Dall'esofago di Barrett all'adenocarcinoma: fisiopatologia e diagnosi - Gastrolearning®

Edoardo V. Savarino MD, PhD
Assistant Professor of Medicine
UOC di Gastroenterologia
Azienda Ospedaliera Universitaria di Padova
Università di Padova
GASTRO-LEARNING 2014
Secondo Modulo: Oncologia Gastrointestinale
L’ ESOFAGO DI BARRETT:
FISIOPATOLOGIA, DIAGNOSI
E TRATTAMENTO CHIRURGICO DELLE
SUE COMPLICANZE NEOPLASTICHE
Esofago
diBarrett

Definition of Barrett’s Esophagus
Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42
AGA 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 Esophagus
Risk increased:
• White Male
• Age >40 years
• Smoking
• Obesity
• Esophageal Reflux
o7.7 x with reflux symptoms
o43.5 x with severe reflux symptoms > 20 years
Spechler SJ. N Engl J Med 2002; 346: 836–42
Lagergren 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 80-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age (years)
Patientsendoscoped
whohadBE(%)
Male
Male + female
Female
Cameron et al, Gastrointestinal Endoscopy 1992; 103(4):1241-5
Mean age of developing BE ~ 40
Mean 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 13

Barrett’s Esophagus: Genetic Factors
Acid peptic disease
Adenocarcinoma
Barrett's esophagus
Deceased
I
II
III
IV
V
Pattern
Autosomic
Dominant
Jochem 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

29%
71% 72%
96%
0%
20%
40%
60%
80%
100%
NERD EE SSBE LSBE
%ofpatientswithhiatalhernia
(<3cm) (>3cm)
Cameron AJ. Am J Gastroenterol 1999; 94: 2054–59

Coenraad et al, Am J Gastroenterol 1998; 93:1068-1072
16
11.9
9.3
8
1.8
10.4
17.5
21.5
0
5
10
15
20
25
Normal subjects
(n=24)
Esophagitis I-II
(n=45)
Esophagitis III-IV
(n=30)
BE (n=51)
LES pressure % pH<4

Savarino et al, Alim Pharmacol Ther 2011; 34: 476–486
* p<0.01 vs. NERD, FH and HV
85% 77%
45% 43%
15% 23%
55% 57%
0%
20%
40%
60%
80%
100%
FUNCTIONAL
HEARTBURN
NERD EE BARRETT
Normal BT % Abnormal BT %
* *
Patients(%)
4% 9%
23%
38% 42%
13%
19%
14%
16% 14%
83%
73%
63%
46% 44%
0%
20%
40%
60%
80%
100%
HEALTHY
VOLUNTEERS
FUNCTIONAL
HEARTBURN
NERD EE BARRETT
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
**&# #
Patients(%)
36% 31%
52% 56%
0% 4%
22% 21%
0%
20%
40%
60%
80%
100%
FH (N=39) NERD (N=122) EE (N=65) BARRETT
(N=34)
Combined Impedance Manometry
Conventional Manometry
Patients(%)
a)
b)
#
*
*
*
§
§222
182
95
31
0 50 100 150 200 250
LSBO
SSBO
EO
Healthy Volunteers
Acid Clearance Time (sec)
#
*
*
* §23
15
17
11
0 5 10 15 20 25 30
LSBO
SSBO
EO
Healthy Volunteers
Volume Clearance Time (sec)

Savarino et al, Neurogastroenterol Motil 2010; 22:1061-e280.
N HVs = 48
N (EE 50 + SSBE 75 + LSBE 25) = 150

0
5
10
15
20
25
CRD (56) ERO (76) NERD 88)
21.2
14.7
9.2
17.7
14.5 14.3
% AET
Supine
nocturnal
Upright
diurnal
Frazzoni et al, Aliment Pharmacol Ther 2003; 18:1091-8

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

y = 0.0423x - 0.3219
R² = 0.5101
0
2
4
6
8
10
12
0 20 40 60 80 100 120 140 160 180
LengthofBarrettmucosa(cm)
Total Number of Reflux episodes

Natural History of Barrett’s Esophagus
Epitelio 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

BARRETT’S ESOPHAGUS RISK AND SCREENING

Endoscopic Definition of Barrett’s Esophagus
3 cm
IM
IM
IM
Long BE Short BE IM-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: Diagnosis
HISTOLOGIC DIAGNOSIS

MEDICAL THERAPY

ACID EXPOSURE
AND
SYMPTOMS
BARRETT
EPITHELIUM
LENGHT
PROGRESS TO
MALIGNANCIES

ACID EXPOSURE
AND
SYMPTOMS
Yew et al., Dis Esophagus 2003; 16, 193–198
Mediannumberofrefluxes
Frazzoni et al., Aliment Pharmacol Ther 2009; 30:508-515

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 mg
Lansoprazole 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

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
Dysplasiarate%
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: Therapy
ENDOSCOPIC 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

Dall'esofago di Barrett all'adenocarcinoma: fisiopatologia e diagnosi - Gastrolearning®

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