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IBD and Neoplastic Progression: A Contemporary Approach to Diagnosis and Management
Maui, HI 2018
Robert D. Odze, MD, FRCPCChief, Division of GI Pathology
Professor of PathologyBrigham and Women’s Hospital
Harvard Medical SchoolBoston, MA
Lecture Outline
1. Malignancy risk
2. Surveillance
3. Pathology of dysplasia
4. Natural history and management
5. Summary
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Comprehensive meta-analysis of the risk of colorectal cancer in ulcerative colitis and Crohn’s disease
• 48 studies included in the meta-analysis
• Included both population based and referral centers
• Included 131,743 persons-years of follow up
• Overall cumulative risk at 10, 20 and 20 + years is 1%, 3% and 7%
• Rate higher in referral centers and those with extensive disease
Lutgens MW, et al. DDW 2008: #194
10 20 >20
Years from diagnosis
Cum
ulat
ive
prob
abil
ity
(%)
Overall Population based
Referral center
Cumulative risk in IBD patients
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Factors That Increase Risk of CRC in IBD
• Duration of colitis
• Anatomic extent of disease– No increase in proctitis patients, SIR 2.8 (CI 1.6-4.4) in left sided UC and 14.8
(11.4-18.9) in pancolitis
• Primary sclerosing cholangitis
• Family history of colorectal cancer– Two fold increase
• Age of IBD onset (possibly)
• Severity of endoscopic and histologic inflammationFarraye FA, Odze R, Eaden J, Itzkowitz S. Diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138:746-774.
Extent of Colitis and Cancer Risk(Ekbom et al NEJM 1990)
Extent R.R.
Proctitis 1.7
Left sided 2.8Pancolitis 14.8
Severity of Inflammation is a Risk Factor for Colorectal Neoplasia in Ulcerative Colitis
Variable Cases (neoplasia)* Controls
N=68 N=136 P
Colonoscopy inflammation score
2.22 (0.78) 1.89 (0.52) 0.001
Histology inflammation score
2.38 (0.56) 2.05 (0.41) <0.001
Rutter et al, Gastroenterology 2004;126:451-9Neoplasia = Dysplasia or cancerInflammation grade 0 = normal, 1 = chronic inflammation
2 = mild (cryptitis) 3 = mod (few crypt abscesses)4 = severe (numerous crypt abscesses)
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Inflammation is an Independent Risk Factor for Colonic Neoplasia in Patients with UC: A Case-Control Study
Risk factor AOR P AOR* P
(95% CI) (95% CI)
Inflammation Score
1 unit increase 3.68 (1.7-8.0) 0.001 - -
2 vs 0-1 4.9 (1.7 – 14.3) 0.004
3-5 vs 0-1 7.1 (1.7 – 30.0) 0.007
Immunomodulators 0.24 (0.1 – 0.7) 0.013 0.25 (0.1 – 0.7) 0.01
Male gender 5.45 (1.8 – 16.6) 0.003 5.69 (1.9 – 17.1) 0.002
59 UC pts with neoplasia (LGD, HGD, cancer)141 UC pts without neoplasia
Rubin et al. Clin Gastroenterol and Hepatol 2013;11:1601-1608
Score 0 = normal 1 = inactive2 = LP neutrophils 3 = epithelial neutrophils4 = crypt abscesses <50% 5 = crypt abscess >50% or erosion
*Adjusting for variables in table
Inflammation is an Independent Risk Factor for Colonic Neoplasia in Patients with UC: A Case-Control Study
Risk factor AOR P AOR* P
(95% CI) (95% CI)
Inflammation Score
1 unit increase 3.68 (1.7-8.0) 0.001 - -
2 vs 0-1 4.9 (1.7 – 14.3) 0.004
3-5 vs 0-1 7.1 (1.7 – 30.0) 0.007
Immunomodulators 0.24 (0.1 – 0.7) 0.013 0.25 (0.1 – 0.7) 0.01
Male gender 5.45 (1.8 – 16.6) 0.003 5.69 (1.9 – 17.1) 0.002
59 UC pts with neoplasia (LGD, HGD, cancer)141 UC pts without neoplasia
