IBD: Dysplasia Surveillance and Managementd2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2015/01/15ACG...Risk of CRC in IBD is elevated Inflammation of the colon is the key factor

Fernando S. Velayos, MD

IBD: Dysplasia Surveillance and Management

ACG Regional CourseJanuary 24, 2015Fernando Velayos MD MPH

Associate Professor of MedicineCo-Medical Director

Center for Crohn’s and ColitisUniversity of California, San Francisco

Risk of CRC in IBD is elevatedInflammation of the colon is the key factor

• Risk of CRC in IBD is 7-18% in newer studies

Site RR 95% CI

All CD 2.5 1.3-4.7

Colon 4.5 1.3-14.9

Ileum 1.1 0.8-1.5

Canavan C et al. Aliment Pharmacol Ther 2006:23;1097

Ileum 1.1 0.8 1.5

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Known risk factors are almost all non-modifiable

• Non-modifiable risk factors:– Duration (increases after 10 years)– Extent (15X greater in pancolitis)– PSC (5X greater)2

– Family history of CRC (2.5X greater) 1

– Inflammatory polyps (“pseudopolyps”-2.5X) 3,4

• Potentially modifiable risk factor:– Histologic inflammation at surveillance colonoscopy3

1Askling J, et al. Gastroenterology 20012Lindberg BU, et al. Dis Colon Rectum 20013Rutter, et al. Gastroenterology 2004. Bansal, et al. Presented at ACG 2005, Honolulu. Rubin et al. Presented at DDW 2006, Los Angeles.4Velayos et al. Gastroenterology 2006

Two Aspects of Dysplasia to Discuss

• How to look (and find) dysplasiaHow to look (and find) dysplasia• What to do when dysplasia is found


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Major GI society surveillance guidelines-which to choose?

Society First colonoscopy (Screening)

Interval subsequent colonoscopy

AGA and US Multisociety Task Force on Colorectal

All patients 8-10 years after diagnosis

Surveillance colonoscopy with systemic biopsies should be consideredTask Force on Colorectal

Cancer (2003)after diagnosis should be considered.

ACG (2004) and ASGE (2006)

All patients 8-10 years after diagnosisImmediately in PSC

Every 1-2 years

Crohn’s and Colitis Foundation (2006)

All patients 8-10 years after diagnosisImmediately in PSC

- Next 2 in 1-2 years-Then every 1-3 years until 20 years of disease, then return to every 1-2 years- Yearly in PSC

British Society All patients 10 years after - Yearly in pancolitis with active/moderate yGastroenterology (2010)

p ydiagnosis to determine extent and endoscopic risk factors

y pinflammation or stricture or PSC or history of dysplasia or FH CRC age <50-Every 3 years in pancolitis with mild inflammation or inflammatory polyps or FH CRC >50 years- Every 5 years in quiescent pancolitis or left sided colitis

Summary of Current Guidelines for Cancer Prevention in UC and Crohn’s Colitis

• Start at 8-10 years after diagnosis (except PSC)• Intervals of subsequent colonoscopies vary• Biopsies at 10 cm intervals (at least 33)• Biopsy any suspicious lesions• Important move toward establishing chromoendoscopy as

standard in high risk groups

Kornbluth A, Sachar DB. Am J Gastroenterol 2010;105:501-523. Biacone L, Michetti P, Travis S, et al. J Crohns Colitis 2008;2:63-92.

Cairns S and Schofield JH. Gut 2009.


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Key is to look for dysplasia-“Invisible” dysplasia happens in IBD surveillance• Rutter 2006

– 25/110 (22.7%) LGD “invisible” or flat

• Rubin 2007– 29/75 LGD invisible (38.7%)

• Velayos 2009– 16/61 (26.2%) LGD invisible

M i 2008• Marion 2008– 3/12 LGD invisible (25%)

Rutter MD et. al.. GI Endoscopy 2004: 60(3):334Rubin DT et. al.. GI Endoscopy 2007: 65 (7): 998Velayos FS et al ACG 2009Marion JF et al AJG 2008: 103: 2342

Two off-the shelf enhanced dysplasia detection techniques

• Chromoendoscopy– Dye spray through catheter– Absorptive dye: (stain taken up by noninflamed mucosa but poorly

taken up by active inflammation and dysplasia): methylene blue– Contrast dye (coats surface to highlight subtle disruptions of normal

contours): indigo carmine

• Virtual chromoendoscopy– Rotating color filters the R-G-B bands while increasing the relative

intensity of blue bands– Post-processing techniques to achieve pseudocolored image– Enhance tissue vasculature (differential optical absorption of light by Hb

associated with dysplasia [blue band]) or mucosal contours


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Role of Chromoendoscopy in Surveillance

• Two main uses in IBD Surveillance– Improve detection of subtle colonic lesions

(increase sensitivity of surveillance)– Once lesion detected-to aid in differentiating

between neoplastic and non-neoplastic based on crypt architecture and modified pit pattern

Significance of Pit Patterns

Type I/II predict non-neoplastic lesions Type III/IV/V predict neoplastic lesions

Kudo S et al. Endoscopy 1993


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Chromoendoscopy Finds More Dysplasia than Conventional Exams

Author (Year)

Institution# of UC Patients

Type of Imaging

Number of Dysplastic Lesions

Chromo ConventionalSensitivity / Specificity

Kiesslich (2003)

University of Mainz, Germany 263 Methylene

blue 32 1093% sens.

