Barrett`s Esophagus:Screening, Surveillance, Treatment.

Are all questions answered?

Florian SchreiberInternal Department, Medical University of GrazDivision of Gastroenterology and Hepatology

Barrett`s EsophagusNorman Rupert Barrett

* Adelaide, May, 16th, 1903• Education at Eton, Cambridge• Rockefeller Scholar at Mayo Clinic 1935• Trainee for thoracic surgery at

St. Thomas Hospital, London• President of Thoracic Surgeons

of England and Ireland 1962• Founder Editor of Thorax 1946 - 1971† London, 1979

1957 firstly described „ The lower esophagus lined by columnar epithelium “, what he later called „ endobrachyesophagus “. *

leads to 19 900 000 hits in a searching machine ( 06/ 2007 ) in 0.4 sec

leads to ~ 5000 publications 1973 – 2007

Barrett´s Esophagus is a „ theme of interest “* Barrett N; Surgery 1957; 41( 6 ): 881 - 94

Barrett`s Esophagusare all questions answered?

• Epidemiologyfacts and some mysterious

• Definitionfacts

• Classificationfacts

• Diagnosisfacts and myths

• Surveillancefacts, some myths again

• Treatmentfacts and, perhaps some visions

Barrett`s EsophagusEpidemiology I

• 10 – 20% of caucasian patients with chronic GERD endoscopically are found with Barrett`s ( 1 )

• in autopsy studies 1:60 – 1:80 is found to have Barrett`s ( 2 )

• gender specific distribution ♂ : ♀ = 5.9 : 1

• mystery 1: since african – americans do not seem to be protected from developing GERD, they are largely protected from developing Barrett`s Esophagus and esophageal adenocarcinoma ( 3 )

• myth 1: only patients with symptomatic GERD develop Barrett`s - 25% of asymptomatic male veterans older than 50 had BE ( 4 )

1) Lieberman DA et al; A J Gastroenterol 1997; 92: 1293 – 972) Cameron AJ et al; GE 1990, 99: 918 – 223) Phillips RW et al; GE Clin NA 1991, 20: 791 - 8164) Gerson LB et al; GE 2002, 123: 461 - 67

Barrett`s EsophagusEpidemiology II

6.01.7Histologic diagnosis of Barrett`s carcinoma( in 1000 endoscopies )

229.3Histologic diagnosisBarrett`s( in 1000 endoscopies )

40. 519.8endoscopic diagnosis Barrett`s( in 1000 endoscopies )

20021997

Bergmann JJ et al, Endos 2004

Barrett`s Esophagusrisk factors

• white/ hispanic people > coloured/ asian people ( 1 )

long standing GERD ( 2 )

• bile acids, Bilirubin ( 3 )

• BMI > 30 ( 1. 5 – 2 fold ) ( 4, 5 )

• Hp ( 6 )

1) Phillips RW et al, GE Gastro N Am 1991, 20: 791 – 8162) Lieberman DA et al, Am J Gastro 1997, 92: 1293 - 12973) Haggitt RC et al, Hum Patol 1998, 24: 982 - 934) El Serag HB, AM J GE 2005; 100: 2152 – 56.5) Lagergren J et al; Ann Int Med 1999, 130: 883 - 906) Genta RM, Graham DY; Hum Pathol 1994; 25: 915 - 19

Barrett`s Esophagusrisk factors for Barrett`s Carcinoma

• LSBE ( 1 )

• intraepithelial neoplasia ( 2 )

• mucosal “ irregularity “ ( 3 )

• erosion/ ulcer ( 4 )

• insufficient acid suppression ( 5 )

• insufficient Nissen`s ?

1) Weston AP et al, Am J Gastro 1999, 94: 3413 – 34192) Sampliner RE, Am J Gastro 1998, 93: 1028 – 10323) Buttar NS et al, GE 2001; 120: 1630 – 394) Van der Burgh et al, Gut 1996; 39: 5 – 85) Buttar NS, GE 2004; 123: 1630 - 9

Barrett`s EsophagusDefinition

Barrett´s esophagus should be defined as a change in the esophageallining of ANY LENGTH that can be recognized at upper endoscopy and is confirmed to have intestinal metaplasia by biopsy.