Rubin et al. Clin Gastroenterol and Hepatol 2013;11:1601-1608
Score 0 = normal 1 = inactive2 = LP neutrophils 3 = epithelial neutrophils4 = crypt abscesses <50% 5 = crypt abscess >50% or erosion
*Adjusting for variables in table
Inflammation is an Independent Risk Factor for Colonic Neoplasia in Patients with UC: A Case-Control Study
Risk factor AOR P AOR* P
(95% CI) (95% CI)
Inflammation Score
1 unit increase 3.68 (1.7-8.0) 0.001 - -
2 vs 0-1 4.9 (1.7 – 14.3) 0.004
3-5 vs 0-1 7.1 (1.7 – 30.0) 0.007
Immunomodulators 0.24 (0.1 – 0.7) 0.013 0.25 (0.1 – 0.7) 0.01
Male gender 5.45 (1.8 – 16.6) 0.003 5.69 (1.9 – 17.1) 0.002
59 UC pts with neoplasia (LGD, HGD, cancer)141 UC pts without neoplasia
Rubin et al. Clin Gastroenterol and Hepatol 2013;11:1601-1608
Score 0 = normal 1 = inactive2 = LP neutrophils 3 = epithelial neutrophils4 = crypt abscesses <50% 5 = crypt abscess >50% or erosion
*Adjusting for variables in table
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Effect of Surveillance on Mortality from Colorectal Cancer in UC
Author Locale and study dates
Cancers within surveillance
5-yearsurvival
Cancers outside of surveillance
5 yearsurvival
P value
Guiardeillo28 Johns Hopkins, 1956-1991
18* 88% 22 15% <0.001
Choi27 Lahey Clinic, 1974-1991
19 77% 22 36% 0.026
Connell29 St. Mark’s,1947-1992
16 87% 114 55% 0.024
*Includes cancers detected at surveillance colonoscopy or prophylactic colectomy
Chromoendoscopy Examples
(A) The native colonic mucosa shows areas of focal erythema
(B) After CE, a flat lesion is seen that correlates with HGD on histology
Kiesslich R, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastro 2003;124:880-8.
Controlled Studies on the Use of Chromoendoscopy in Patients with Ulcerative Colitis
Study Number of patients
DyeMB=methylene blueIC=Indigocarmine
Number of lesions Difference (x-fold)
Kiesslich et al. (2003) 165 MB 42 (32 vs 10) 3.07
Hurlstone et al. (2004) 324 IC and magnification 93 (69 vs 24) 3.81
Rutter et al. (2004) 100 IC 7 (7 vs 0) 4.50
Kiesslich et al. (2007) 153 MB and Confocal Endomicroscopy
23 (19 vs 4) 4.75
Marion et al. (2008) 102 MB 20 (17 vs 9) 5.66
Kiesslich R, et al. Endoscopic Surveillance in UC: Smart biopsies do it better. Gastro 2007;133:742-5. Kiesslich R, et al. Is chromoendoscopy the new standard for cancer surveillance in patients with ulcerative colitis? Nat Clin Pract Gastroenterol Hepatol. 2009 Mar;6(3):134-5.
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The Future of Endoscopic Imaging in Patients with IBD
Kiesslich R, et al. Endoscopic Surveillance in UC: Smart biopsies do it better. Gastro 2007;133:742-5.
What role do the newer imaging techniques play in identifying and managing dysplasia?
• The sensitivity of chromoendoscopy for detecting dysplasia is higher than white light endoscopy in the hands of endoscopists who have expertise with this technique.
• The natural history of chromoendoscopically detected dysplasia is unknown.
• Additional studies are needed to evaluate the efficiency of other imaging methods, such as narrow band imaging and confocal endomicroscopy, in detecting dysplasia.
Farraye FA, Odze R, Eaden J, Itzkowitz S. Diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138:746-774.
Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59(5):666-89.
