dysplasia in ibd: update on surveillance and...

David T. Rubin, MD, FACG, FASGE

Dysplasia in IBD: Update on Surveillance and Management

David T. Rubin, MD, FACG, FASGEJoseph B. Kirsner Professor of Medicine

Chief, Section of Gastroenterology, Hepatology and Nutrition

@IBDMD

The IBD-Cancer Prevention Formula

Accurate Risk Identification

Effective Prevention Strategies

Accurate Detection of

Precancer

• Which patients?

• How to quantify risks?

• Pts and MDs implement strategies

• Colectomy• Polypectomy• Chemoprevention

Outcome of interest

• Cancer•Mortality• Colectomy•HRQoL

• Understanding of predictive value of lesions

• Colonoscopy• Accurate biopsies• Reliable pathology

2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology

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IMMUTABLEMODIFIABLE (Potentially)

Updated Risk Factors for Dysplasia and Colorectal Cancer in Ulcerative Colitis

• Increased inflammatory activity

• Backwash ileitis• Pseudopolyps• Prior dysplasia • Mass/stricture

• Male gender• Longer duration of disease• Greater extent of colonic

involvement • Family history of CRC• Primary sclerosing

cholangitis• Younger age of diagnosis

Askling J, et al. Gastroenterology. 2001;120(6):1356–1362.Lindberg BU, et al. Dis Colon Rectum. 2001; 44(1):77-85.Lutgens M, et al. Inflamm Bowel Dis. 2013;19(4):789-99.

Rutter M, et al. Gastroenterology. 2004 ;126(2):451-9.Rubin DT, et al. Clin Gastroenterol Hepatol. 2013;11(12):1601-8.

Evolution of Cancer Prevention in IBD

Modality Primary Lesion Detected Outcome Intervention

Physical examination

Metastatic disease Death Prophylactic colectomy

Barium enemasMasses, tubular colons Insensitive to early

stage lesions; Cancerdetected later

Colectomy

Fiberoptics Masses, “DALMs” Dysplasia thought to be “invisible”

Colectomy

Digital scopes (CCD

technology)

Polypoid/raised lesions Era of random biopsies

Colectomy

HD scopes

Raised lesions, mucosal defects/abnormal pit patterns

Random/Targeted biopsies

Lesion resection, follow-up with more “intensive” surveillance

Chromoscopy

Raised lesions, flat lesions/mucosaldefects/abnormal pit patterns

Targeted biopsies(fewer?)


PRO

GRES

S


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Barium enemas Masses, tubular colonsInsensitive to early stage lesions; Cancerdetected later

Colectomy

Fiberoptics Masses, “DALMs” Dysplasia thought to be “invisible” Colectomy

Digital scopes (CCD

technology)Polypoid/raised lesions Era of random

biopsies Colectomy

HD scopesRaised lesions, mucosal defects/abnormal pit patterns



Chromoscopy




PRO

GRES

S






Colectomy


Digital scopes (CCD


biopsies Colectomy




Chromoscopy




PRO

GRES

S


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Colectomy


Digital scopes (CCD


biopsies Colectomy




Chromoscopy




PRO

GRES

S

Movement away from random

biopsiesMovement away

from surgery


Newer Approaches to Dysplasia Management

Technique Levels of Evidence• Some dysplasia does not require

proctocolectomy• Polypectomy sufficient• Endoscopic mucosal resection• Endoscopic Submucosal

Dissection• Subtotal colectomy

• Cohort studies of outcomes1,2

• Case series3

• Case reports • Anecdotal

1. Pekow JR, et al. Inflamm Bowel Dis. 2010;16(8):1352-6.2. Ullman T, et al. Gastroenterology. 2003;125(5):1311-9.

3. Lang GD, et al. Am J Gastroenterol. 2013;108:S597.


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There is Low Yield of Random Biopsies in Colitis Surveillance

• N=167 patients, 466 surveillance colonoscopies• 24 of 11,772 random biopsies detected neoplasia (0.2% per-

biopsy yield)

• ~1 in 500 random biopsies

van den Broek FJ, et al. Am J Gastroenterol. 2014;109(5):715-22.

Resected “Raised” Dysplasia has Less Risk of Progression than “Flat” Dysplasia

Pekow JR, et al. Inflamm Bowel Dis. 2010;16(8):1352-6.

n= 41

Flat dysplasia

Raised dysplasia


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Quality of Pathology and Pathologists Important!

There is Poor Correlation for Some Grades of Dysplasia

No dys IND LGD HGD Cancer

?

Odze RO, et al. Mod Pathol. 2002;15(4):379-86.

K=0.51Good

K=0.18Poor

K=0.36Fair

K=0.54Good ?

Expert review of digitized slides

• Adequate biopsy specimens• Labeled properly• Communication with your pathologist is key!

