1. Luigi Bonavina,MD Cattedra e U.O. Chirurgia Generale, Policlinico San Donato Università degli Studi di Milano XXIV Congresso Nazionale A.C.O.I. Montecatini Terme, 27 Maggio 2005 TERAPIA CHIRURGICA DELLA DISPLASIA GRAVE IN ESOFAGO DI BARRETT

2. Rate ratio (relative to 1975) Esophageal adenocarcinoma Melanoma Prostate Cancer Breast Cancer Lung Cancer Colorectal Cancer Pohl H, J Natl Cancer Inst 2005

3. 1 cm 5-YR SURVIVAL RATES ACC. TO WALL INFILTRATION 90% 80% 70% 30%

4. % PREVALENCE OF NODE+ ACC. TO WALL INFILTRATION Bonavina et al, WJS 2003

5. Barrett’s metaplasia High grade dysplasia (in situ carcinoma) Low grade dysplasia Invasive carcinoma GASTROESOPHAGEAL REFLUX DISEASE

6. MOLECULAR EVENTS IN THE SEQUENCE BARRETT’S ESOPHAGUS-ADENOCARCINOMA Barrett M, Nature Genetics 1999 Diploid cell p53/p16 mutation Clonal expansion and multicentricity Unpredictable molecular alterations (5q,18q,13q) Adenocarcinoma

7. HIGH-GRADE DYSPLASIA Dysplasia is the histological expression of genetic alterations that favor cell growth and neoplasia. Glands show severe cytologic atypia, gland complexity with cribriform change and complete loss of nuclear polarity

8. 1.0 0.8 0.6 0.4 0.2 0.0 0 24 6 810 12 14 Probability Years HGD # Ca / n = 33/76 p <.001 Negative, Indefinite, LGD # Ca / n = 9/251 Reid et al, AJG 2000 CUMULATIVE CANCER INCIDENCE

9. HISTOLOGIC CHANGES AFTER TREATMENT OF BE (median F/U > 5 yrs) Medical group (n=45) Surgical group (n=58) Successful surgical group (n= 49) Dysplasia “de novo” 20%6%2% HGD 2/82/30/2 Parrilla et al, 2003

10. p< 0.01 OUTCOME OF RESECTION ACC. TO SURVEILLANCE months Cumulative survival % Incarbone et al, Surg Endosc 2002

11. DIFFICULTIES WITH THE DIAGNOSIS OF HGD Interobserver agreement is 85% for distinguishing HGD from lesser lesions There can be substantial disagreement when distinguishing HGD from intramucosal cancer Dysplastic areas and foci of invasive cancer can be missed by 4-quadrant biopsy technique

12. EXTENT OF HGD FOCAL (histologic abnormalities confined to single focus involving up to 5 crypts) DIFFUSE (abnormalities present in more than 5 crypts or in multiple biopsy specimen) Buttar, 2001

13. EXTENT OF HGD AND CANCER RISK n=100 4-quadrant biopses every 2 cm Focal 4/33 (14%) Diffuse28/67 (56%) Buttar et al., Gastroenterology 2001 p<0.001

14. RECCOMENDATION OF PRACTICE PARAMETERS COMMITTEE OF A.C.G. “…patients with focal HGD may be followed with intensive endoscopic surveillance (every 3 months), whereas intervention (e.g. endoscopic ablation or esophagectomy) should be considered for patients with diffuse HGD” Sampliner et al, 2002

15. Can extent of high grade dysplasia in Barrett’s oesophagus predict the presence of adenocarcinoma at oesophagectomy? Revision of preop biopsy specimen in 42 patients who had esophagectomy for HGD Acc. to Cleveland Clinic criteria, 48% with focal and 67% with diffuse HGD had cancer (pNS) Acc. to Mayo Clinic criteria, 72% with focal and 54% with diffuse HGD had cancer (pNS) Dar et al, Gut 2003

16. RATE OF “OCCULT” INVASIVE CARCINOMA IN HGD

17. Erroneous definition of HGD (missed intramucosal ADC) Inclusion of patients with warning signs (presence of nodules/ulcers) Failure to f/u closely during the first year (cancer missed at 1st endoscopy because of sampling error) HIGH RATE OF OCCULT CARCINOMA