The American College of Gastroenterology 2005

macroscopic/ endoscopic definition

…“ a displacement of the squamocolumnar junction proximal of the gastro –esophageal junction with the presence of intestinal metaplasia … “

Barrett`s Esophagus Chicago Workgroup, 2003

myth ( to be continued ): endoscopic diagnosis of BE is reliable

“ since endoscopic diagnosis of BE is not possible in most cases, histologicconfirmation is mandatory….“

Sampliner RE ; Am J Gastro 1998, 93: 1028 - 1032

Barrett`s Esophagusendoscopic diagnosis/ measurement

Prague C and M criteria:

circumferential extent of the esophageal columnar tissue Clongitudinal measurememt of the esophageal columnar tissue M

( C3M5 or C0M3 …. )

The international working group on BE, Prague 2005

recognition of endoscopic landmarks:gastro-oesophageal junction, squamo-columnar junction, diaphragmatic hiatus, top of gastric folds

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Barrett`s Esophaguspathophysiology I

Barrett esophagus develops when defense mechanisms in the esophageal

mucosa ( luminal secretion of mucus, bicarbonate ) are overwhelmed by an

ongoing cycle of mucosal injury and repair. Hydrogen ion, pepsin, trypsin and

bile acids are invading the mucosal layer leading to progressive reepithelization

of areas lined with destroyed squamos epithelium by a colummnar epithelium

originating by stem cells located in the basal layer or the ducts of mucosal

glands. Thus may be understood as an adaptive or even as a protective response

to injury of the lining.

Guillem PG; Dig Dis Sci 2005; 50: 415 - 24

Barrett`s Esophaguspathophysiology II

microscopic/ histologic hypothesis:there are at least 3 possible mechanisms for the genesis of Barrett`s:

1) ulceration at the Z – line with subsequent repair by cellswhich differentiate into Barrett`s epithelium

2) metaplasia through multilayered epithelium3) creeping columnar metaplasia at the Z - line proximally

followed by intestinalisation.those 3 hypotheses may mutually not work exklusive but all may be operativedepending on the local circumstances ( inflammation, erosion, ulcers, healing,acid, bile, use of PPI etc.

Squamous epithelium columnar lining spezialized intestinal metaplasia

Ridell RH; Arch Pathol Lab Med 2005; 129: 164 - 9

Barrett`s Esophaguspathophysiology III

Carcinogenesis in Barrett`s esophagus from the molecular point of view involves some steps which 1) enable cells to provide their own growth signals

2) ignore growth – inhibitory signals3) avoid apoptosis4) replicate without limit5) sustain angiogenesis6) invade and proliferate in unnatural locations.

Recent data suggest that the gastroesophageal reflux of acid and bile can activate molecular pathways that promote proliferation and interfere with apoptosis in Barrett`s metaplastic cells. Inactivation of the suppressor genes P16 and p53 through promoter methylation, gene mutation and/ or loss of heterozygocity seems to be one of the key mechanisms for carcinogenesis in this entitiy.

Spechler SJ; Curr Gastroenterol Rev 2005;7: 177 - 81

Barrett`s EsophagusClassification

• long segment Barrett`s - LSBE ( 8. 5% )columnar epithelium > 3 cm

• short segment Barrett`s - SSBE ( 4. 8% )columnar epithelium < 3 cm

• ultra short Barrett`s - USSBE ( ? )colummnar epithelium < 1 cm

mystery : progression from USSB to LSBE/ primary multifocal development to LSBE ?

Barrett`s Esophagusendoscopic classification

LSBE SSBE

Barrett`s Esophagusscreening

• endoscopic screening w 4 quadrant biopsies

• endoscopic screening w zoom/chromoendoscopy

• endoscopic screening w narrow band imaging - NBI

• endoscopic screening w optical coherence tomography - OCT

• endoscopic screening w autofluorescence

• endoscopic screening w microendoscopy ( confocal laser endomicroscopy - CLE)

• video capsule endoscopy – PillCam Eso®

Barrett`s Esophagusscreening

94% 98% ( 5 )BE NPL

98% 93% ( 5 ) BE NPL

microendoscopy

92% ( 4 ) 42% ( 4 ) autofluorescence

82% ( 3 ) 68% ( 3 ) OCT

91% ( 1 )93% ( 1 )NBI

59% ( 1 )66% ( 2 )

86% ( 1 )100% ( 2 )

chromoscopy + zoom acetic acid + zoom

57% ( 1 )79% ( 1 )quadrant biopsies/ unguided biopsies

specificitysensitivitymethod

1) Bergman JJ et al, Endos 37; 2005: 929 – 362) Kieslich R et al; GI Endos 64; 2006: 1 – 83) Isenberg G er al; GI Endos 62; 2005: 825 - 31

4) Borovicka et al; Endos 38; 2006: 867 - 725) Kiesslich R et al; Clin Gastro Hepatol 4; 2006: 979-87

Barrett`s Esophagussurveillance

18%

34%

progression into cancer within 1. 5 – 4. 3yprogression within0. 2 – 4. 3y

3%progression into cancer within 3. 4 – 10y

LGIEN HGIENno evidence of IEN

Sampliner RE, Am J Gastro 1998; 93: 1028 - 32

Barrett`s Esophagussurveillance

no dysplasia low grade dysplasia high grade dysplasia

2- 3 years

which collective ( all/ IEN/ HGIEN ? )what technique ???

