Nuts and Bolts of Dysplasia in IBD Tad Dryden, MD, MSPH Associate Professor of Medicine University of Louisville 1

Objectives What is dysplasia, and where does it come from? Natural history of dysplasia How do we find it, and what do we do about it? Prevention of dysplasia 2

Dysplasia Dysplasia Dysplasia in IBD Dysplasia in a non-IBD Polyp Unequivocally neoplastic transformation Dysplasia in IBD May be flat, difficult to detect at early stage May be visible on endoscopy (elevated) Dysplasia in a non-IBD Polyp Even in the absence of IBD, every adenoma is dysplastic in normal people ALL ADENOMAS ARE DYSPLASTIC BY DEFINITION 3

Why Do We Care? 4

Cumulative Risk of CRC in UC 0. 5-1 Cumulative Risk of CRC in UC 0.5-1.0% per year after 10 years of disease Eaden et al. Gut 48:526, 2001 5

Risk of CRC in Crohn’s Canavan, APT, 2006 6

Dysplasia-Carcinoma Sequence Non IBD Vs. IBD 7

Proposed Role of Inflammation in Dysplasia Genetic factors, which are poorly characterized, IBD duration, severity, and proportion of bowel affected by the condition are all factors that contribute to the severity of colonic inflammation. Inflammation in turn causes oxidative DNA damage, which results in growth-promoting mutations whose number is influenced by the severity of the inflammation. b | Schematic representation of how accumulation of growth-promoting genetic alterations leads to dysplasia and cancer. Abbreviation: CRC, colorectal cancer Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer Nat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44 8

Proposed Role of Inflammation in Dysplasia Genetic factors, which are poorly characterized, IBD duration, severity, and proportion of bowel affected by the condition are all factors that contribute to the severity of colonic inflammation. Inflammation in turn causes oxidative DNA damage, which results in growth-promoting mutations whose number is influenced by the severity of the inflammation. b | Schematic representation of how accumulation of growth-promoting genetic alterations leads to dysplasia and cancer. Abbreviation: CRC, colorectal cancer Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer Nat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44 9

Flavors of Dysplasia Flat dysplasia Raised dysplasia Low grade High grade 10

DALM Two types of definitions by clinicians: 1: any protruded lesion with dysplasia This leads to lots of misunderstanding This is not the original description 2: ominous looking lesion that cannot be removed colonoscopically 11

DALM Definition (1981) Single discrete polypoid or nodular mass Discrete plaque like lesion Abnormal appearing mucosa Raised irregular or nodular area Original report: lesion that could not be removed endoscopically If it can be removed colonoscopically, it is not a DALM by definition The term DALM has been misinterpreted Blackstone MO, Riddell R, Rogers G, Levin B. Dysplasia associated lesion or mass (DALM) detected by colonoscopy in longstanding ulcerative colitis: An indication for colectomy. Gastro 1981;80:366-74. 12

Differentiating Polypoid Lesion in IBD Patient If an adenoma (mass) is found in IBD, it must always be dysplastic: by definition, it is a Dysplasia Associated Lesion or Mass (DALM) The finding of dysplasia in this setting is not necessarily a trigger for colectomy Difference defined by the morphology A DALM is different than an Adenoma-Like Mass (ALM) 13

Dysplasia Associated Lesions or Masses Non Adenoma Like Mass or NALM or NALD or DALM Adenoma Like Mass ALM not a DALM THE DIFFERENCE IS: CAN IT BE REMOVED…. BY WHOM? 14

Dysplasia An important concept: Malignant colon lesions are dysplastic BUT Not all dysplastic lesions are malignant LGD and HGD lesions if totally removed and no invasive component: CURED! 15

Dysplasia in Ulcerative Colitis Significance of a dysplastic lesion depends on: Morphology Completeness of removal Biopsies of surrounding tissue Ullman, Odze, Farraye. Inflamm Bowel Dis 2009;15:630–638 16

Non-Controversies Regarding Dysplasia in IBD HGD found under the following conditions requires surgery: - Biopsy of a non-removable mass - A malignant appearing lesion - When in flat mucosa - -If it is confirmed – By another pathologist (?) – By another biopsy (?) HGD: no surgery if in resected adenoma, totally removed and no adjacent dysplasia Get the easy one out of the way first 17

