Nuts and Bolts of Dysplasia in IBD

Tad Dryden, MD, MSPH Associate Professor of Medicine University of Louisville

Objectives

• What is dysplasia, and where does it come from?

• Natural history of dysplasia • How do we find it, and what do we do about it?

• Prevention of dysplasia

Dysplasia

• • •

Dysplasia

– Unequivocally neoplastic transformation

Dysplasia in IBD

– May be flat, difficult to detect at early stage – May be visible on endoscopy (elevated)

Dysplasia in a non-IBD Polyp

–

Even in the absence of IBD, every adenoma is dysplastic in normal people

–

ALL ADENOMAS ARE DYSPLASTIC BY DEFINITION

Why Do We Care?

Cumulative Risk of CRC in UC 0.5-1.0% per year after 10 years of disease

Eaden et al. Gut 48:526, 2001

Risk of CRC in Crohn’s

Canavan, APT, 2006

Dysplasia-Carcinoma Sequence Non IBD Vs. IBD

Non IBD IBD

Proposed Role of Inflammation in Dysplasia

Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer Nat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44

Proposed Role of Inflammation in Dysplasia

Feagins LA et al. (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer Nat Rev Gastroenterol Hepatol doi:10.1038/nrgastro.2009.44

Flavors of Dysplasia

• Flat dysplasia • Raised dysplasia • Low grade • High grade

DALM

Two types of definitions by clinicians: • 1: any protruded lesion with dysplasia - This leads to lots of misunderstanding - This is not the original description • 2: ominous looking lesion that cannot be removed colonoscopically

DALM Definition (1981)

• Single discrete polypoid or nodular mass • Discrete plaque like lesion • Abnormal appearing mucosa • Raised irregular or nodular area • Original report: lesion that could not be removed endoscopically • If it can be removed colonoscopically, it is not a DALM by definition • The term DALM has been misinterpreted

Blackstone MO, Riddell R, Rogers G, Levin B. Dysplasia associated lesion or mass (DALM) detected by colonoscopy in longstanding ulcerative colitis: An indication for colectomy. Gastro 1981;80:366-74.

Differentiating Polypoid Lesion in IBD Patient

• If an adenoma (mass) is found in IBD, it must always be dysplastic: by definition, it is a Dysplasia Associated Lesion or Mass (DALM) • The finding of dysplasia in this setting is not necessarily a trigger for colectomy • Difference defined by the morphology • A DALM is different than an Adenoma-Like Mass (ALM)

Dysplasia Associated Lesions or Masses

Adenoma Like Mass ALM not a DALM Non Adenoma Like Mass or NALM or NALD or DALM THE DIFFERENCE IS: CAN IT BE REMOVED….

BY WHOM?

Dysplasia

An important concept:

• Malignant colon lesions are dysplastic BUT • Not all dysplastic lesions are malignant • LGD and HGD lesions if totally removed and no invasive component: CURED!

Dysplasia in Ulcerative Colitis

• Significance of a dysplastic lesion depends on: - Morphology - Completeness of removal - Biopsies of surrounding tissue

Ullman, Odze, Farraye. Inflamm Bowel Dis 2009;15:630 –638

Non-Controversies Regarding Dysplasia in IBD

• HGD found under the following conditions requires surgery: - Biopsy of a non-removable mass - A malignant appearing lesion - When in flat mucosa - -If it is confirmed – By another pathologist (?) – By another biopsy (?) • HGD: no surgery

if in resected adenoma, totally removed and no adjacent dysplasia

What is the Natural History of High-Grade Dysplasia?

Probability of Finding Cancer

1 Bernstein et al. Lancet 343:71, 1994 2 Connell et al. Gastroenterology, 1994 3 Rutter et al, Gastroenterology, 2006

Recommended Repeat Surveillance Interval for Occult HGD

•

None —Requires Colectomy

Controversies Regarding Dysplasia in IBD

• Does low grade dysplasia require colectomy?

• What should the gastroenterologist do with dysplasia in IBD?

• Can polypoid dysplasia in IBD be managed endoscopically?

• What is the trigger for surgery when pathology report comes back with dysplasia in the setting of IBD?

What is the Natural History of Low-Grade Dysplasia?

Mount Sinai flat LGD experience

• 46 patients with flat LGD at index from 1994-2000; nonprotocol-based surveillance • F/U of all surveillance examinations • Progression defined as HGD or CRC • Is unifocal LGD a less dangerous subset?