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Dysplasia in IBDClassification
1. Endoscopic (gross)• Flat (endoscopically undetectable)• Elevated (“DALM”) (endoscopically
detectable)
2. Microscopic• Negative• Indefinite• Positive (low or high grade)
New IBD Dysplasia Classification (SCENIC)
Term Definition
VISIBLE DYSPLASIA Dysplasia identified on targeted biopsies from a lesion visualized at colonoscopy
Polypoid Lesion protruding from the mucosa into the lumen R2.5 mm
Pedunculated Lesion attached to the mucosa by a stalk
Sessile Lesion not attached to the mucosa by a stalk: entire base is contiguous with the mucosa
Nonpolypoid Lesion with little (<2.5 mm) or no protrusion above the mucosa
Superficial elevated Lesion with protrusion but <2.5 mm above the lumen (less than the height of the closed cup of a biopsy forceps)
Flat Lesion without protrusion above the mucosa
Depressed Lesion with at least a portion depressed below the level of the mucosa
INVISIBLE DYSPLASIA Dysplasia identified on random (non-targeted) biopsies of colon mucosa without a visible lesion
General descriptors
Ulcerated Ulceration (fibrinous-appearing base with depth) within the lesion
Border
Distinct border Lesion’s border is discrete and can be distinguished from surrounding mucosa
Indistinct border Lesion’s border is not discrete and cannot be distinguished from surrounding mucosa
Laine et al. Gastroenterology 2015; 148:639-651
Vienna System and Dysplasia Morphology Study GroupClassification of Dysplasia in GI Tract
_______________________________________________________________________
Vienna DMSG_________________________________________________________________
1. Negative for neoplasia/dysplasia Negative for dysplasia2. Indefinite for neoplasia/dysplasia Indefinite for dysplasia3. Non-invasive low-grade neoplasia Low-grade dysplasia
(low-grade adenoma/dysplasia)4. Non-invasive high-grade neoplasia High-grade dysplasia
4.1 High-grade adenoma/dysplasia4.2 Non-invasive carcinoma
(carcinoma in situ)4.3 Suspicious of invasive carcinoma
5. Invasive Neoplasia Adenocarcinoma*5.1 Intramucosal Adenocarcinoma Intramucosal5.2 Submucosal carcinoma or beyond Invasive
__________________________________________________________________*not described by DMSG (Dysplasia Morphology Study Group)
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Negative (regeneration)
Dysplasia in IBDMorphologic subtypes
Intestinal (“adenomatous”)
Serrated
Mucinous
Crypt dysplasia
Other
Intestinal dysplasia
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Low-grade
High-grade
High-grade
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High-grade
Unconventional Dysplasia
• Serrated
• Mucinous
• Crypt dysplasia
• Other
Serrated Change in IBD?
1. Hyperplastic polyp-like
2. SSP-like
3. “Atypical” hyperplastic/serrated change
4. Low-grade dysplasia
5. High-grade dysplasia
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Hyperplastic change
“Atypical”
Serrated: Low-Grade
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Serrated: High-Grade
Hyperplastic Polyps and SSP in IBD
Type of Metachronous Lesion CD UC All IBD
N=50 N=65 N=115
# Patients with any lesion 16/35 (46%) 33/59 (56%) 49/94 (52%)
HP 13/16 30/33 43/49
SSP 4/16 2/33 6/49
TSA 0 2/33 2/49
Sporadic adenoma 2/16 4/33 6/49
Adenoma-like DALM 1/16 7/33 8/49
Flat dysplasia 0 1/33 (3%) 1/49 (2%)
Adenocarcinoma 0 0 0
Shen et al. Hum Pathol. 2015 Oct;46(10):1548-56
Mucinous
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Mucinous
Crypt Dysplasia
Crypt Dysplasia