What is the Natural History of High-Grade Dysplasia? 18

Probability of Finding Cancer 1Bernstein et al. Lancet 343:71, 1994 2Connell et al. Gastroenterology, 1994 3Rutter et al, Gastroenterology, 2006 19

Recommended Repeat Surveillance Interval for Occult HGD None—Requires Colectomy 20

Controversies Regarding Dysplasia in IBD Does low grade dysplasia require colectomy? What should the gastroenterologist do with dysplasia in IBD? Can polypoid dysplasia in IBD be managed endoscopically? What is the trigger for surgery when pathology report comes back with dysplasia in the setting of IBD? 21

What is the Natural History of Low-Grade Dysplasia? 22

Mount Sinai flat LGD experience • 46 patients with flat LGD at index from 1994-2000; nonprotocol-based surveillance • F/U of all surveillance examinations • Progression defined as HGD or CRC • Is unifocal LGD a less dangerous subset? Ullman, Gastro, 2003 23

Timelines: fLGD → CRC (N=7) 0 12 24 36 48 60 72 Months Initial fLGD Ullman et al. Gastro, 2003 24

DALM Adenoma-like Non-Adenoma-like (broad-base, irregular cannot remove) Outside colitis Inside colitis Colectomy Polypectomy Regular surveillance Polypectomy Absence of flat dysplasia Increase surveillance 25

Colectomy vs. Polypectomy and continued surveillance Flat dysplasia or adenocarcinoma Present Yes No Endoscopic Appearance Broad-based/mass Irregular Ulcerated Plaque-like Constricting Small Discrete Amenable to polypectomy 26

Probability of Finding Cancer 27

Recommended Interval for LGD Raised with incomplete polypectomy: - Colectomy Raised with complete polypectomy - 3-6 months Flat - Chromo in 3 months OR colectomy 28

Decisions with LGD, HGD Raised LGD: - is it removable? Do it - Bx around Raised HGD: Is it removable? Must it look like a polyp? - If removable, it is an ALM Biopsy around Needs surgery if cannot remove Complete removal, biopsies nearby negative - Follow up in short interval: 3-6 months 29

Endoscopic Mucosal Resection Possible in IBD polyps More difficult due to inflammatory process If it lifts, it is possible If it does not lift, it may still be possible Take care not to try removal of a CRCa Take multiple biopsies before ablating with the APC. Technique same as non IBD. 30

IND and NoD? Ullman, CGH 6:1225-30, 2008 31

Recommended Interval for IND and NoD IND: Repeat in 0.5-1 years NoD: Repeat in 1-2 years 32

Traditional Surveillance Colonoscopy Guidelines Extent based on endoscopic or histologic involvement (whichever is greater) 4 quadrant biopsies every 10 cm (minimum 4 quadrant biopsies every 10 cm (minimum 32 for pancolitis ) Dysplasia confirmed by second pathologist 33

White Light Colonoscopy for Detecting Dysplasia Random biopsies sample a tiny portion of the total surface area of the colorectum SA of colorectum: 1578.1+/- 301.0 cm2 Surface area of biopsy forceps: 2.2-5 mm2 33 biopsies x 5mm2 = 165mm2 Percent surface area sampled with this approach: 0.05%-0.1% Sadahiro S. et al. Cancer, 1991. Rubin CE, et al. Gastroenterol, 1992. Kornbluth and Sachar. Am J Gastroenterol, 2004. 34

Methods of Surveillance: White Light Colonoscopy Biopsy Numbers Performed/Predicted Dysplasia and Cancer Detection Confidence Dysplasia Cancer 90% 33 35 95% 56 64 Poor overall detection rates for dysplasia in non-targeted biopsies - Rates as low as 0.1% or 1/1000* *Hurlstone. Endoscopy 2005;37:1186-1192. *Hurlstone. Gut 2008;57:196-204 35

Methods to Enhance Detection of IBD Associated Dysplasia 36

Chromoendoscopy Contrast dyes: Indigo carmine - Coat mucosa Absorptive dyes: Methylene Blue - Poorly stain active inflammation and dysplasia 37

Chromoendoscopy Method* 0.1% indigo carmine or 0.1% methylene blue Dye spray catheter protrudes 2-3cm from scope. Spraying segmental every 20-30cm Excess suctioned Wait few seconds for indigo carmine and 60 seconds for methylene blue (absorption) Kiesslich R. Gastroenterol Clin N Am. 2006;35:605-619. 38

