Controversies in Surveillance and Therapy for Colorectal Dysplasia in IBD: Case Studies Thomas Ullman MD Mount Sinai, New York Fernando Velayos MD MPH

Controversies in Surveillance and Therapy for Colorectal Dysplasia in IBD:

Case Studies

Thomas Ullman MDMount Sinai, New York

Fernando Velayos MD MPHUniversity of California, San Francisco

Advances in Inflammatory Bowel DiseaseHollywood, FloridaDecember 13, 2013

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

Crohn’s disease

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

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

**

*

Ulcerative colitis

General population

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

Normal Epithelium

Inflamed Epithelium

High-Grade Dysplasia

Low-Grade Dysplasia Cancer

Indefinite Dysplasia

Controversies to cover today1. Surveillance: Is it effective, when to start, in whom,

how frequent to repeat colonoscopy?2. Vocabulary of dysplasia: time to simplify?3. What to do when dysplasia in detected:

polypectomy, proctocolectomy, partial resection?4. Performance of surveillance and role of

chromoendoscopy: what is standard of care?5. New algorithm for thinking and managing dysplasia

in IBD: Can we mimic what we are doing in non-IBD patients?

Controversy 1

Surveillance: Is it effective, when to start, in whom, how frequent to repeat colonoscopy?

45 year old man with L sided ulcerative colitis diagnosed 5 years ago. Based on 2010 AGA guidelines what strategy is recommended?

A. Begin screening at 15 years, then every 5 years

B. Begin screening at 8 years, and then every 1-2 years

C. Begin screening at 8 years, then every 1-5 years

D. Average risk screening, not at increased risk based on his limited extent

Is there sufficient rationale for performing surveillance

colonoscopy in patients with IBD?

Grade B: There is moderate certainty that surveillance colonoscopy results in at least

moderate reduction of CRC risk in patients with IBD.

• Despite the lack of randomized controlled trials, surveillance colonoscopy is recommended for patients with IBD at increased risk for developing CRC.

• Patients with extensive UC or CD of the colon are most likely to benefit from surveillance.

Farraye FA, Odze R, Eaden J, Itzkowitz S. Diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138:746-774.

Most recent GI society surveillance guidelines-which to choose?

Society First colonoscopy (Screening)

Interval subsequent colonoscopy

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

AGA (2010) All patients 8 years after symptom onset (except proctitis and procotosigmoiditis)

-Every 1-2 years after screening-Every 1-3 years after 2 negative examinations

British Society Gastroenterology (2010)

All patients 10 years after diagnosis to determine extent and endoscopic risk factors

- Yearly in pancolitis with active/moderate inflammation 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

Controversy 2

Vocabulary of dysplasia: time to simplify?

You are performing surveillance in pt with UC and biopsies of lesion in area inflammation-path shows

tubular adenoma. Assuming area around lesion shows no dysplasia, what would you call this lesion?

A. Sporadic adenomaB. Adenoma-like lesion or mass (ALM)C. Dysplasia-associated lesion or mass (DALM)D. Raised DysplasiaE. Flat Dysplasia

A. Sporadic adenomaB. Adenoma-like lesion or mass (ALM)C. Dysplasia-associated lesion or mass (DALM)D. Raised DysplasiaE. Flat Dysplasia

You are performing surveillance in pt with UC and biopsies of lesion in area inflammation-path shows

tubular adenoma. Assuming area around lesion shows no dysplasia, what would you call this lesion?

A. Adenoma-like lesion or mass (ALM)B. Dysplasia-associated lesion or mass (DALM)C. Raised DysplasiaD. Flat DysplasiaE. Occult dysplasia

You are performing surveillance in pt with UC and path shows tubular adenoma. What would you

call this lesion?

Pathologist cannot decide-importance of dysplasia is given by

endoscopic context

• Tubular adenoma= low-grade dysplasia

IndefiniteIndefinite Low-GradeLow-Grade High-GradeHigh-Grade

Vocabulary for dysplasia in IBD

• Traditional: Macroscopic classification

• Better: • How detected (Non-targeted vs. targeted biopsies)• Can borders be defined

Itzkowitz S. and Harpaz N. Itzkowitz S. and Harpaz N. Gastroenterology Gastroenterology 126:1634, 2004 126:1634, 2004

““FlatFlat””

““Invisible?”Invisible?”““ElevatedElevated””

““sporadic”sporadic” ““DALM”DALM” ““ALM”ALM”

Controversy 3

What to do when dysplasia in detected: polypectomy, proctocolectomy, partial resection?