93% spec.

Rutter

(2004)

St. Mark’s Hospital, Harrow, UK

100 Indigo carmine 7 0 Not given

Hurlstone (2005)

The Royal HallamshireHospital, Sheffield, UK

350Indigo

Carmine-and Magnification

69 2493% sens.

88% spec.

94.7% sens.

Kiesslich (2007)

University of Mainz, Germany 161

Confocal endomicrosco

py19 4

9 % se s

98.3% spec.

97.8% accuracy

Dekker

(2007)

Academic Medical Center, Amsterdam, The Netherlands

42 Narrow-band imaging 8 7 Not given

Marion

(2008)Mount Sinai, New York, USA 102 Methylene

Blue 17 9 Not given

Narrow Band Imaging is not Superior to Conventional Colonoscopy for Dysplasia Detection in UC

Study Design N NBI WLE

Dekker et al.(2007) Tandem 42 8/11a) (73%) 7/11a) (64%)

Van den Broek et al.

(2011)Tandem 48 8/11a) (73%) 9/11a) (82%)

Ignjatovic et al (2012)

Parallelgroup 112 5/56b) (9%) 5/56b) (9%)al. (2012) group

East JE. Clin Endosc. 2012;45:274-277.


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Challenges to using chromoendoscopy in IBD

• Perception of time consuming and expensive (time plus supplies)plus supplies)

• Unclear if it changes outcomes (cancer or mortality)• Many patients don’t “qualify” for it due to poor prep

or too much inflammation• No consensus on its use in our field • No defined training pathway or competencyNo defined training pathway or competency

requirement• Comparison to newer high definition scopes not

completed

What to do when dysplasia is found?

Normal Epithelium

Inflamed Epithelium

High-Grade Dysplasia

Low-Grade Dysplasia Cancer

Indefinite Dysplasia

Colectomy? SecondaryColectomy?

Polypectomy?

Watch closely?

yPrevention


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Recommendations from a recent guideline are mostly grade A

Farraye Gastroenterology 2010;138:738

First, let’s define dysplasia types and start with a common vocabulary

• Macroscopic classification

• Microscopic classification““FlatFlat””

““ElevatedElevated””

• How detected– Non-targeted vs. targeted biopsies

ItzkowitzItzkowitz S. and S. and HarpazHarpaz N. N. Gastroenterology Gastroenterology 126:1634,2004 126:1634,2004

NormalNormal IndefiniteIndefinite LowLow--GradeGrade HighHigh--GradeGrade


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Kappa statistic indicates how much greater observer

t i t th ld bP13P12P11P10P9P8P7P6P5P4P3P2P1

GI Pathologists General Pathologists

First-get second opinion on reading-Low reliability on the diagnosis of dysplasia

agreement exists than would be expected by chanceRange -1.0 to +1.0Value 0= pure chance onlyValue 1.0= perfect agreementValue >0.75 =excellent agreementValue 0.4-0.74= fair to good agreementValue <0.4= poor agreement

P1 P2 P3 P4 P5 P6 P7P8 P9 P10

0.43 -

0.25 0.12 -

0.12 0.16 0.44 -

0.15 0.24 0.38 0.44 -

0.59 0.40 0.27 0.18 0.27 -

0.48 0.36 0.39 0.17 0.26 0.51 -

0.2 0.24 0.18 0.25 0.29 0.14 0.13 -

0.22 0.15 0.24 0.17 0.14 0.35 0.32 0.13 -

0.37 0.28 0.47 0.20 0.29 0.36 0.39 0.21 0.32

0.19 0.19 0.33 0.27 0.2 0.24 0.34 0.13 0.28 0 21

0.23 0.27 0.52 0.31 0.48 0.38 0.43 0.33 0.25 0 48

0.33 0.26 0.35 0.17 0.12 0.43 0.40 0.11 0.26 0 3

-

- Eaden J J of Pathol 2001; 194:152

P10 P11 P12 P13

- 0.21 -

0.48 0.39 -

0.3 0.43 0.29 -

Kappa statistic indicates how much greater observer

t i t th ld bP13P12P11P10P9P8P7P6P5P4P3P2P1

GI Pathologists General Pathologists

First-get second opinion on reading-Low reliability on the diagnosis of dysplasia

agreement exists than would be expected by chanceRange -1.0 to +1.0Value 0= pure chance onlyValue 1.0= perfect agreementValue >0.75 =excellent agreementValue 0.4-0.74= fair to good agreementValue <0.4= poor agreement

