dall'esofago di barrett all'adenocarcinoma: fisiopatologia e diagnosi - gastrolearning®

Edoardo V. Savarino MD, PhDAssistant Professor of Medicine

UOC di GastroenterologiaAzienda Ospedaliera Universitaria di Padova

Università di Padova

GASTRO-LEARNING 2014Secondo Modulo: Oncologia Gastrointestinale

L’ ESOFAGO DI BARRETT: FISIOPATOLOGIA, DIAGNOSI E TRATTAMENTO CHIRURGICO DELLE SUE COMPLICANZE NEOPLASTICHE

Eso

fag

o

di B

arre

tt

Definition of Barrett’s Esophagus

Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091

Barrett’s Esophagus is a metaplastic change of the lining of the oesophageal mucosa, such that the normal squamous epithelium is replaced with specialised or intestinalised

columnar epithelium

Barrett’s Esophagus: Endoscopic Incidence

Savarino, et al. Nat Rev Gastroenterol Hepatol 2013; 10:371-80

Barrett’s found at endoscopy: 0.5–2%1

Barrett’s found while investigating GORD: 10–15%2,3

Barrett’s increases the risk of oesophageal cancer 50–100-fold4

1. Jankowski et al., The Lancet 2000; 356: 2079–85.2. Gore et al., Aliment Pharmacol Ther 1993; 7: 623–8.

3. Spechler. Digestion 1992; 51(Suppl 1): 24–9.4. Peters et al., Gut 1999; 45: 489–94.

Risk Factors for Barrett’s EsophagusRisk increased:• White Male

• Age >40 years

• Smoking

• Obesity

• Esophageal Refluxo7.7 x with reflux symptomso43.5 x with severe reflux symptoms > 20 years

Spechler SJ. N Engl J Med 2002; 346: 836–42Lagergren et al, N Engl J Med 1999; 18;340(11):825-31

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

0 1 2 3 4 5 6 7 8

0-90-9 10-1910-19 20-2920-29 30-3930-39 40-4940-49 50-5950-59 60-6960-69 70-7970-79 80-8980-89

Age (years)Age (years)

Pat

ien

ts

end

osc

op

edw

ho

had

BE

(%

)

Pat

ien

ts

end

osc

op

edw

ho

had

BE

(%

)

MaleMale

Male + femaleMale + female

FemaleFemale

Cameron et al, Gastrointestinal Endoscopy 1992; 103(4):1241-5Cameron et al, Gastrointestinal Endoscopy 1992; 103(4):1241-5

Mean age of developing BE ~ 40Mean age at diagnosis of BE was 63Mean age of developing BE ~ 40Mean age at diagnosis of BE was 63

Barrett’s Esophagus: Reflux Disease

Visceral abdominal obesity → Increased risk of several disorders (diabetes, ischaemic heart disease and malignancies including colorectal cancer)

Visceral abdominal fat is metabolically active → low serum levels of potentially protective adipokines (eg, adiponectin) and high pro-inflammatory cytokines (eg, leptin, interleukin-1β, interleukin-6 and tumour necrosis factor-α) → increase the inflammation and hence the malignant transformation in patients with BE

Visceral abdominal obesity → increased intragastric pressure, hiatus formation and TLESRs

Procedure for measurement of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) CT scan at L4–L5 level. Thresholding was used and tissue with attenuation of −150 to −50 Hounsfield Units was designated as FAT and rest as NON-FAT (RED). Para vertebral and intramuscular fat (YELLOW) was selected and not included in the analysis

El Serag et al, Gut.2014 Feb;63(2):220-9. doi: 10.1136/gutjnl-2012-304189. Epub 2013 Feb 13El Serag et al, Gut.2014 Feb;63(2):220-9. doi: 10.1136/gutjnl-2012-304189. Epub 2013 Feb 13

Barrett’s Esophagus: Genetic Factors

Acid peptic diseaseAcid peptic disease

AdenocarcinomaAdenocarcinoma

Barrett's esophagusBarrett's esophagus

DeceasedDeceased

II

IIII

IIIIII

IVIV

VV

Pattern Autosomic Dominant

Jochem et al, Gastroenterology 1992; 102(4 Pt 1):1400-2Jochem et al, Gastroenterology 1992; 102(4 Pt 1):1400-2

Barrett’s Esophagus: Genetic Factors n LSBE %

BE relatives with 196 15 7.7% reflux symptoms

Non-relatives with 300 13 4.3% reflux symptoms

BE RELATIVES WITH REFLUX X 2.2 (CI 1.1-4.8) MORE LIKELY TO HAVE BE THAN OTHER PERSONS WITH REFLUX

Romero et al. Am J Gastroenterol 2002; 97: 1127–3

Pairs, n Correlation Male, MZ 918 0.29 (0.15-0.43)Male, DZ 1379 0.13 (0.02-0.25)