Normal Epithelium

Inflamed Epithelium

High-Grade Dysplasia

Low-Grade Dysplasia Cancer

Indefinite Dysplasia

A. Ongoing surveillance with white light endoscopy

B. Ongoing surveillance with chromoendoscopyC. ProctocolectomyD. Segmental resectionE. No recommendation

You are performing surveillance in pt with UC and path shows dysplasia. Based on 2010 AGA

Guidelines, what is the recommended action

2010 AGA Guidelines for management dysplasia-mostly grade A

Farraye Gastroenterology 2010; 138: 738

Perspective: What proportion of dysplasia fall into the “flat” category

• 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

• 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

Gastroenterology 2010; 138: 738

Perspective: What proportion of dysplasia fall into this category

~25% ~75%

AGA Guidelines-management of dysplasia

Questions and parameters to decide

“non-adenoma like dysplasia lesion or mass”

“adenoma-like lesion or mass and no flat dysplasia elsewhere”

“flat high-grade dysplasia”

“flat low-grade dysplasia”

Treatment? Surgery(grade A)

Polypectomy(grade A)

Surgery(grade A)

Insufficient (grade I)

* Further adenoma 50%-need close surveillance

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

Controversy 4

Performance of surveillance and role of chromoendoscopy: what is standard of care?

You are planning to perform surveillance colonoscopy on patient with IBD and are deciding on what is the current

standard of care with regard to enhanced dysplasia detection technique. Which of the following statements is

true based on 2010 AGA Guidelines?

A. Chromoendoscopy is superior to white light colonoscopy for detecting dysplasia and should be performed for every surveillance

B. NBI/iScan (virtual chromoendoscopy) is superior to white light colonoscopy for detecting dysplasia and is an easier alternative to chromoendoscopy

C. Chromoendoscopy is an acceptable alternative to white light colonoscopy in those experienced in the technique

D. Chromoendoscopy does not eliminate the need for random biopsies

23

Surveillance Technique• Based on expert opinion

• Technique: 4-quadrant biopsies every 10 cm of mucosa; at least 33 biopsies; extra focus on nodules, masses, strictures; every 5 cm in rectosigmoid

Kornbluth and Sachar, Am J Gastro, 2004.Itzkowitz and Present, Inflammatory Bowel Diseases, 2005.Itzkowitz and Harpaz, Gastroenterology 126:1634, 2004.

Chromoendoscopy proposed as means of improving sensitivity of colonoscopy

• 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

“Invisible” dysplasia happens in IBD-Reason for “enhanced” surveillance techniques

Rutter MD et. al.. GI Endoscopy 2004: 60(3):334Toruner et. al.. Inflamm Bowel Dis 2005: 11:428

Significance of Pit Patterns

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

Kudo S et al. Endoscopy 1993

Difference Between Chromoendoscopy and Virtual chromoendoscopy

• Chromoendoscopy– Dye spray through catheter– Absorptive dye: (stain taken up by noninflammed 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 (i-Scan/Fujinon) to achieve pseudocolored

image– Enhance tissue vasculature (differential optical absorption of light by Hb

associated with dysplasia (blue band)) or mucosal contours

SURFACE guidelines for chromoendoscopy

• Strict patient selection– Avoid active disease

• Unmask the mucosal surface– Excellent bowel prep; remove mucus and debris

• Reduce peristaltic waves• Full-staining length of the colon• Augmented detection with dyes

– 0.4% indigo carmine; 0.1% methylene blue• Crypt architecture analysis

– Pit pattern III/IV of concern• Endoscopic targeted biopsies

– Biopsy all mucosal alterations, especially pit pattern III/IV

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 Hallamshire Hospital, Sheffield, UK

350Indigo

Carmine-and Magnification

69 2493% sens.

88% spec.

Kiesslich (2007)

University of Mainz, Germany 161

Confocal endomicrosco

py19 4

94.7% sens.