P1 P2 P3 P4 P5 P6 P7P8 P9 P10

0.43 -

0.25 0.12 -

0.12 0.16 0.44 -

0.15 0.24 0.38 0.44 -

0.59 0.40 0.27 0.18 0.27 -

0.48 0.36 0.39 0.17 0.26 0.51 -

0.2 0.24 0.18 0.25 0.29 0.14 0.13 -

0.22 0.15 0.24 0.17 0.14 0.35 0.32 0.13 -

0.37 0.28 0.47 0.20 0.29 0.36 0.39 0.21 0.32

0.19 0.19 0.33 0.27 0.2 0.24 0.34 0.13 0.28 0 21

0.23 0.27 0.52 0.31 0.48 0.38 0.43 0.33 0.25 0 48

0.33 0.26 0.35 0.17 0.12 0.43 0.40 0.11 0.26 0 3

-

- Eaden J J of Pathol 2001; 194:152

P10 P11 P12 P13

- 0.21 -

0.48 0.39 -

0.3 0.43 0.29 -

Very few kappa values over 0.5All pathologists agreed only on 4 of 51 (7.8% agreement (all HGD))GI pathologists agreed only on 6 slides (11.7% agreement (4 HGD, 2 reactive atypia))General pathologists agreed on 8 slides ( 15.7 % agreement (5HGD,2LGD,1 atypia))


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Study Setting LGD (n) Rate

Connell 1994 St Mark’s 9 54% @5y

Prognosis of “flat” LGD to HGD or Cancer depends on the reader

Co e 99 St Mark s 9 5 % @5y

Ullman 2002 Mayo Clinic 18 33% @5y

Ullman 2003 Mount Sinai 46 53% @5y

Rutter 2006 St Mark’s 36 25% @5y

Van Schaik 2010 6 Dutch centers 21 37% @5y

Lindberg 1996 Huddinge 37 35% @20yLindberg 1996 Huddinge 37 35% @20y

Befrits 2002 Karolinska 60 2% @10y

Lim 2003 Leeds, UK 29 10% @10y

Study Setting LGD (n) Rate

Connell 1994 St Mark’s 9 54% @5y

Prognosis of “flat” LGD to HGD or Cancer depends on the reader

Co e 99 St Mark s 9 5 % @5y

Ullman 2002 Mayo Clinic 18 33% @5y

Ullman 2003 Mount Sinai 46 53% @5y

Rutter 2006 St Mark’s 36 25% @5y

Lindberg 1996 Huddinge 37 35% @20yLindberg 1996 Huddinge 37 35% @20y

Befrits 2002 Karolinska 60 2% @10y

Lim 2003 Leeds, UK 29 10% @10y

Van Schaik 2010 6 Dutch centers 70 12% @5y


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Second let’s define the three parameters we already use in deciding what to do in dysplasia in non-IBD

patients

1. Rate of progression of dysplasia to advanced dysplasia or CRC (metachronous)

2. Rate of occult cancer in patients diagnosed with dysplasia (synchronous)

3 Resectability of the dysplastic lesion

Is it discreet?

Can I resect it?

Can I see it?

3. Resectability of the dysplastic lesion

AGA guidelines for managing dysplasia based on these parameters

Questions and parameters to decide

“non-adenoma like dysplasia

“adenoma-like lesion or mass and no flat

“flat high-grade dysplasia”

“flat low-grade dysplasia”decide dysplasia

lesion or mass”

and no flat dysplasia elsewhere”

dysplasia dysplasia

Progression No info

Occult Cancer 43%

Resectability No

Treatment? SurgeryTreatment? Surgery(grade A)

* Further adenoma 50%-need close surveillance

Farraye F Gastroenterology 2010;138:738Bernstein C Lancet 1994


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“flat low-grade dysplasia”


decide dysplasia lesion or mass”


dysplasia dysplasia

Progression No info <5%*

Occult Cancer 43% <5%

Resectability No Yes

Treatment? Surgery PolypectomyTreatment? Surgery(grade A)

Polypectomy(grade A)


Farraye F Gastroenterology 2010; 138: 738Bernstein C Lancet 1994









dysplasia dysplasia

Progression No info <5%* High

Occult Cancer 43% <5% 42%

Resectability No Yes No

Treatment? Surgery Polypectomy SurgeryTreatment? Surgery(grade A)


Surgery(grade A)




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dysplasia dysplasia

Progression No info <5%* High 1-12% vs 25-55%

Occult Cancer 43% <5% 42% 19%

Resectability No Yes No No

Treatment? Surgery Polypectomy Surgery InsufficientTreatment? Surgery(grade A)


Surgery(grade A)

Insufficient (grade I)



Summary Key Points• GI society guidelines share first exam 8-10

yrs/PSC at diagnosis– Next exam varies (1-3 years)– 33 bx for “invisible” dysplasia is 25%; sample raised

lesions or subtle abnormalities (75%)!• Chromoendoscopy detects more dysplasia than

white light, no role virtual chromoendoscopy• Simplified approach to dysplasia-based on how S p ed app oac to dysp as a based o o

found: targeted vs. non-targeted biopsy• Proposal: the 3 parameters we use to manage

non-IBD dysplasia can be applied to IBD-dysplasia (to be tested)


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Documents

IBD: Dysplasia Surveillance and Managementd2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2015/01/15ACG...Risk of CRC in IBD is elevated Inflammation of the colon is the key factor