Rubin DT, Turner JR. CGH. 2006 Nov;4(11):1309-13.

This is Not Your Mentor’s Dysplasia!

• OLD: dysplasia “invisible”

• NEW: technology makes most “visible”

• HYPOTHESIS: Dysplasia found by newer technologies may not have the same meaning as that found in the past

• PROPOSED: This should allow a different approach to detection and follow-up


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Changing Terminology: Need for Consistency!

The terms “DALM” and “ALM” are being replaced by:“polypoid”

“non-polypoid” “flat”

“invisible” dysplasia

Pictures from Neumann H, et al. World J Gastroenterol 2011;17(27):3184-91.

Previously called ALM Previously called DALM

Modified from Rubin DT, Turner JH. Clin Gastroenterol Hepatol. 2006;4(11):1309-13.

Dysplasia

Multifocal?

ColectomyColectomy vs.

aggressive follow-up

Grade?

Flat*

High Low

Yes No

Endoscopic appearance

Complete endoscopic resection

Colonoscopy ≤6 months and

follow-up

Visible by WLE/raised

Flat = diagnosed by random biopsy or only visibile by chromoendoscopy.

Approach to Visible Dysplasia in IBD


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What Is The Utility of Enhanced Visualization?

Chromoendoscopy is Highly Sensitive and Specific for Dysplasia in UC

• Meta-analysis of 6 randomized controlled trials comparing dye-spray to white light/conventional colonoscopy

• Methylene blue or indigo carmine

Wu L, et al. Colorectal Dis. 2012;14(4):416-20.


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Polypectomy with Methylene Blue


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What Happens to Dysplasia Found on Chromoendoscopy?

• Are we missing occult cancers?• Dysplasia in the current age has a different predictive value

than dysplasia found with earlier technology• Current therapies prevent progression of dysplasia• Chromoendoscopy studies:

• Follow-up in only one study• Marion (NYC)

– Follow-up with colectomy specimens– 5 of original 102 had colectomy due to unresectable LGD – No CRC

Marion J, et al. Am J Gastroenterol. 2008;103(9):2342-9..

Which Dye Should You Use?

Methylene Blue Indigo Carmine• Interactions with Serotonergic

medications (eg. SSRIs)? 1,2

• Carcinogenic? (DNA damage to colonocytes) 3

• Absorptive, rich dye coloring• Doesn’t require moving patient

around• Cost comparable to IC• Shortage (on back order) 5

• No known drug interactions• Not thought to be carcinogenic3

• Surface dye, less rich staining• Requires moving patient around

to get even distribution of dye• Cost comparable to MB• Shortage (was on back order) 6

1. Shah-Khan, et al. Am J Surg. 2012; 204(5):798-9.2. http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm3. Davies J, et al. Gut, 2007;56(1):155-156..4. Lee M, Sharifi R. Urology. 1996;47(5):783-4.

5. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=27

6. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=861


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Challenges to Chromoendoscopy in IBD

• Perception of time consuming and expensive (time 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 competency requirement• Comparison to newer high definition scopes not

completed

Billing for Chromoendoscopy

• There is no CPT code for this procedure,1 nor is there one in the revised Procedural Codes.

• Can try to use -22 modifier (I do)– “unusual time, intensity, technical difficult or severity”– May pay +10-20% of allowable charge for procedure.

Reports as well that it may result in decreasedreimbursement2

• 43499 and -59 modifier, indicate “chromoendoscopy”2

– “most time the insurance will deny…”

1ASGE Technology Committee report, 2007.2http://www.aapc.com/memberarea/forums/ accessed December 14, 2012


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Consider Chromoendoscopy for:

• Patients with previous confirmed dysplasia (flat or raised) and high risk and not going to colectomy

• Lesions found and require clarification (selective chromo)

• Patient has minimal inflammation and very good to excellent prep

Farraye FA, et al. Gastroenterology. 2010;138(2):738-45.

More Sensitivity to Detect Dysplasia is Not Necessarily Better?

0

0.10.20.3

0.40.5

0.60.7

0.80.9

1

Increased Sensitivity for Dysplasia

Spec

ifici

ty fo

r “Cl

inic

ally

Sig

nific

ant”

Le

sions DALM seen by

White Light (or Barium Enema)

Polypoid dysplasia seen by White

Light

Raised lesion identified by chromoendoscopy

Flat lesion identified by chromoendoscopy

TimeTrainingDirect Costs


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• Surveillance for Colorectal Endoscopic Neoplasia detection and management in Inflammatory bowel disease patients: International Consensus (March 7-8, 2014).

• Rated statements related to surveillance practices based on multiple factors.

• Systematic reviews performed on each topic based on Cochrane methodology.

