1. Controversies in Surveillance and Therapy for Colorectal Dysplasia in IBD: Case Studies Thomas Ullman MD Mount Sinai, New York Fernando Velayos MD MPH University of California, San Francisco Advances in Inflammatory Bowel Disease Hollywood, Florida December 13, 2013

2. Risk of CRC in IBD is elevated Inflammation of the colon is the key factor Crohn’s disease Canavan C et. al.Aliment Pharmacol Ther 2006: 23; 1097 SiteRR95% CI All CD2.51.3-4.7 Colon4.51.3-14.9 Ileum1.10.8-1.5 * * * Ulcerative colitis General population

3. Known risk factors are almost all non-modifiable Non-modifiable risk factors: – Duration (increases after 10 years) – Extent (15X greater in pancolitis) – PSC (5X greater) 2 – Family history of CRC (2.5X greater) 1 – Inflammatory polyps (“pseudopolyps”-2.5X) 3,4 Potentially modifiable risk factor: – Histologic inflammation at surveillance colonoscopy 3 1 Askling J, et al. Gastroenterology. 2001 2 Lindberg BU, et al. Dis Colon Rectum. 2001 3 Rutter, et al. Gastroenterology. 2004. Bansal, et al. Presented at ACG 2005, Honolulu. Rubin et al. Presented at DDW 2006, Los Angeles. 4 Velayos et. al. Gastroenterology. 2006 Normal Epithelium Inflamed Epithelium High-Grade Dysplasia Low-Grade Dysplasia Cancer Indefinite Dysplasia

4. Controversies to cover today 1.Surveillance: Is it effective, when to start, in whom, how frequent to repeat colonoscopy? 2.Vocabulary of dysplasia: time to simplify? 3.What to do when dysplasia in detected: polypectomy, proctocolectomy, partial resection? 4.Performance of surveillance and role of chromoendoscopy: what is standard of care? 5.New algorithm for thinking and managing dysplasia in IBD: Can we mimic what we are doing in non-IBD patients?

5. Controversy 1 Surveillance: Is it effective, when to start, in whom, how frequent to repeat colonoscopy?

6. 45 year old man with L sided ulcerative colitis diagnosed 5 years ago. Based on 2010 AGA guidelines what strategy is recommended? A.Begin screening at 15 years, then every 5 years B.Begin screening at 8 years, and then every 1- 2 years C.Begin screening at 8 years, then every 1-5 years D.Average risk screening, not at increased risk based on his limited extent

7. Is there sufficient rationale for performing surveillance colonoscopy in patients with IBD? Grade B: There is moderate certainty that surveillance colonoscopy results in at least moderate reduction of CRC risk in patients with IBD. Despite the lack of randomized controlled trials, surveillance colonoscopy is recommended for patients with IBD at increased risk for developing CRC. Patients with extensive UC or CD of the colon are most likely to benefit from surveillance. Farraye FA, Odze R, Eaden J, Itzkowitz S. Diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138:746-774.

8. Most recent GI society surveillance guidelines -which to choose? Society First colonoscopy (Screening) Interval subsequent colonoscopy ACG (2004) and ASGE (2006) All patients 8-10 years after diagnosis Immediately in PSC Every 1-2 years Crohn’s and Colitis Foundation (2006) All patients 8-10 years after diagnosis Immediately in PSC - Next 2 in 1-2 years -Then every 1-3 years until 20 years of disease, then return to every 1-2 years - Yearly in PSC AGA (2010)All patients 8 years after symptom onset (except proctitis and procotosigmoiditis) -Every 1-2 years after screening -Every 1-3 years after 2 negative examinations British Society Gastroenterology (2010) All patients 10 years after diagnosis to determine extent and endoscopic risk factors - Yearly in pancolitis with active/moderate inflammation or stricture or PSC or history of dysplasia or FH CRC age <50 -Every 3 years in pancolitis with mild inflammation or inflammatory polyps or FH CRC >50 years - Every 5 years in quiescent pancolitis or left sided colitis