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Risk of Malignancy in UCAdjunctive Methods
• Histochemical ……….. mucin, sialosyn TN
• Impox ………………... proliferation
• Molecular defects …….P53, Rb, APC, MI, CIN, P27, P16, aneuploidy
• Laser fluorescence …..dysplasia
AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in BE, UC and CD
AMACR PositiveDysplasia BE UC/CD
Negative 0% 0%Indefinite 21% 14%Low Grade 38% 96%High Grade 81% 80%AdenoCa 72% 71%
Dorer et al, Am J Surg Pathol 2006;30:871-877
AMACR/P53 to Identify Dysplasia in IBD
Antibody IBD
Neg Indef LGD HGD
AMACR 1.6% 36% 97% 90%
P53 9.4% 75% 97% 90%
Both 0.6% 30% 94% 88%*1 Specificity 99%, sensitivity 76%*2 30% progressed to dysplasia/cancer (<4 mths)
Marx et al, Hum Pathol 2009;40:166-173
*2 *1
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Low Grade DysplasiaOutcome in UC
Study Design Follow-up # Patients Rate of progression (years) (HGD/CA)
Bernstein 94 Review 11 69 (210) 29%Connell 94 Pro 7.5 44 54% (5 year)Lindberg 96 Pro 20 37 35%Befrits 02 Pro 10 60 3.3%Lim 03 Pro 17 40 3% (5 year )Hata 03 Pro 23 9 22%Brentnall 05 Pro 5 40 22%Ullman 02 Retro 3 18 38% (5 year)Ullman 03 Retro 1.3 46 56% (5 year)
Dysplasia Natural History
Grade HGD or Cancer
Low Grade 22-56% (5 years)
High Grade 40-67% (at colectomy)
40-90% (5 years)
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Progression of flat LGD to Advanced Neoplasia in UC
(Ullman, Gastro 2003:125;1315)
• Followed 46 pts with flat LGD at surveillance
• 4/17 (24%) had unexpected HGD/Ca at colectomy
• 7(15%) had carcinoma (5>stage II)
• Rate of progression to HGD/Ca = 53% (5year)
• Recommend colectomy
High Grade Dysplasia (HGD)
Review of Ten Prospective Surveillance Trials of 1225 patients
• 42% of patients with HGD who underwent immediate colectomy had synchronous CRC
• 32% of patients with HGD who underwent colectomy at a later date had CRC
Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994;343:71-74
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Management of Flat Dysplasia in UC
7 - 8 yrs Pancolitis, 10 – 15 yrs left colitis
Initial Screening
No Dysplasia Indefinite Low grade High grade
•multifocal unifocal•prevalent dysplasia•synchronous
•Surveillance • Repeat in • colectomy • Surveillance Colectomy Q 1-2 yrs 3-6 mths Q3-6 mths
vs.Colectomy
Management of Flat Dysplasia in UC
7 - 8 yrs Pancolitis, 10 – 15 yrs left colitis
Initial Screening
No Dysplasia Indefinite Low grade High grade
•multifocal unifocal•prevalent dysplasia•synchronous
•Surveillance • Repeat in • colectomy • Surveillance ColectomyQ 1-2 yrs 3-6 mths Q3-6 mths
vs.Colectomy
Management of Flat Dysplasia in UC
7 - 8 yrs Pancolitis, 10 – 15 yrs left colitis
Initial Screening
No Dysplasia Indefinite Low grade High grade
•multifocal unifocal•prevalent dysplasia•synchronous
•Surveillance • Repeat in • colectomy • Surveillance Colectomy Q 1-2 yrs 3-6 mths Q3-6 mths
vs.Colectomy
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Indefinite for Dysplasia
• Not a Diagnostic entity
• “Indefinite Pathologist”
• Many reasons to use the term
Indefinite for DysplasiaCauses
• Inflammation/ulceration induced atypia
• Technical issues: poor tissue processing
• Hollandes/Bouins fixative
• Lack of orientation/surface epithelium
• Other
Indefinite
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Indefinite
Indefinite for DysplasiaTreatment
1. Indefinite due to inflam/ulceration● anti-inflammatory meds● Rebiopsy 3-6 months
2. Indefinite due to technical reasons● New sections/re-orient biopsy● Rebiopsy immediately