Female, MZ 1260 0.33 (0.22-0.44)Female, DZ 1840 0.14 (0.04-0.24)

ABOUT 31% OF GERD IS CAUSED BY GENETIC FACTORS Cameron et al. Gastroenterology 2002; 122(1):55-9

Risk Factors for Barrett’s EsophagusRisk increased:• White Male

• Age >40 years

• Smoking

• Obesity

• Esophageal Refluxo7.7 x with reflux symptomso43.5 x with severe reflux symptoms > 20 years

Spechler SJ. N Engl J Med 2002; 346: 836–42Lagergren et al, N Engl J Med 1999; 18;340(11):825-31

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

0 1 2 3 4 5 6 7 8

0-90-9 10-1910-19 20-2920-29 30-3930-39 40-4940-49 50-5950-59 60-6960-69 70-7970-79 80-8980-89

Age (years)Age (years)

Pat

ien

ts

end

osc

op

edw

ho

had

BE

(%

)

Pat

ien

ts

end

osc

op

edw

ho

had

BE

(%

)

MaleMale

Male + femaleMale + female

FemaleFemale

Cameron et al, Gastrointestinal Endoscopy 1992; 103(4):1241-5Cameron et al, Gastrointestinal Endoscopy 1992; 103(4):1241-5

Mean age of developing BE ~ 40Mean age at diagnosis of BE was 63Mean age of developing BE ~ 40Mean age at diagnosis of BE was 63


NERD EE SSBE LSBE0%

20%

40%

60%

80%

100%

29%

71% 72%

96%

% o

f pati

ents

with

hia

tal h

erni

a

(<3cm) (>3cm)

Cameron AJ. Am J Gastroenterol 1999; 94: 2054–59

P < 0.05

Coenraad et al, Am J Gastroenterol 1998; 93:1068-1072

Normal subjects (n=24)

Esophagitis I-II (n=45)

Esophagitis III-IV (n=30)

BE (n=51)0

5

10

15

20

25

16

11.9

9.38

1.8

10.4

17.5

21.5

LES pressure % pH<4

P < 0.05



Savarino et al, Alim Pharmacol Ther 2011; 34: 476–486

* p<0.01 vs. NERD, FH and HV

FUNCTIONAL HEARTBURN

NERD EE BARRETT0%

10%20%30%40%50%60%70%80%90%

100%

85% 77%

45% 43%

15% 23%

55% 57%

Normal BT % Abnormal BT %

* *

Pat

ien

ts (

%)

HEALTHY VOLUNTEERS

FUNCTIONAL HEARTBURN

NERD EE BARRETT0%

10%20%30%40%50%60%70%80%90%

100%

4% 9%23%

38% 42%13%

19%14%

16% 14%83%

73% 63%46% 44%

IEM DES/NE NORMAL MOTILITY

* p<0.01 vs. NERD, FH and HV& p<0.01 vs. FH and HV# p<0.05 vs. NERD, EE and BE

**&# #

Pat

ien

ts (

%)

FH (N=39) NERD (N=122)

EE (N=65) BARRETT (N=34)

0%10%20%30%40%50%60%70%80%90%

36% 31%52% 56%

0% 4%

22% 21%

Conventional ManometryCombined Impedance Manometry

Pat

ien

ts (

%)

a)

b)

#

**

*

§§LSBO

SSBO

EO

Healthy Volunteers

0 50 100 150 200 250

222

182

95

31

Acid Clearance Time (sec)

#

**

* §LSBO

SSBO

EO

Healthy Volunteers

0 5 10 15 20 25 30

23

15

17

11

Volume Clearance Time (sec)


Savarino et al, Neurogastroenterol Motil 2010; 22:1061-e280.

N HVs = 48N (EE 50 + SSBE 75 + LSBE 25) = 150


CRD (56) ERO (76) NERD 88)0

5

10

15

20

2521.2

14.7

9.2

17.7

14.5 14.3 Supine nocturnal

Upright diurnal

% AET

Frazzoni et al, Aliment Pharmacol Ther 2003; 18:1091-8

P < 0.05

Major Role of:Bile and Duodeno-Gastroesophageal

Reflux

Savarino et al, Neurogastroenterol Motil 2010.;22:1061-e280.