9. Controversy 2 Vocabulary of dysplasia: time to simplify?

10. You are performing surveillance in pt with UC and biopsies of lesion in area inflammation-path shows tubular adenoma. Assuming area around lesion shows no dysplasia, what would you call this lesion? A.Sporadic adenoma B.Adenoma-like lesion or mass (ALM) C.Dysplasia-associated lesion or mass (DALM) D.Raised Dysplasia E.Flat Dysplasia

11. A.Sporadic adenoma B.Adenoma-like lesion or mass (ALM) C.Dysplasia-associated lesion or mass (DALM) D.Raised Dysplasia E.Flat Dysplasia You are performing surveillance in pt with UC and biopsies of lesion in area inflammation-path shows tubular adenoma. Assuming area around lesion shows no dysplasia, what would you call this lesion?

12. A.Adenoma-like lesion or mass (ALM) B.Dysplasia-associated lesion or mass (DALM) C.Raised Dysplasia D.Flat Dysplasia E.Occult dysplasia You are performing surveillance in pt with UC and path shows tubular adenoma. What would you call this lesion?

13. Pathologist cannot decide- importance of dysplasia is given by endoscopic context Tubular adenoma= low-grade dysplasia IndefiniteLow-GradeHigh-Grade

14. Vocabulary for dysplasia in IBD Traditional: Macroscopic classification Better: How detected (Non-targeted vs. targeted biopsies) Can borders be defined Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 “Flat” “Invisible?” “Elevated” “sporadic” “DALM”“ALM”

15. Controversy 3 What to do when dysplasia in detected: polypectomy, proctocolectomy, partial resection? Normal Epithelium Inflamed Epithelium High-Grade Dysplasia Low-Grade Dysplasia Cancer Indefinite Dysplasia

16. A.Ongoing surveillance with white light endoscopy B.Ongoing surveillance with chromoendoscopy C.Proctocolectomy D.Segmental resection E.No recommendation You are performing surveillance in pt with UC and path shows dysplasia. Based on 2010 AGA Guidelines, what is the recommended action

17. 2010 AGA Guidelines for management dysplasia-mostly grade A Farraye Gastroenterology 2010; 138: 738

18. Perspective: What proportion of dysplasia fall into the “flat” category Rutter 2006 – 25/110 (22.7%) LGD “invisible” or flat Rubin 2007 – 29/75 LGD invisible (38.7%) Velayos 2009 – 16/61 (26.2%) LGD invisible Marion 2008 – 3/12 LGD invisible (25%) Rutter MD et. al.. GI Endoscopy 2004: 60(3):334 Rubin DT et. al.. GI Endoscopy 2007: 65 (7): 998 Velayos FS et al ACG 2009 Marion JF et al AJG 2008: 103: 2342

19. Gastroenterology 2010; 138: 738 Perspective: What proportion of dysplasia fall into this category ~25%~75%

20. AGA Guidelines-management of dysplasia Questions and parameters to decide “non- adenoma like dysplasia lesion or mass” “adenoma-like lesion or mass and no flat dysplasia elsewhere” “flat high- grade dysplasia” “flat low- grade dysplasia” Treatment?Surgery (grade A) Polypectomy (grade A) Surgery (grade A) Insufficient (grade I) * Further adenoma 50%-need close surveillance Farraye F Gastroenterology 2010; 138: 738 Bernstein C Lancet 1994

21. Controversy 4 Performance of surveillance and role of chromoendoscopy: what is standard of care?

22. You are planning to perform surveillance colonoscopy on patient with IBD and are deciding on what is the current standard of care with regard to enhanced dysplasia detection technique. Which of the following statements is true based on 2010 AGA Guidelines? A.Chromoendoscopy is superior to white light colonoscopy for detecting dysplasia and should be performed for every surveillance B.NBI/iScan (virtual chromoendoscopy) is superior to white light colonoscopy for detecting dysplasia and is an easier alternative to chromoendoscopy C.Chromoendoscopy is an acceptable alternative to white light colonoscopy in those experienced in the technique D.Chromoendoscopy does not eliminate the need for random biopsies