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Visible Dysplasia
Adenoma-like
DALMs
Non-adenoma-like
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Incidence of Carcinoma in CUC-related DALM
Author Patients % DALM % DALM with
Cancer
Blackstone, 1981 112 11% 58%
Rosenstock, 1985 240 5% 38%
Leonard -Jones, 1990 401 1.5% 83%
Butt, 1983 62 29% 83%
*Bernstein, 1994 1225 3.2% 43%
* Review of 10 studies
Not all DALMS are created equal
Raised Dysplasia(“DALM”)
PolypsPatch/PlaqueNodule/Bump
Wart-like ThickeningMass (broad-based)
StrictureErosion/Ulcer/Necrosis
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Adenoma-like
DALMs
Non-adenoma-like
Non Adenoma like DALM
At resection---adenocarcinoma
Incidence of Carcinoma in CUC-related DALM
Author Patients % DALM % DALM with
Cancer
Blackstone, 1981 112 11% 58%
Rosenstock, 1985 240 5% 38%
Leonard -Jones, 1990 401 1.5% 83%
Butt, 1983 62 29% 83%
*Bernstein, 1994 1225 3.2% 43%
* Review of 10 studies
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74 (87%) polypoid
1 (1%) plaque4 (5%) irregular
6 (7%) microscopic cancer
25 (23%) invisible
85 (77%) visible
56 Patients, 110 Neoplastic Lesions
Prevalence of DALMS(Rutter et al (GastroEndosc 2004;60:336-339)
Visible Invisible
Sporadic Adenoma
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Adenoma-like DALM
Molecular CharacteristicsIBD vs. Sporadic
IBD SporadicGENE Neoplasia Neoplasia
Kras early, frequent early, frequentP53 (17p) early (44%) late (20%)LOH 17P early, (85%) late (20-30%)LOH 9P (P16) early, (50%) rareLOH 3P (50%) early, (50%) rare, lateAPC (5q) late (6%) early (75%)P27 early, (90%) late (30%)
Sporadic Adenoma vs Adenoma-like DALMSummary of Molecular Differences
Feature Sporadic Adenoma-likeAdenoma DALM
P53 + ++APC/-catenin ++ +Kras + +LOH 9p (p16) +/- +LOH 3p (vHL) +/- ++
Adapted from Odze et al (2000), Fogt et al (1999)
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Long-Term Follow-Up After Polypectomy Treatment for Adenoma-Like Dysplastic Lesions in Ulcerative Colitis
FeatureUC patient groups Non-UC patients
Adenoma-like DALM
Sporadic adenoma
Sporadic adenoma
No. of patients 24 10 49
Mean follow-up (mo) 82.1 71.8 60.4
Patients who developed additional polyps
15 (62.5%) 5 (50%) 24 (49%)
Patients who developed flat dysplasia 1 (4%) 0 (0%) 0 (0%)
Patients who developed adenocarcinoma 1 (4%) 0 (0%) 0 (0%)
Odze et al. Clin Gastro and Hepatol 2004;2:534-541
Authors Year IBD Type Number
of Cases
Follow-up Subsequent
Carcinoma
Subsequent
Flat Dysplasia
Kisiel et al. 2012 UC 77 20.1 months (median) 1.3% 5.1%
Quinn et al. 2012 CD 50 39 months (median) 2.0% 2.0%
Goldstone et al. 2011 UC 89 37.5 months (mean) 4.5% 3.4%
Vieth et al. 2006 UC 87 53 months (mean) 2.3% 4.6%
Odze et al. 2004 UC 34 82.1 months (mean) 2.9% 2.9%
Engelsgjerd et al. 1999 UC 34 42 months (mean) 0% 2.9%
Rubin et al. 1999 CD or UC 48 49.2 months (mean) 0% 0%
Studies of Adenoma-like DALMs Treated by Polypectomy and Surveillance
Viani et al. In Kozarek, Chiorean, Wallace d. Endoscopy in IBD 2015;XV:269-278
Management Scheme for Polypoid Dysplasia in IBD
Viani et al. In Kozarek, Chiorean, Wallace d. Endoscopy in IBD 2015;XV:269-278
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Summary
1. Risk of malignancy in UC is lower than originally believed
– Inflammation is a risk factor
2. Advanced endoscopy is the way of the future– Chromoendoscopy is here and now
3. Pathology of dysplasia expanding– Low vs high grade not so important
4. Most dysplasia in IBD is polypoid and can be treated by polypectomy/surveillance