18. TREATMENT OF HIGH-GRADE DYSPLASIA Intensive surveillance Endoscopic ablation Endoscopic mucosectomy Esophagectomy

19. ENDOSCOPIC MUCOSAL RESECTION FOR HGD/IM-Ca 1. Area of Barrett’s < 20 mm in diameter 2. Cancers confined to the lamina propria 3. Involved peripheral or deep margins or extension through muscularis mucosa require esophagectomy

20. S.B., male, 62 yr old: S/P endoscopic mucosectomy: invasive adenocarcinoma on the resected specimen

21. TIMING OF SURGERY AND SURVIVAL Romagnoli, JACS 2003 Prompt Attitude (n=20) 100% Expectant Attitude (n=13) 52.5% p = 0.0094 Cancer-related survival (%) 100 80 60 40 30 0 0 24487296120144168192

22. FREQUENCY OF ESOPHAGECTOMY AND HOSPITAL MORTALITY Mortality rate (%) Case load/year Metzger,Dis Esoph 2004

23. PARTIAL ESOPHAGECTOMY AND JEJUNAL INTERPOSITION Theoretical drawbacks High mediastinal anastomosisHigh mediastinal anastomosis Incomplete Barrett’s ablationIncomplete Barrett’s ablation Limited clinical experience (Siewert)Limited clinical experience (Siewert)

24. NERVE SPARING ESOPHAGECTOMY

25. LAPAROSCOPIC + TRANS-CERVICAL VIDEOASSISTED MEDIASTINAL DISSECTION Bonavina et al, J Lap Adv Surg Tech, 2004

26. University of Milano, Department of Surgery ADENOCARCINOMA OF EGJ 506 consecutive patients (1992-2004) (31%)

27. PATIENTS REFERRED FOR HGD n=30 Sex (M/F)27/3 Mean age (yrs)58 Range35-78 GERD23/30 Surveillance22/30 Symptom duration (yrs)7 Mean no. previous endoscopies6

28. STAGING PROTOCOL Operative risk assessment Repeat endoscopy + Lugol staining Brushing cytology 4-quadrant biopsies every cm Look for nodules/ulcers EUS/CT scan if doubtful High-dose PPI if less than HGD Repeat endoscopy (at 1-3 months)

29. RESULTS OF STAGING AND THERAPY (n=30) 1st endoscopy: 7 invasive carcinoma (>surgery) 1 LGD 22 HGD (73%) 2nd endoscopy: 5 invasive carcinoma (>surgery) 1 LGD 17 HGD (57%) 15 surgery (9 TME, 6 TTE) 1 PDT 1 PPI therapy

30. No operative mortality Morbidity 2 atelectasis 1 chylothorax Pathology 1 LGD 4 invasive carcinoma (27%) 10 confirmed HGD RESULTS OF ESOPHAGECTOMY FOR HGD n=15

31. ESOPHAGECTOMY FOR HGD Actuarial survival (n=15)

32. ONGOING RESEARCH PROTOCOLS Tailored lymphadenectomy based on the sentinal node concept Endoscopic peritumoral ink injection Laparoscopic nodal removal Histopathological assessment

33. CONCLUSIONS Prevalence of adenocarcinoma detected at endoscopy was 40% in patients referred with diagnosis of HGD 27% of patients with confirmed endoscopic diagnosis of HGD had cancer in the resected specimen E.M.R. should be recommended only in patients with low likelihood of lymphatic spread Videoassisted transmediastinal esophagectomy is the approach of choice in intramucosal tumors

34. “Surgery remains radical prophylaxis.…offering a massive macroscopic morbid solution for a microscopic mucosal problem” Barr, Gut 2003; 52:14-5

35. FUTURE SCENARIO Improved reflux control by fundoplication Barrett’s ablation and chemoprevention of genomic instability (Aspirin?) Tailored surgical approach (vagal sparing procedures, sentinel node technology)