2 x 6 mo, then 1 y 3 mo or Rx

Barrett`s Esophagussurveillance for all ?

risk to develop cancer is overestimated ( 3 )i. e. 0.5% / year

patients with BE don`t die withBarrett`s cancer ( 2 )

increased detection rates of curable cancers ( ** )( retrospective design )

24 700 $ / EGD/ saved life in USA ( 1 )15 000 £/ diagnosed cancer in male42 000 £/ diagnosed cancer in female

earlier detection of cancer by endoscopic/ bioptic surveillance ( * )( retrospective design )

conpro

1) Soni A et al; AM J Gastro 2000; 95: 2086 – 20932) Eckhardt VF et al; Am J Med 2001; 111: 33 -7 3) Shaheen N et al; GE 2000; 119: 333 - 8

*) Corley DA et al; GE 2002; 122: 633 – 40**) Fitzgerald RC et al; Dif Dis Sci 2001; 46: 1892 - 98

Barrett`s EsophagusSurveillance, which technique ?

100% **60% **video capsule endoscopyPilCam Eso ®

94% 98%BE NPL

98% 93%BE NPL

microendoscopy

92%42%autofluorescence

82%68%OCT

91%93%NBI

59%66%

86%100%

chromoscopy + zoom acetic acid + zoom

57% 79% quadrant biopsies/ guided biopsies

specificitysensitivitymethod

** Coron et al; DDW 2007

Barrett`s EsophagusTherapy I

• medical therapy

• endoscopic therapy w PDT

• endoscopic therapy w thermal ablation ( APC, HALO® )

• endoscopic therapy w EMR

• surgical therapy open/ laparoscopic Nissens`sMerendino etc

Barrett`s Esophagustherapy II

8% ( 5 – 20% mortality )0

94%

63% p < 0.03

surgical therapy vs

PPI ( 6 )

24% ( 17% relapsor multifocal )

98%EMR ( 5 )

94%10%

13% Adenoca20% Adenoca p < 0.006

photodynamic therapyvs PPI ( 4 )

10%9%

77%90%

thermal ablation APC( 2

Halo ( 3 )

088% after 5 day treatment

medical therapyPPI 40 mg/ day ( 1 )

complicationsefficacymethod restricted to HGIEN

1) Spechler SJ et al; AM J Gastro 2006: 1964 – 71 4) Overholt BF et al; GI Endos 2005 : 488 – 498 2) Spechler SJ et al; Am J Gastro 2006: 1770 – 2 5) Ell et al; Endos 37; 2000: 999 - 10053) Bergman J et al; GI Endos 2007: 456 – 63 6) Rossi M et al; Ann Surg 2006; 243: 58 - 63

Barrett`s Esophagustherapy: what for whom ?

gold standard but high morbidity/ mortality

surgical therapy shows morbitiy up to 40%mortality ~ 8%

no controlled dataconfirming regression of BE

endoscopic ( ablative ) therapy seems to be promising ( even in early cancer )

endoscopic ( ablative ) therapy shown to be effective,low morbitity/ mortality

no rationale for therapy in asymptomatic patients ( controlled data not available )

neither acid supresssion nor surgical therapy is able to show regression

acid suppression shows no regression

same therapy as goodas for GERD, only insymptomatic patients

HGIEN/ early cancer

LGIENBE, no evidence of IEN

Barrett`s Esophagustherapy III

• neither PPI treatment ( representing the less invasive step of treatment ) nor surgical therapy as the most aggressive regime is able to reduce the risk developing Barrett`s carcinoma in patients with LGIEN or even HGIEN !

Barrett`s Esophagussummary

• Barrett`s is a topic of main interest• patients with long standing GERD are high at risk to

develop Barrett`s • BMI > 30/ bile as new players for risk• the main goal for endoscopists is to identify

dysplastic areas within Barrett`s, as it is to establish the diagnosis itself

• endoscopic screening/ surveillance is feasable and effective but the best technique is not clearly identified yet

• endoscopic techniques are on a good way representing the new therapeutic gold standard if dysplasia occurs

Barrett`s Esophagusconclusion

• groups high at risk to develop HGIEN are to be identified better

• need for more data to establish best screening/ surveillance practice

• best therapeutic approach is not established yet