al. – 80 patients Distinct morphology - Distinct morphology - Ridged/villous/ Circular/ Ridged/villous/ Circular/

Irregular&DistortedIrregular&Distorted All 6 HGD were irregular and distortedAll 6 HGD were irregular and distorted Limitations -Limitations - Cannot distinguish LGD; Difficult for surveillance Cannot distinguish LGD; Difficult for surveillance

of large area; Results very preliminaryof large area; Results very preliminary

Intestinal Metaplasia High Grade Dysplasia

METHYLENE BLUE METHYLENE BLUE CHROMOENDOSCOPYCHROMOENDOSCOPY

RationaleRationale

• MB absorption by absorptive columnar MB absorption by absorptive columnar

cells (small bowel and colon)cells (small bowel and colon)

• MB not absorbed by dysplastic cellsMB not absorbed by dysplastic cells

Focal Diffuse

Methylene blue selectively stains SCE in Methylene blue selectively stains SCE in Barrett’s esophagusBarrett’s esophagus

Summary of StudiesSummary of Studies

FavorableFavorable MixedMixed UnfavorableUnfavorable

Canto 96-01 Canto 96-01 (>250(>250)) Horwhat 1999 A Horwhat 1999 A (42)(42)

Wo 2001 (47)Wo 2001 (47)

Kiesslich 2000 (Kiesslich 2000 (7373)) Breyer 2000 A (30)Breyer 2000 A (30) Jobson 1999 A (33)Jobson 1999 A (33)

Sharma 2001 (Sharma 2001 (7575)) Hasan 1998 A (16)Hasan 1998 A (16) Gangarosa 2000 Gangarosa 2000 (10)(10)

Sueoka 2001 (Sueoka 2001 (6060)) Dave 2001 (10)Dave 2001 (10)

Gossner 1999 A Gossner 1999 A ((6161))

LIMITATIONS OF MB DIRECTED LIMITATIONS OF MB DIRECTED SURVEILLANCESURVEILLANCE

Stains inflammationStains inflammation

Staining paradoxStaining paradox

No time savingNo time saving

MessyMessy

Operator dependent; not sensitive enoughOperator dependent; not sensitive enough

EUS For SurveillanceEUS For Surveillance

Theory of Ultrasound ImagingTheory of Ultrasound Imaging• Sound reflects at tissue interfaceSound reflects at tissue interface• Higher frequency equals higher Higher frequency equals higher

resolution but lower penetrationresolution but lower penetration• Useable frequencies do not provide Useable frequencies do not provide

cellular resolutioncellular resolution

When not to do EMRWhen not to do EMR

20 Mhz probe EUS at 7.5 MHz

LIMITATIONS OF EUSLIMITATIONS OF EUS

CANNOT DETECT DYSPLASIACANNOT DETECT DYSPLASIA

May or may not identify cancer May or may not identify cancer

reliably in HGDreliably in HGD

Accuracy for identifying malignant Accuracy for identifying malignant

nodal spread is limited.nodal spread is limited.

LASER INDUCED FLUORESCENCE (LIF)LASER INDUCED FLUORESCENCE (LIF)

Theory Theory • Dysplastic tissue is biochemically different and Dysplastic tissue is biochemically different and

thus fluoresces differently from normal; thus fluoresces differently from normal; • Dysplastic tissue may also absorb fluorophores Dysplastic tissue may also absorb fluorophores

differentiallydifferentially Autofluorescence alone not accurate Autofluorescence alone not accurate

enoughenough Local or systemic ALA (Messman et al.) Local or systemic ALA (Messman et al.)

absorbed by dysplastic cellsabsorbed by dysplastic cells

DIFFICULTIES WITH L.I.F.DIFFICULTIES WITH L.I.F.

Inflammation may cause false positivesInflammation may cause false positives

Dysplasia -- sensitivity < 80%, specificity Dysplasia -- sensitivity < 80%, specificity

< 70%< 70%

Cost of fluorophoreCost of fluorophore

Cost of LIF scopesCost of LIF scopes

More research; better fluorophores neededMore research; better fluorophores needed

OPTICAL COHERENCE TOMOGRAPHYOPTICAL COHERENCE TOMOGRAPHY

Theory – Coherent back scattered Theory – Coherent back scattered light provides imaging resolution at light provides imaging resolution at microscopic level.microscopic level.

Figure 3A

Figure 3B

Figure 4A

DIFFICULTIES WITH OCTDIFFICULTIES WITH OCT

Limited sensitivityLimited sensitivity

Surveillance of large areasSurveillance of large areas

Further studies of dysplastic tissue Further studies of dysplastic tissue

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