0 20 40 60 80 100 120 140 160 1800

2

4

6

8

10

12

f(x) = 0.0423177356795415 x − 0.321908529545226R² = 0.510098931379707

Total Number of Reflux episodes

Le

ng

th o

f B

arr

ett

mu

co

sa

(c

m)



<40% have symptomatic

Reflux (heartburn, regurgitation, etc)

Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42

Natural History of Barrett’s EsophagusEpitelio Squamoso

dell‘Esofago

Metaplasia Intestinale Esofagea = Barrett

Barrett + LGD

Barrett + HGD

Adenocarcinoma

Noxae: HCO, NO, Bile Salts

SCREENING

SURVEILLANCE

Incidenza per Barrett: 0.5% /y

Flogosi Cronica

Fattori genetici


AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091

BARRETT’S ESOPHAGUS RISK AND SCREENING

Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42

Endoscopic Definition of Barrett’s Esophagus

3 cm3 cm

IM

IM

IM

Long BELong BE Short BEShort BE IM-CardiaIM-Cardia

Sharma P et al . Gastroenterology 2006; 131:1392–1399

Endoscopic Definition of Barrett’s Esophagus



ENDOSCOPIC SURVEILLANCE

USE OF BIOMARKERS



BIOPSY PROTOCOL

Barrett’s Esophagus: DiagnosisHISTOLOGIC DIAGNOSIS


MEDICAL THERAPY


Barrett’s Esophagus: Diagnosis

PPI

PPI

PPI

ACID EXPOSURE AND

SYMPTOMS

BARRETT EPITHELIUM

LENGHT

PROGRESS TO MALIGNANCIES


PPI ACID EXPOSURE AND

SYMPTOMS

Yew et al., Dis Esophagus 2003; 16, 193–198

Med

ian

num

ber

of r

eflu

xes

Frazzoni et al., Aliment Pharmacol Ther 2009; 30:508-515


PPI BARRETT EPITHELIUM

LENGHT

Authors n° EB Follow-up (mounths)

PPI/die Results

Sampliner et al (1993) 64 6-76 Lansoprazole 60 mg NO regression

Gore et al (1993) 30 24 Omeprazole 40 mg Regression

Neumann et al (1995) 24 12-24 Omeprazole 20 mg NO regression

Malesci et al (1996) 14 12 Omeprazole 60 mg Partial regression

Cooper et al (1998) 47 24-60 Omeprazole 20 mg NO regression

Wilkinson et al (1999) 23 60 Omeprazole 20 mg Partial regression

Srinivasan et al (2001) 9 >12 Omeprazole 40 mgLansoprazole 60 mg

+/- ranitidine

Partial regression

1. Different Patients Populations (SSBE or LSBE)

2. Different Duration and Extent of Acid Suppression (not always confirmed by

pH testing)3. Different Methodology to Assess

Metaplastic Regression


PPI PROGRESS TO MALIGNANCIES

Kastelen et al. Clin Gastroenterol Hepatol 2013; 11:382-399El-Serag et al, Am J Gastroenterol 2004; 99(10):1877-83

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Years of follow-up

Dys

plas

ia r

ate

%

0

10

20

30

40

50

60

70

80

No PPI Therapy

PPI Therapy

Proton Pump Inhibitors Are Associated with Reduced Incidence of Dysplasia in Barrett's EsophagusProton Pump Inhibitors


N=236


Eliminate GORD symptoms

Control Acid and Reduce Barrett

epithelium length

Prevent progress to malignancy


Barrett’s Esophagus: Therapy

A large, prospective, RCT in the UK is investigating the chemopreventive effects of PPIs alone and in combination with aspirin (AspECT), and the results of that study are eagerly awaited (2016).

Chronic inflammation

• COX-2 blocks the apoptosis signaling pathway• COX-2 promotes angiogenesis via induction of the vascular endothelial growth factor (VEGF)• COX-2 expression in OAC• COX-2 stimulation by bile salts• COX-2 increase and PPI-induced hypergastrinaemia?

squamous epithelium Barrett’s metaplasia Adenocarcinoma

Barrett’s Esophagus: TherapyENDOSCOPIC THERAPY


Radiofrequency Ablation Endoscopic Mucosal Resection

Cases / 100,000 males / year, 1993-1997

Czech Republic 0.5

Sweden 1.0

Italy 1.5

USA 3.2

United Kingdom 5.8

Bollschweiler et al, Cancer 2001; 92(3):549-55

Barrett’s Esophagus: EAC

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dall'esofago di barrett all'adenocarcinoma: fisiopatologia e diagnosi - gastrolearning®

Education

barretts esophagus risk

reflux x

male male

n engl j med

severe reflux symptoms

reflux symptoms o43

n correlation male

reflux romero