• Panel voted on recommendations

Laine L, et al. Gastrointest Endosc. 2015;81(3):489-501.Laine L, et al. Gastroenterology. 2015;148(3):639-651.

SCENIC International Consensus StatementsSelected Statements for Consideration

1. When performing surveillance with white-light colonoscopy, high definition is recommended rather than standard definition.

2. When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy.

3. When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy.

4. After complete removal of endoscopically resectable polypoid dysplastic lesions, surveillance colonoscopy is recommended rather than colectomy.

5. After complete removal of endoscopically resectable nonpolypoid dysplastic lesions, surveillance colonoscopy is suggested rather than colectomy.

6. For patients with endoscopically invisible dysplasia (confirmed by a GI pathologist) referral is suggested to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy.

Laine L, et al. Gastrointest Endosc. 2015;81(3):489-501.Laine L, et al. Gastroenterology. 2015;148(3):639-651.


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What Do the Guidelines Tell Us?

East J. Clin Endosc. 2012;45(3):274-277.

Because the sensitivity for detecting dysplasia by chromoendoscopy is higherthan that of white light endoscopy, chromoendoscopy with targeted biopsies is recommended as an alternative to random biopsies for endoscopists who have

expertise with this technique.-AGA Technical Review 2010

Screening colonoscopy at 10 years(preferably in remission, pancolonic dye-spray)

Lower RiskExtensive colitis with NO ACTIVE

endoscopic/histological inflammation

OR left-sided colitisOR Crohn’s colitis of <50% colon

Intermediate RiskExtensive colitis with MILD ACTIVE


OR post-inflammatory polypsOR family history CRC in FDR aged 50+

Higher RiskExtensive colitis with MODERATE/SEVERE ACTIVE


OR stricture in past 5 yearsOR dysplasia in past 5 years declining surgeryOR PSC / transplant for PSCOR family history CRC in FDR aged <50

FDR, first-degree relative; PSC, primary sclerosing cholangitisCairns SR, et al. Gut. 2010;59(5):666-89.

British Society Guidelines 2010


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5 Years 3 Years 1 Year

British Society Guidelines 2010Screening colonoscopy at 10 years

(preferably in remission, pancolonic dye-spray)











Pancolonic dye spraying with targeted biopsy of abnormal areas is recommended, otherwise 2–4 random biopsies from every 10 cm of the colorectum should be taken

Other ConsiderationsPatient preference, multiple post-inflammatory polyps, age and comorbidity, accuracy and completeness of examination

5 Years 3 Years 1 Year

Screening colonoscopy at 10 years(preferably in remission, pancolonic dye-spray)










British Society Guidelines 2010



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What We Still Need!

• Updated guidelines• Clarification of quality measures

– Prep– Detection rates

• Uniformity of endoscopy reports• Improved techniques

Rubin DT, et al. Gastrointest Endosc. 2014;80(5):849-851.

Future Techniques

• Fecal DNA– Stool assays of methylated genes (such as

vimentin, EYA4, BMP3, NDRG4) may detect colorectal neoplasms1

• Other Markers (mucosal antigens, genetics)

• Confocal Laser Endomicroscopy2

1Kisiel JB, et al. Alliment Pharmacol Ther. 2013;37(5):546-54.2Teubner D, et al. Gastrointestinal Endscopy Clin N Am. 2014;24(3):427-34.


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Why It’s Time to Enter a NEW Era of Surveillance and Cancer Prevention in IBD

• Evidence for guidelines is weak or moderate at best

• Clinicians don’t follow existing guidelines

• We can stratify based on individual risk factors for neoplasia– Includes inflammation

• We can learn and apply new techniques

Dysplasia-related factors:• Grade:

– IND vs. LGD vs. HGD

• Morphology– Flat vs. Polypoid– “Invisible” vs. raised

• Field effect/Synchronicity: – Unifocal vs. multifocal

• Longitudinal follow-up?– Dysplasia on a single exam vs. metachronous

lesions on serial exams

Pt/disease-related factors:• PSC• Family history of CRC• Duration• Degree of inflammation over time

and on last exam• Male v Female• Willingness and ability to follow

your recommendations

Risk Stratification of Dysplasia in Colitis Guide Follow-up and Colectomy Recommendations


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Summary: Dysplasia in IBD: Update on Surveillance and Management

• Evolving optical technology has made identification of dysplasia easier.• Random biopsies for surveillance are of limited utility.• Not all dysplasia requires immediate colectomy.• Stratify your UC (and Crohn’s colitis) patients by individual risk factors.• Consider chromoendoscopy (with methylene blue or indigo carmine)

– when you have been trained– in higher risk patients– previous confirmed dysplasia (flat or raised) – lesions found and require clarification

• Don’t hesitate to get a second opinion (from IBD endoscopist or surgeon).


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