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Nuts and Bolts of Dysplasia in IBD

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

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Nuts and Bolts of Dysplasia in IBD

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

  2. 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

  3. Dysplasia Dysplasia 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

  4. Why Do We Care?

  5. Cumulative Risk of CRC in UC0.5-1.0% per year after 10 years of disease Eaden et al. Gut 48:526, 2001

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

  7. Dysplasia-Carcinoma SequenceNon IBD Vs. IBD Non IBD IBD

  8. Proposed Role of Inflammation in Dysplasia Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancerNat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44

  9. Proposed Role of Inflammation in Dysplasia Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancerNat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44

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

  11. 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

  12. 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.

  13. Differentiating Polypoid Lesion in IBD Patient • If an adenoma (mass) is found in IBD, it mustalways 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)

  14. Dysplasia AssociatedLesions 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?

  15. 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!

  16. 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

  17. 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

  18. What is the Natural History ofHigh-Grade Dysplasia?

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

  20. Recommended Repeat Surveillance Interval for Occult HGD • None—RequiresColectomy

  21. 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?

  22. What is the Natural History ofLow-Grade Dysplasia?

  23. 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

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

  25. 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

  26. Colectomy vs. Polypectomyand continued surveillance

  27. Probability of Finding Cancer

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

  29. 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

  30. Endoscopic MucosalResection • 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.

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

  32. Recommended Interval forIND and NoD • IND: Repeat in 0.5-1 years • NoD: Repeat in 1-2 years

  33. 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

  34. White Light Colonoscopy for Detecting Dysplasia Sadahiro S. et al. Cancer, 1991. Rubin CE, et al. Gastroenterol, 1992. Kornbluth and Sachar. Am J Gastroenterol, 2004. 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%

  35. Methods of Surveillance:White Light Colonoscopy • 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

  36. Methods to Enhance Detection of IBD Associated Dysplasia

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

  38. 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.

  39. 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

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

  41. 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.

  42. Indigo Carmine Assisted HighMagnification 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.

  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 IncreaseRisk • • 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 DecreaseRisk • • 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 ?

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