Indigo Carmine* No dysplasia in 2904 white light non-targeted biopsies. Dysplasia in 2/43 (5%) white light targeted biopsies. 7/114 (6%) (includes 2 above) indigo carmine spray targeted biopsies showed dysplasia. Dysplasia detection 7/100 patients indigo carmine compared to 0/100 non-targeted (p=0.06) Rutter MD. Gut 2004;53:256-260 39

Rutter et al. Gut 2004;53:256-60 40

Chromoscopy Alone Part of surveillance guidelines by CCFA1 One report of methylene blue related DNA damage.2 Follow-up after 23 months showed less neoplasia in methylene blue group.3 1Itkowitz SH Inflamm Bowel Dis. 2005;11:314-321 2Olliver JR. Lancet 2003;362:373-4 3Kiesslich R. Gastrointest Endos 2004:59:AB97. 41

Indigo Carmine Assisted High Magnification Chromoscopy Total colonoscopy Suspicious mucosal changes stained with indigo carmine. Lesions examined using high magnification mode and classified by Kudo class. Compared to standard control population. 42

Normal Hyperplastic Dysplasia Tubular adenoma Villous adenoma Cancer 43

Results: Dysplasia detection Non targeted biopsies: 0.16% Targeted biopsies by white light alone: 1.6% Targeted biopsies by indigo carmine/magnification: 8% Overall 53 flat lesions (369 patients) indigo carmine magnification compared to 14 in control group (366 patients) (p<0.001). 44

Current Practice Use Pan-colonic dye spray with targeted biopsy - 0.2% indigocarmine in high volume pump is very convenient Random biopsy still performed, but likely to change soon Endoscopic equipment advances appear highly promising to target biopsy among “detected” lesions 45

CCFA Consensus Recommendations: How to Perform Surveillance Initiate at 8 years of disease for patients with 1/3 or more of their colon involved Start immediately for patients with IBD/PSC 4 quadrant biopsies every 10 cm for minimum of 32 biopsies per exam Separate jar for all suspicious lesions Each quartet goes in single specimen jar Perform every 1-2 years Itzkowitz/Present, IBD 2005 46

Can We Alter the Development of Cancer in IBD? 47

Risk of CRC in IBD: Factors that Increase Risk • Duration >8-10 years - Extent of colitis: - Extensive disease • Backwash ileitis • Family history of colon cancer • Primary sclerosing cholangitis • Early age at onset of colitis • Histologic activity • Pseudopolyps • Dysplasia at surveillance 48

Risk of CRC in IBD: Factors that Decrease Risk • Prophylactic Colectomy • Surveillance colonoscopy • Regular doctor visits • Chemoprevention? - 5-ASA ? - Ursodeoxycholic Acid Yes (PSC patients) - Folate ? - Purine Analogs No 49

Chemoprevention Pharmacologic interruption of the sequence to neoplasia 5ASA’s Yes/? Purine analogs No Folic Acid Yes/? Urso (in PSC) Yes Anti-TNF’s ? 50

Possible Dysplasia/CRC Chemopreventive Agents in IBD Evidence in IBD Folic acid Rationale, safety good; not significant1 Calcium and vitamin D Rationale 6-mercaptopurine azathioprine Case-control suggests not3 New evidence suggest possible4 Ursodeoxycholic acid In PSC with UC, yes2; other UC, unknown 5-aminosalicylic acid Studied retrospectively; case control, cohort, population Statins Limited, registry, population-based 1Lashner BA et al. Gastroenterology. 1997. 2Pardi D et al. Gastroenterology. 2003. 3Matula et al. Clin Gastro and Hep, 2005. 4Rubin et al. DDW 2006. 51

Ullman, Clin Gastro Hep, 2008 52

5-ASA Use After IND Ullman, Clin Gastro Hep, 2008 53

Chemopreventive Effect of 5-ASA: Small if at All 5ASA Exposure Any Use >2 g/day Avg Dose Any Neoplasia HR (95% CI) 0.86 (0.40-1.82) 0.91 (0.47-1.77) 1.01 (0.80-1.28) Advanced 0.70 (0.20-2.44) 0.77 (0.22-2.67) 0.92 (0.58-1.47) Ullman, CGH 6:1225-30, 2008 54

