1. Di fronte alla displasia intestinale Colon e Retto G C Sturniolo Università degli Studi di Padova Dipartimento di Scienze Chirurgiche e Gastroenterologiche

2. DIAGNOSIS OF DYSPLASIA Macroscopic heterogeneity Flat Itzkowitz et al., 2004 Elevated (polyp-like, DALM, ALM) Gastroenterologia Padova, 2005

3. SURVEILLANCE IN IBD 8-10 years for Crohn ’ s disease colitis and extensive ulcerative colitis 15-20 years left sided ulcerative colitis Two-four random biopsies every 10 cm, additional samples of suspicious areas no<33biopsies (British and American guidelines recommendations 2003) Colonoscopic surveillance is able to reduce CRC-related mortality Case-control studies Vleggaar,AP&T,2007

4. RISK OF CRC IN UC & CD Cumulative Incidence for CRC Based on Extent of Disease and Age at Diagnosis Cumulative CRC (%) 0 10 20 30 40 020304050 Age at diagnosis pancolitis Proctitis or ileal CD Oldenburg, UEGW, 2008 Life-time Cumulative risk Population based studies Referral center studies UC3.79 colonic CD2.76.9

5. NOT ALL PATIENTS WITH IBD HAVE THE SAME CRC RISK! Rubin, World J Gastroenterol,2008 Factors that increase CRC risk Factors that decrease CRC risk Long duration of colitis Extensive colonic involvement Family history of CRC PSC Young age of IBD onset Backwash ileitis Severity of inflammation Prophylactic total proctolectomy Regular doctor visits Colonoscopy Chemoprevention

6. EARLY COLORECTAL CANCER IN IBD Lutgens, Gut 2008 6.7% simoultaneously IBD/CRC 22% early CRC *patient with left-sided colitis who developed CRC before 15 or 20 years

7. Microscopic classification Low Grade DysplasiaHigh Grade Dysplasia Itzkowitz et al., 2004; Lim et al 2003 DIAGNOSIS OF DYSPLASIA Indefinite for Dysplasia Interobserver agreement for LGD 0.06 – 0.39 between each pair of the 5 gastrointestinal pathologists

8. Low Grade Tubuloglandular Adenocarcinoma (LGTGA): from LGTGA to Cancer Harpaz, Am J Surg Pathol, 2006 LGTGA not a rare entity (11%) Relatively young patients (mean age 41.5 years) with extensive and long-standing colitis 23% small size (max 2.2 cm) and flat, escape detection during initial gross examination

9. Low Grade Tubuloglandular Adenocarcinoma (LGTGA): from LGD to Cancer Harpaz, Am J Surg Pathol, 2006

10. PROSPECTIVE TRIAL CHROMOENDOSCOPY vs RANDOM BIOPSIES Random Non-dye targed Dye targed p=0.001 p=0.057 79 UC 23 CD colitis n° of patients PtsRandomNDTDye-TColectomy findings 1NegLGDNo dysp 1NegLGDNR LGDLGD HGD 2Neg NR LGDLGD MEDIAN TIME Random/Non-dye targed: 22:11min Dye targed: 15:12 min POST COLECTOMY FINDINGS Marion, Am J Gastroenterol, 2008

11. NBI for the study of DYSPLASIA in UC: a pilot study Matsumoto, Gastrointest Endosc, 2007 Honeycomb likeMild chronic inflammation Tortuos patternLGD Tortuos patternHGD ColonoscopyHoneycombTortuousTotal Protruding lesion 0% (0/18) 100% (2/2) 10% (2/20) Flat mucosa0.4% (1/228) 4.2% (2/48) 1.1% (3/276) Total0.4% (1/246) 8% (4/50) 1.6% (5/296) NBI + p=0.003, * p=0.038, not confirmed with multiple testing * + + + Incidence if dysplasia

12. Autofluorescence improves neoplasia detection NBI has a moderate accuracy for prediction of histology

13. More detection of neoplasia 4.75-fold with 50% fewer biopsies Kiesslich, Gastroenterology, 2007 Chromoscopy-guided endomicroscopy increases the diagnostic yield of intra-epithelial neoplasia in UC Gastroenterologia Padova, 2008

14. Probability of finding CRC at colectomy for LGD/HDG DysplasiaProbability of finding CRCReference DALM17/40 (43%)Bernestein, Lancet ‘94 HGD10/24 (42%)Bernestein, Lancet ‘94 HGD8/12 (67%)Connel, Gastrenterol’94 HGD5/11 (46%)Rutter, Gastrenterol ’06 LGD3/16 (19%)Bernestein, Lancet ‘94 LGD2/10 (20%)Rutter, Gastrenterol ’06 LGD2/11 (19%)Ullman, Gastrenterol ’03 LGD3/8 (37%)Merlini ’06 (UEGW)

15. COLONOSCOPIC MARKERS FOR DYSPLASIA & CRC IN UC Rutter Gut 2004 Multivariate analysis of Case Control Studies VariableGroupOR (95% CI)p Value Normal colonic appearanceNo1 Yes0.38 (0.19, 0.73)0.003 Post-inflammatory polyps*No1 Yes2.29 (1.28, 4.11)0.005 Colonic stricture *No1 Yes4.62 (1.03, 20.8)0.05 * Indicative of severe inflammation

16. Gupta, Gatroenterology 2007 For any unit increase in inflammation score a 3-fold increase of advanced neoplasia

17. BLOCKING TNF-α IN MICE REDUCES CRC CARCINOGENESIS TNF-alfa increases with time after AOM and DSS treatment proportionately to tumor formation Popivanova, J Clin Invest, 2008 m-RNA level Anti TNF-α administration reduces number and tumor size

18. SECONDARY CANCER PREVENTION in LGD: COLECTOMY? PALAZZO DELLA RAGIONE, PADOVA 20% of concurrent CRC No clinical feature discriminates progressors to no progressors Progression to CRC even with surveillance Once detected 9 X risk of CRC and 12 x risk of any advanced lesion (HGD, DALM, CRC) during surveillance NNC(olonoscope) 6 for advanced histology and NNC 8 for CRC once LGD detected Incontinence Adhesions Pouchitis Fertility

19. Dysplasia, CRC and IBD Understanding the definition, pathogenesis and biological significance of dysplasia is crucial to the proper management of CRC Chronic inflammation, the persistent state of tissue repair and cell renewal play a key role in colorectal carcinogenesis associated with IBD Colonoscopy plus biopsies is the main method for CRC prevention

20. Chromoendoscopy and targeted biopsies have a greater yield for detection of dysplasia LGD is clinically important endpoint in the surveillance Endoscopic resectability determine the management of polypoid dysplasia in IBD Dysplasia, CRC and IBD

21. distance between the invasive tumor and the cauterized biopsy margin tumor differentiation status of lymphatic or vascular invasion (present or absent) Prognostically significant histologic features lymphnode +ve if LGD polpys: Colacchio 4% Cranley 0% Geraghty 0% Kyzer 0% Dell’Abate 0% lymphnode +ve if HGD polpys: Cranley 18% Geraghty 11.1% Kyzer 5.6% Dell’Abate 14.3%