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