23. 23 Surveillance Technique Based on expert opinion Technique: 4-quadrant biopsies every 10 cm of mucosa; at least 33 biopsies; extra focus on nodules, masses, strictures; every 5 cm in rectosigmoid Kornbluth and Sachar, Am J Gastro, 2004. Itzkowitz and Present, Inflammatory Bowel Diseases, 2005. Itzkowitz and Harpaz, Gastroenterology 126:1634, 2004.

24. Chromoendoscopy proposed as means of improving sensitivity of colonoscopy Two main uses in IBD Surveillance – Improve detection of subtle colonic lesions (increase sensitivity of surveillance) – Once lesion detected-to aid in differentiating between neoplastic and non-neoplastic based on crypt architecture and modified pit pattern

26. “Invisible” dysplasia happens in IBD- Reason for “enhanced” surveillance techniques Rutter MD et. al.. GI Endoscopy 2004: 60(3):334 Toruner et. al.. Inflamm Bowel Dis 2005: 11:428

27. Significance of Pit Patterns Type I/II predict non-neoplastic lesions Type III/IV/V predict neoplastic lesions Kudo S et al. Endoscopy 1993

28. Difference Between Chromoendoscopy and Virtual chromoendoscopy Chromoendoscopy – Dye spray through catheter – Absorptive dye: (stain taken up by noninflammed mucosa but poorly taken up by active inflammation and dysplasia): methylene blue – Contrast dye (coats surface to highlight subtle disruptions of normal contours): indigo carmine Virtual chromoendoscopy – Rotating color filters the R-G-B bands while increasing the relative intensity of blue bands – Post-processing techniques (i-Scan/Fujinon) to achieve pseudocolored image – Enhance tissue vasculature (differential optical absorption of light by Hb associated with dysplasia (blue band)) or mucosal contours

29. SURFACE guidelines for chromoendoscopy Strict patient selection – Avoid active disease Unmask the mucosal surface – Excellent bowel prep; remove mucus and debris Reduce peristaltic waves Full-staining length of the colon Augmented detection with dyes – 0.4% indigo carmine; 0.1% methylene blue Crypt architecture analysis – Pit pattern III/IV of concern Endoscopic targeted biopsies – Biopsy all mucosal alterations, especially pit pattern III/IV

30. Chromoendoscopy Finds More Dysplasia than Conventional Exams Author (Year) Institution # of UC Patients Type of Imaging Number of Dysplastic Lesions ChromoConventional Sensitivity / Specificity Kiesslich (2003) University of Mainz, Germany 263 Methylene blue 3210 93% sens. 93% spec. Rutter (2004) St. Mark’s Hospital, Harrow, UK 100 Indigo carmine 70 Not given Hurlstone (2005) The Royal Hallamshire Hospital, Sheffield, UK 350 Indigo Carmine-and Magnification 6924 93% sens. 88% spec. Kiesslich (2007) University of Mainz, Germany 161 Confocal endomicrosco py 194 94.7% sens. 98.3% spec. 97.8% accuracy Dekker (2007) Academic Medical Center, Amsterdam, The Netherlands 42 Narrow-band imaging 87 Not given Marion (2008) Mount Sinai, New York, USA 102 Methylene Blue 17 9 Not given

31. Role of chromoendoscopy in surveillance Not yet standard of care Chromoendoscopy (not virtual chromo)-is an alternative surveillance technique mentioned in guidelines from Crohn’s and Colitis Foundation of America (2006) and AGA (2010) and British Society of Gastroenterology Guidelines (2010)

32. Controversy 5 Can we create a new/unified algorithm for thinking and managing dysplasia in IBD: Can we mimic what we are doing in non-IBD patients?

