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Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseasesSunday, July 8 - Friday, August 3, 2007Amsterdam, Academisch Medisch Centrum
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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development
Ileana Lulic, Ivor Kovic
“... a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy ...”
American College of Gastroenterology
Definition
Characteristics
• Caucasian males – middle age
• Rapidly rising incidence in Western countries
• Around 150x higher risk of esophageal adenocarcinoma compared to general population
• 0.5% of BE patients will develop EAC
• Overall survival rate of EAC = 20-25%
Progression
Squamous esophageal epithelium
Intestinal metaplasia
Dysplasia
Esophageal adenocarcinoma
Progression
Squamous esophageal epithelium
Intestinal metaplasia
Dysplasia
Esophageal adenocarcinoma
GERD
Progression
Squamous esophageal epithelium
Intestinal metaplasia
Dysplasia
Esophageal adenocarcinoma
GERD
ObesityDietTobaccoAlcoholBacteria
?
Progression
Squamous esophageal epithelium
Intestinal metaplasia
Dysplasia
Esophageal adenocarcinoma
GERD
ObesityDietTobaccoAlcoholBacteria
?
Low grade
High grade
Diagnosis
Endoscopy
Pathology
Normal Metaplasia Adenocarcinoma
Diagnosis
Endoscopy
Pathology
Normal Metaplasia Adenocarcinoma
http://www.gastrointestinalatlas.com/
Diagnosis
Endoscopy
Pathology
Normal Metaplasia Adenocarcinoma
Surveillance problems
• Difficulty of identifying early neoplastic lesions
• Sampling errors
• Expensive and time consuming
• Intra-observer variability
• Inter-observer variability
Endoscopy Pathology
Surveillance problems
• Difficulty of identifying early neoplastic lesions
• Sampling errors
• Expensive and time consuming
• Intra-observer variability
• Inter-observer variability
Endoscopy Pathology
Questionable cost-effectiveness
Potential of genetic markers
• Prediction of risk for disease progression in endoscopic surveillance program
• Early detection of high grade dysplasia and invasive adenocarcinoma
• Staging and prognosis
• Prediction of chemosensitivity
• Novel targets for anticancer therapies
Genetic markersp16/9p-loss
p53/17p-loss
Y chromosome loss
Aneuploidy/tetraploidy
Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q
Genetic markersp16/9p-loss
p53/17p-loss
Y chromosome loss
Aneuploidy/tetraploidy
Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q
No dysplasia
Low grade dysplasia
High grade dysplasia
Esophageal adenocarcinoma
Genetic markersp16/9p-loss
p53/17p-loss
Y chromosome loss
Aneuploidy/tetraploidy
Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q
Genetic markersp16/9p-loss
p53/17p-loss
Y chromosome loss
Aneuploidy/tetraploidy
Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q
Fluorescent in situ hybridization
Image cytometry
Procedure
Brush cytology
FISH
Slides preparation
Image cytometry
FISH
• Fluorescent probe
• Fluorescent microscopy
FISH
• Numerical chromosomal changes: aneuploidy
• Locus specific losses: tumor suppressor genes
• Amplifications: oncogenes and growth factor
Image cytometry• DNA ploidy analysis
• Aneuploidy – from 2N to 4N, DNA index
• Measurement of optical density
FISH results
Patient HystologyCep1 p16 p53
loss gain loss gain loss gain
1 LGD + +2 LGD +3 HGD + + +4 HGD + +5 HGD + + +6 HGD + +
Total 2 3 5 0 3 0
Image cytometry results
Image cytometry results
Results
0
1
2
3
4
5
6
Cep 1 gain p16 loss p53 loss
LGD HGD
Results from 151 patients
(n=114)(n=24)
(n=13)
Conclusion
• p53 loss and aneuploidy are promising markers for dysplasia development in BE
• Ongoing follow up study to demonstrate the true predictive value of these markers
Agnieszka Rygiel
Francesca Milano
Sheila Krishnadath
Wendy Bruins
Willemijn van Dop