Purine Analogs: Surveillance Cohort (n=315) 6MP Exposure Any Exposure ≥25mg/d Avg Daily Dose Neoplasia HR (CI) 1.30 (0.45-3.75) 0.88 (0.47-1.65) 1.01 (0.80-1.28) Advanced (0.48-1.59) 1.46 (0.51-4.21) 1.95 (0.82-4.60) Matula, CGH 2005 55

Urso Protects Against Neoplasia in PSC Patients Pardi, et al. Gastro 2003 56

Mucosal Healing Reduces Colectomy Rate in UC Froslie KF et al Gastroenterology 133 (2007) 412-422. * Oral 5-ASA, topical 5-ASA, sulfasalazine, antibiotics, corticosteroids, azathioprine, and/or metronidazole 57

Histologic Inflammation Is Associated with Progression to HGD or CRC in UC Gupta, Gastro 2007 58

Questions? 59

Increased Inflammation Leads to Increased Risk of Colectomy • UC surveillance database of 561 patients • Median follow up of 21.4 years Hefti M et al. Dis Col Rectum 2009; 52: 193-197 60

Cumulative Risk of CRC Among 376 UC Patients From Olmsted County, Minnesota, 1940-2001 Jess T, et al, Gastroenterology 2006; 130:1039-46. 61

Colonoscopy Surveillance Guidelines Pancolitis (or Left (or Left-sided) : Every 1-2 years after 8-10 years. Proctitis: Risk not greater than non-IBD Begin surveillance immediately in PSC patients Recommendations also apply to Chrohn's disease. 62

Limitations of Surveillance 1. Poor levels of agreement among pathologists 2. Dysplasia is patchy/Poor detection 3. Natural history of dysplasia poorly understood 4. Cancers can arise without any apparent prior dysplasia 5. Incomplete patient follow-up 63

“Natural” History of Dysplasia in IBD 64

Endoscopy in IBD Diagnosis - IBD versus non-IBD diagnosis - Distinguish UC from Crohn’s Assess Activity - Change therapy - Effect of therapy - Prognosis Dysplasia Surveillance Therapeutics - Stricture - Polypectomy 65

Issues in Diagnosis Endoscopist: messenger boy/girl Pathologist: makes diagnosis based on features of chronicity Architectural distortion Basal plasmacytosis Increased lamina propria cellularity Pyloric gland +/- Paneth cell metaplasia Granulomata (15-35%) 66

Differential Infectious and other “acute-selflimited” colitis NSAID and other drug-induced colitis Ischemic colitis Radiation changes Diverticular colitis (SCAD) Neoplasia 67

Ileocolonoscopy Preferred Single Test Even for Small Bowel CD Diagnosis Solem et al, Gastrointest Endosc 2008;68:255-66 68

Historic Endoscopic Features Distinguishing UC from CD Rectal sparing “Patchiness” Small bowel involvement Discrete and aphthous ulcers Serpiginous ulcers Cobblestoning 69

Rectal Sparing: Not your father’s IBD? Treated UC1 - Rectal sparing in 13% - Endoscopic patchiness in 44% Untreated UC later leading to surgery2 - Rectal attenuation in 31% 1Bernstein et al, Gastrointest Endoscop 1995; 42:232-7 2Robert et al, Am J Clin Pathol. 2004; 122:94-9 70

Mayo Scoring 0= Normal or inactive disease 1= Mild disease: erythema, decreased vascular pattern, mild friability 2= Moderate disease: marked erythema, absent vascular pattern, friability, erosions 3= Severe disease: spontaneous bleeding, ulceration 71

Mucosal Healing 72

Nested Case Control Uppsala, SWE Karlen et al, Gut 1998 73

CRC Risk Reduction in UC: Colonoscopy Eaden et al, Aliment Pharmacol Ther 14:145, 2000 74

CRC Risk Reduction in UC: Colonoscopy Velayos et al, Gastroenterology 130:1941, 2006 75

Mount Sinai: Is the Curve Changing? Ullman, CGH 6:1225-30, 2008 76

Number of Biopsies Needed Per Site To detect dysplasia with 95% confidence: 56 biopsies * To detect dysplasia with 90% confidence: 33 biopsies * *Rubin et al, Gastroenterol 1992 77

Biopsy Practices: Mount Sinai Ullman, ACG 2007 78

Low Rate of Breakthrough CRC with current practices Ullman, ACG 2007 79

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