33. You are performing colonoscopy on a non-IBD patient and come across the following lesion in the ascending colon. You are able to define borders and lifts with saline. What would you do? A.Biopsy, if no cancer, schedule colonoscopy later to remove endoscopically (yourself or refer) B.Attempt complete endoscopic removal at the time of procedure, if no cancer confirmed, continue surveillance C.Biopsy, if no cancer, refer to surgeon for segmental resection D.Biopsy, if no cancer, refer to surgeon for proctocolectomy

34. Proposal-three parameters relevant for preventing CRC and CRC mortality in IBD once any type of dysplasia is detected- NOTE: it is what you are already doing in non-IBD patients 1.Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous) 2.Rate of occult cancer in patients diagnosed with dysplasia (synchronous) 3.Resectability of the dysplastic lesion

35. Is it discreet? Is it discreet? Can I resect it? Can I resect it? Can I see it? Can I see it? 1.Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous) 2.Rate of occult cancer in patients diagnosed with dysplasia (synchronous) 3.Resectability of the dysplastic lesion Proposal-three parameters relevant for preventing CRC and CRC mortality in IBD once any type of dysplasia is detected- NOTE: it is what you are already doing in non-IBD patients

36. 3 questions to ask in this case 1.Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous) 2.Rate of occult cancer in patients diagnosed with dysplasia (synchronous) 3.Resectability of the dysplastic lesion

37. Controversy regarding progression of “flat” LGD to HGD or Cancer StudySettingLGD (n)Rate Connell 1994St Mark’s954% @5y Ullman 2002Mayo Clinic1833% @5y Ullman 2003Mount Sinai4653% @5y Rutter 2006St Mark’s3625% @5y Lindberg 1996Huddinge3735% @20y Befrits 2002Karolinska602% @10y Lim 2003Leeds, UK2910% @10y Van Schaik 20106 Dutch centers7012% @5y

38. StudySettingLGD (n)Rate Connell 1994St Mark’s954% @5y Ullman 2002Mayo Clinic1833% @5y Ullman 2003Mount Sinai4653% @5y Rutter 2006St Mark’s3625% @5y Van Schaik 20106 Dutch centers2137% @5y Lindberg 1996Huddinge3735% @20y Befrits 2002Karolinska602% @10y Lim 2003Leeds, UK2910% @10y Controversy regarding progression of “flat” LGD to HGD or Cancer

39. - Eaden J J of Pathol 2001; 194:152 Kappa statistic indicates how much greater observer agreement exists than would be expected by chance Range -1.0 to +1.0 Value 0= pure chance only Value 1.0= perfect agreement Value >0.75 =excellent agreement Value 0.4-0.74= fair to good agreement Value <0.4= poor agreement P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 0.43 - 0.25 0.12 - 0.12 0.16 0.44 - 0.15 0.24 0.38 0.44 - 0.59 0.40 0.27 0.18 0.27 - 0.48 0.36 0.39 0.17 0.26 0.51 - 0.2 0.24 0.18 0.25 0.29 0.14 0.13 - 0.22 0.15 0.24 0.17 0.14 0.35 0.32 0.13 - 0.37 0.28 0.47 0.20 0.29 0.36 0.39 0.21 0.32 - 0.19 0.19 0.33 0.27 0.2 0.24 0.34 0.13 0.28 0.21 - 0.23 0.27 0.52 0.31 0.48 0.38 0.43 0.33 0.25 0.48 0.39 - 0.33 0.26 0.35 0.17 0.12 0.43 0.40 0.11 0.26 0.3 0.43 0.29 - - P13P12P11P10P9P8P7P6P5P4P3P2P1 Very few kappa values over 0.5 All pathologists agreed only on 4 of 51 (7.8% agreement (all HGD)) GI pathologists agreed only on 6 slides (11.7% agreement (4 HGD, 2 reactive atypia)) General pathologists agreed on 8 slides ( 15.7 % agreement (5HGD,2LGD,1 atypia)) GI PathologistsGeneral Pathologists Controversy in the agreement of dysplasia

