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

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 2

3. 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

4. Why Do We Care? 4

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

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

7. Dysplasia-Carcinoma Sequence Non IBD Vs. IBD7

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: /nrgastro 8

9. 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: /nrgastro 9

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

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 11

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: 12

13. 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

14. 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

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! 15

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 16

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
Get the easy one out of the way first 17

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

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

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

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? 21

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

23. Mount Sinai flat LGD experience
• 46 patients with flat LGD at index from ; 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

24. Timelines: fLGD → CRC (N=7)
Months
Initial
fLGD
Ullman et al. Gastro, 2003 24

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 25

26. 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

27. Probability of Finding Cancer27

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

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 29

30. 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

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

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

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 33

34. White Light Colonoscopy for Detecting Dysplasia
Random biopsies sample a tiny portion of the total surface area of the colorectum
SA of colorectum: / cm2
Surface area of biopsy forceps: 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

35. 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: *Hurlstone. Gut 2008;57: 35

36. Methods to Enhance Detection of IBD Associated Dysplasia36

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

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: 38

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: 39

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

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:
2Olliver JR. Lancet 2003;362:373-4
3Kiesslich R. Gastrointest Endos 2004:59:AB97. 41

42. 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

43. Normal Hyperplastic Dysplasia Tubular adenoma Villous adenoma Cancer43

44. 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

45. 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

46. 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

47. Can We Alter the Development of Cancer in IBD?47

48. 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

49. 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

50. 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

51. 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 Pardi D et al. Gastroenterology
3Matula et al. Clin Gastro and Hep, Rubin et al. DDW 2006. 51

52. Ullman, Clin Gastro Hep, 2008 52

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

54. 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
( )
0.91
( )
1.01
( )
Advanced
0.70
( )
0.77
( )
0.92
( )
Ullman, CGH 6: , 2008 54

55. Purine Analogs: Surveillance Cohort (n=315)
6MP Exposure
Any
Exposure
≥25mg/d
Avg Daily
Dose
Neoplasia
HR (CI)
1.30
( )
0.88
( )
1.01
( )
Advanced
( )
1.46
( )
1.95
( )
Matula, CGH 2005 55

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

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

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

59. Questions? 59

60. 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: 60

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

62. 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

63. 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

64. “Natural” History of Dysplasia in IBD64

65. 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

66. 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

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

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

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

70. 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

71. 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

72. Mucosal Healing 72

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

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

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

76. Mount Sinai: Is the Curve Changing?
Ullman, CGH 6: , 2008 76

77. 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

78. Biopsy Practices: Mount Sinai
Ullman, ACG 2007 78

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

80. 80

81. 81