Identification of Barrett’s
 esophagus patients at higher risk
for adenocarcinoma development

           Ileana Lulic, Ivo...
Definition


“... a change in the esophageal epithelium of any length
that can be recognized at endoscopy and is confirmed
t...
Characteristics
• Caucasian males – middle age
• Rapidly rising incidence in Western countries
• Around 150x higher risk o...
Progression
Squamous esophageal epithelium




     Intestinal metaplasia


          Dysplasia



  Esophageal adenocarci...
Progression
Squamous esophageal epithelium

       GERD

     Intestinal metaplasia


          Dysplasia



  Esophageal ...
Progression
Squamous esophageal epithelium
                 Obesity
                 Diet
                            ?
  ...
Progression
Squamous esophageal epithelium
                 Obesity
                 Diet
                             ?
 ...
Diagnosis
            Normal    Metaplasia   Adenocarcinoma



Endoscopy




Pathology
Diagnosis
            Normal              Metaplasia         Adenocarcinoma



Endoscopy




Pathology
                   ...
Diagnosis
            Normal    Metaplasia   Adenocarcinoma



Endoscopy




Pathology
Surveillance problems
         Endoscopy                      Pathology

•                              • Intra-observer v...
Surveillance problems
         Endoscopy                        Pathology

•                                • Intra-observ...
Potential of genetic markers
• Prediction of risk for disease progression in endoscopic
    surveillance program
•   Early...
Genetic markers
p16/9p-loss
p53/17p-loss


Y chromosome loss
Aneuploidy/tetraploidy


Losses - 3p, 4p, 7q, 12q,17q
Gains –...
Genetic markers
p16/9p-loss                          No dysplasia
p53/17p-loss

                                  Low grad...
Genetic markers
p16/9p-loss
p53/17p-loss


Y chromosome loss
Aneuploidy/tetraploidy


Losses - 3p, 4p, 7q, 12q,17q
Gains –...
Genetic markers
p16/9p-loss                Fluorescent in situ hybridization
p53/17p-loss


Y chromosome loss
            ...
Procedure
                                      Image cytometry

Brush cytology   Slides preparation




                 ...
FISH


•   Fluorescent probe


• Fluorescent microscopy
FISH

•   Numerical chromosomal
    changes: aneuploidy
• Locus specific losses: tumor
    suppressor genes
•   Amplificatio...
Image cytometry
•   DNA ploidy analysis

•   Aneuploidy – from 2N to 4N, DNA index

•   Measurement of optical density
FISH results
                             Cep1             p16            p53
Patient      Hystology
                     ...
Image cytometry results
Image cytometry results
Results
                 LGD          HGD
6


5


4


3


2


1


0
    Cep 1 gain     p16 loss         p53 loss
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 st...
Agnieszka Rygiel

Francesca Milano

Sheila Krishnadath

Wendy Bruins

Willemijn van Dop
Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development
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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

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Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseases
Sunday, July 8 - Friday, August 3, 2007
Amsterdam, Academisch Medisch Centrum

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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

  1. 1. Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development Ileana Lulic, Ivor Kovic
  2. 2. Definition “... 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
  3. 3. 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%
  4. 4. Progression Squamous esophageal epithelium Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  5. 5. Progression Squamous esophageal epithelium GERD Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  6. 6. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  7. 7. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Low grade High grade Esophageal adenocarcinoma
  8. 8. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  9. 9. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology http://www.gastrointestinalatlas.com/
  10. 10. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  11. 11. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming
  12. 12. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming Questionable cost-effectiveness
  13. 13. 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
  14. 14. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  15. 15. Genetic markers p16/9p-loss No dysplasia p53/17p-loss Low grade dysplasia Y chromosome loss Aneuploidy/tetraploidy High grade dysplasia Losses - 3p, 4p, 7q, 12q,17q Esophageal adenocarcinoma Gains – 2p, 8q, 20q
  16. 16. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  17. 17. Genetic markers p16/9p-loss Fluorescent in situ hybridization p53/17p-loss Y chromosome loss Image cytometry Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  18. 18. Procedure Image cytometry Brush cytology Slides preparation FISH
  19. 19. FISH • Fluorescent probe • Fluorescent microscopy
  20. 20. FISH • Numerical chromosomal changes: aneuploidy • Locus specific losses: tumor suppressor genes • Amplifications: oncogenes and growth factor
  21. 21. Image cytometry • DNA ploidy analysis • Aneuploidy – from 2N to 4N, DNA index • Measurement of optical density
  22. 22. FISH results Cep1 p16 p53 Patient Hystology 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
  23. 23. Image cytometry results
  24. 24. Image cytometry results
  25. 25. Results LGD HGD 6 5 4 3 2 1 0 Cep 1 gain p16 loss p53 loss
  26. 26. Results from 151 patients (n=114) (n=24) (n=13)
  27. 27. 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
  28. 28. Agnieszka Rygiel Francesca Milano Sheila Krishnadath Wendy Bruins Willemijn van Dop

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