40. 3 questions to ask in this case 1.Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous) 2.Rate of occult cancer in patients diagnosed with dysplasia (synchronous) 3.Resectability of the dysplastic lesion

41. What is the probability of finding occult (synchronous) cancer after a diagnosis fLGD? StudyIf colectomy done immediately Bernstein 19943/16 (19%) Ullman 20032/11 (19%) Rutter 20062/10 (20%)

42. 3 questions to ask in this case 1.Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous) 2.Rate of occult cancer in patients diagnosed with dysplasia (synchronous) 3.Resectability of the dysplastic lesion

43. Characteristics to resectability You already ask yourself this when you do screening and surveillance in patients without IBD Is it discreet? Is it discreet? Can I resect it? Can I resect it? Can I see it? Can I see it?

44. Fact: Non-resectable colonic dysplasia is managed with surgery Concern in IBD is typically the type of surgery – Colectomy in IBD vs. limited resection in non-IBD

45. Proposal: 3 parameters relevant for managing dysplasia Questions and parameters to decide “non- adenoma like dysplasia lesion or mass” “adenoma-like lesion or mass and no flat dysplasia elsewhere” “flat high- grade dysplasia” “flat low- grade dysplasia” ProgressionNo info Occult Cancer43% ResectabilityNo Treatment?Surgery (grade A) * Further adenoma 50%-need close surveillance Farraye F Gastroenterology 2010; 138: 738 Bernstein C Lancet 1994

46. Proposal: 3 parameters relevant for managing dysplasia Questions and parameters to decide “non- adenoma like dysplasia lesion or mass” “adenoma-like lesion or mass and no flat dysplasia elsewhere” “flat high- grade dysplasia” “flat low- grade dysplasia” ProgressionNo info<5%* Occult Cancer43%<5% ResectabilityNoYes Treatment?Surgery (grade A) Polypectomy (grade A) * Further adenoma 50%-need close surveillance Farraye F Gastroenterology 2010; 138: 738 Bernstein C Lancet 1994

47. Proposal: 3 parameters relevant for managing dysplasia Questions and parameters to decide “non- adenoma like dysplasia lesion or mass” “adenoma-like lesion or mass and no flat dysplasia elsewhere” “flat high- grade dysplasia” “flat low- grade dysplasia” ProgressionNo info<5%*High Occult Cancer43%<5%42% ResectabilityNoYesNo Treatment?Surgery (grade A) Polypectomy (grade A) Surgery (grade A) * Further adenoma 50%-need close surveillance Farraye F Gastroenterology 2010; 138: 738 Bernstein C Lancet 1994

48. Proposal: 3 parameters relevant for managing dysplasia Questions and parameters to decide “non- adenoma like dysplasia lesion or mass” “adenoma-like lesion or mass and no flat dysplasia elsewhere” “flat high- grade dysplasia” “flat low- grade dysplasia” ProgressionNo info<5%*High1-12% vs 25- 55% Occult Cancer43%<5%42%19% ResectabilityNoYesNo Treatment?Surgery (grade A) Polypectomy (grade A) Surgery (grade A) Insufficient (grade I) * Further adenoma 50%-need close surveillance Farraye F Gastroenterology 2010; 138: 738 Bernstein C Lancet 1994

49. Our approach to these controversies 1.Grade B evidence for surveillance in IBD. GI society guidelines share first exam 8-10 yrs/PSC at diagnosis – Next exam varies (1-3 years) 2.Simplified approach to dysplasia-based on how found: targeted vs. non-targeted biopsy and if can define borders 3.Dysplasia mngmt: polypectomy-ALM; surgery-HGD/DALM; not clear-flat LGD 4.Follow either surveillance technique based on expert opinion or chromo, no role virtual chromo – More likely to come across raised lesions or subtle abnormalities (75%)-don’t just focus on 33 biopsies/dye spray – No need random biopsy with chromo after training 5.Proposal: the 3 parameters we use to manage non-IBD dysplasia can be applied to IBD-dysplasia (to be tested)