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

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Dall'esofago di Barrett all'adenocarcinoma: fisiopatologia e diagnosi
Dr. E. Savarino - Università di Padova

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

  1. 1. 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
  2. 2. 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
  3. 3. 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.
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. Barrett’s Esophagus: Reflux Disease 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
  10. 10. 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 Barrett’s Esophagus: Reflux Disease
  11. 11. Barrett’s Esophagus: Reflux Disease 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)
  12. 12. Barrett’s Esophagus: Reflux Disease Savarino et al, Neurogastroenterol Motil 2010; 22:1061-e280. N HVs = 48 N (EE 50 + SSBE 75 + LSBE 25) = 150
  13. 13. Barrett’s Esophagus: Reflux Disease 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
  14. 14. Savarino et al, Neurogastroenterol Motil 2010.;22:1061-e280. Barrett’s Esophagus: Reflux Disease
  15. 15. Savarino et al, Neurogastroenterol Motil 2010.;22:1061-e280. Barrett’s Esophagus: Reflux Disease 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
  16. 16. Barrett’s Esophagus: Reflux Disease Savarino et al, Neurogastroenterol Motil 2010.;22:1061-e280.
  17. 17. Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42 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
  18. 18. Barrett’s Esophagus: Reflux Disease AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 BARRETT’S ESOPHAGUS RISK AND SCREENING
  19. 19. Spechler SJ. Barrett’s esophagus. N Engl J Med 2002; 346: 836–42 Endoscopic Definition of Barrett’s Esophagus 3 cm IM IM IM Long BE Short BE IM-Cardia
  20. 20. Sharma P et al . Gastroenterology 2006; 131:1392–1399 Endoscopic Definition of Barrett’s Esophagus
  21. 21. Barrett’s Esophagus: Reflux Disease AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 ENDOSCOPIC SURVEILLANCE USE OF BIOMARKERS
  22. 22. Barrett’s Esophagus: Reflux Disease AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 BIOPSY PROTOCOL
  23. 23. Barrett’s Esophagus: Diagnosis HISTOLOGIC DIAGNOSIS AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091
  24. 24. MEDICAL THERAPY AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 Barrett’s Esophagus: Diagnosis
  25. 25. ACID EXPOSURE AND SYMPTOMS BARRETT EPITHELIUM LENGHT PROGRESS TO MALIGNANCIES Barrett’s Esophagus: Diagnosis
  26. 26. 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’s Esophagus: Diagnosis
  27. 27. 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 Barrett’s Esophagus: Diagnosis
  28. 28. 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 Barrett’s Esophagus: Diagnosis N=236
  29. 29. AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 Eliminate GORD symptoms Control Acid and Reduce Barrett epithelium length Prevent progress to malignancy Barrett’s Esophagus: Diagnosis
  30. 30. 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
  31. 31. Barrett’s Esophagus: Therapy ENDOSCOPIC THERAPY AGA Medical Position Statement the Management of Barrett’s Esophagus. Gastroenterology 2011; 140:1084–1091 Radiofrequency Ablation Endoscopic Mucosal Resection
  32. 32. 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
  33. 33. THANK YOU FOR YOUR ATTENTION

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