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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