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

Role of chromoendoscopy in surveillance

• Not yet standard of care• Chromoendoscopy (not virtual chromo)-is an

alternative surveillance technique mentioned in guidelines from Crohn’s and Colitis Foundation of America (2006) and AGA (2010) and British Society of Gastroenterology Guidelines (2010)

Controversy 5

Can we create a new/unified algorithm for thinking and managing dysplasia in IBD: Can we mimic what we are doing in non-IBD patients?

You are performing colonoscopy on a non-IBD patient and come across the following lesion in the ascending colon. You are able to define borders and lifts with saline. What would

you do?

A. Biopsy, if no cancer, schedule colonoscopy later to remove endoscopically (yourself or refer)

B. Attempt complete endoscopic removal at the time of procedure, if no cancer confirmed, continue surveillance

C. Biopsy, if no cancer, refer to surgeon for segmental resection

D. Biopsy, if no cancer, refer to surgeon for proctocolectomy

Proposal-three parameters relevant for preventing CRC and CRC mortality in IBD once any type of

dysplasia is detected-NOTE: it is what you are already doing 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?

Is it discreet?

Can I resect it?

Can I resect it?

Can I see it?Can I see it?

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



Proposal-three parameters relevant for preventing CRC and CRC mortality in IBD once any type of

dysplasia is detected-NOTE: it is what you are already doing in non-IBD

patients

3 questions to ask in this case1. Rate of progression of

dysplasia to advanced dysplasia or CRC (metachronous)



Controversy regarding progression of “flat” LGD to HGD or Cancer

Study Setting LGD (n) Rate

Connell 1994 St Mark’s 9 54% @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% @20y

Befrits 2002 Karolinska 60 2% @10y

Lim 2003 Leeds, UK 29 10% @10y

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

Study Setting LGD (n) Rate

Connell 1994 St Mark’s 9 54% @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% @20y

Befrits 2002 Karolinska 60 2% @10y

Lim 2003 Leeds, UK 29 10% @10y

Controversy regarding progression of “flat” LGD to HGD or Cancer

- Eaden J J of Pathol 2001; 194:152

Kappa statistic indicates how much greater observer 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 P7 P8 P9 P10 P11 P12 P13

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 0.39 -

0.33 0.26 0.35 0.17 0.12 0.43 0.40 0.11 0.26 0.3 0.43 0.29 -

-P13P12P11P10P9P8P7P6P5P4P3P2P1

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))

GI Pathologists General Pathologists

Controversy in the agreement of dysplasia





What is the probability of finding occult (synchronous) cancer after a

diagnosis fLGD?

Study If colectomy done immediately

Bernstein 1994 3/16 (19%)

Ullman 2003 2/11 (19%)

Rutter 2006 2/10 (20%)





Characteristics to resectabilityYou already ask yourself this when you do screening

and surveillance in patients without IBD

Is it discreet?

Is it discreet?

Can I resect it?

Can I resect it?

Can I see it?Can I see it?

Fact: Non-resectable colonic dysplasia is managed with surgery

• Concern in IBD is typically the type of surgery– Colectomy in IBD vs. limited resection in non-IBD

Proposal: 3 parameters relevant for managing dysplasia






Progression No info

Occult Cancer 43%

Resectability No










Progression No info <5%*

Occult Cancer 43% <5%

Resectability No Yes











Progression No info <5%* High

Occult Cancer 43% <5% 42%

Resectability No Yes No



Surgery(grade A)









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

Occult Cancer 43% <5% 42% 19%

Resectability No Yes No No



Surgery(grade A)

Insufficient (grade I)



Our approach to these controversies1. Grade B evidence for surveillance in IBD. GI society

guidelines share first exam 8-10 yrs/PSC at diagnosis– Next exam varies (1-3 years)

2. Simplified approach to dysplasia-based on how found: targeted vs. non-targeted biopsy and if can define borders

3. Dysplasia mngmt: polypectomy-ALM; surgery-HGD/DALM; not clear-flat LGD

4. Follow either surveillance technique based on expert opinion or chromo, no role virtual chromo– More likely to come across raised lesions or subtle

abnormalities (75%)-don’t just focus on 33 biopsies/dye spray– No need random biopsy with chromo after training

5. Proposal: the 3 parameters we use to manage non-IBD dysplasia can be applied to IBD-dysplasia (to be tested)

Documents

Controversies in Surveillance and Therapy for Colorectal Dysplasia in IBD: Case Studies Thomas Ullman MD Mount Sinai, New York Fernando Velayos MD MPH