Ullman, Gastro, 2003

Timelines: fLGD → CRC (N=7) 0 12 24 36 48 60 72 Months Initial fLGD

Ullman et al. Gastro, 2003

Adenoma-like

DALM

Non-Adenoma-like

(broad-base, irregular cannot remove)

Inside colitis Outside colitis Colectomy Polypectomy Regular surveillance Polypectomy Absence of flat dysplasia Increase surveillance

Colectomy vs. Polypectomy and continued surveillance Colectomy Polypectomy Flat dysplasia or adenocarcinoma Present Endoscopic Appearance Amenable to polypectomy Yes Broad based/mass Irregular Ulcerated Plaque-like Constricting No No Small Discrete Yes

Probability of Finding Cancer

Recommended Interval for LGD

• Raised with incomplete polypectomy: - Colectomy • Raised with complete polypectomy - 3-6 months • Flat - Chromo in 3 months OR colectomy

Decisions with LGD, HGD

• Raised LGD: - is it removable? Do it - Bx around • Raised HGD: - Is it removable? Must it look like a polyp?

- If removable, it is an ALM - Biopsy around - Needs surgery if cannot remove • Complete removal, biopsies nearby negative - Follow up in short interval: 3-6 months

Endoscopic Mucosal Resection

• Possible in IBD polyps • More difficult due to inflammatory process • If it lifts, it is possible • If it does not lift, it may still be possible • Take care not to try removal of a CRCa • Take multiple biopsies before ablating with the APC.

• Technique same as non IBD.

IND and NoD?

Ullman, CGH 6:1225-30, 2008

Recommended Interval for IND and NoD

• IND: Repeat in 0.5-1 years • NoD: Repeat in 1-2 years

Traditional Surveillance Colonoscopy Guidelines • Extent based on endoscopic or histologic involvement (whichever is greater) • 4 quadrant biopsies every 10 cm (minimum 4 quadrant biopsies every 10 cm (minimum 32 for pancolitis ) • Dysplasia confirmed by second pathologist

White Light Colonoscopy for Detecting Dysplasia • Random biopsies sample a tiny portion of the total surface area of the colorectum • SA of colorectum: 1578.1+/- 301.0 cm 2 • Surface area of biopsy forceps: 2.2-5 mm 2 • 33 biopsies x 5mm 2 = 165mm 2 • Percent surface area sampled with this approach:

0.05%-0.1%

Sadahiro S. et al. Cancer, 1991.

Rubin CE, et al. Gastroenterol, 1992.

Kornbluth and Sachar. Am J Gastroenterol, 2004.

Methods of Surveillance: White Light Colonoscopy

Biopsy Numbers Performed/Predicted Dysplasia and Cancer Detection Confidence

90% 95%

Dysplasia

33 56

Cancer

35 64 • Poor overall detection rates for dysplasia in non targeted biopsies - Rates as low as 0.1% or 1/1000*

*Hurlstone. Endoscopy 2005;37:1186-1192.

*Hurlstone. Gut 2008;57:196-204

Methods to Enhance Detection of IBD Associated Dysplasia

Chromoendoscopy

• Contrast dyes: Indigo carmine - Coat mucosa • Absorptive dyes: Methylene Blue - Poorly stain active inflammation and dysplasia

Chromoendoscopy Method*

• 0.1% indigo carmine or 0.1% methylene blue • Dye spray catheter protrudes 2-3cm from scope.

• Spraying segmental every 20-30cm • Excess suctioned • Wait few seconds for indigo carmine and 60 seconds for methylene blue (absorption)

Kiesslich R. Gastroenterol Clin N Am. 2006;35:605-619.

Indigo Carmine*

• No dysplasia in 2904 white light non targeted biopsies.

• Dysplasia in 2/43 (5%) white light targeted biopsies.

• 7/114 (6%) (includes 2 above) indigo carmine spray targeted biopsies showed dysplasia.

• Dysplasia detection 7/100 patients indigo carmine compared to 0/100 non-targeted (p=0.06)

Rutter MD. Gut 2004;53:256-260

Rutter et al. Gut 2004;53:256-60

Chromoscopy Alone

• Part of surveillance guidelines by CCFA 1 • One report of methylene blue related DNA damage.

2 • Follow-up after 23 months showed less neoplasia in methylene blue group.

3 1

Itkowitz SH Inflamm Bowel Dis. 2005;11:314-321

2

Olliver JR. Lancet 2003;362:373-4

3

Kiesslich R. Gastrointest Endos 2004:59:AB97.

Indigo Carmine Assisted High Magnification Chromoscopy

• Total colonoscopy • Suspicious mucosal changes stained with indigo carmine. • Lesions examined using high magnification mode and classified by Kudo class.

• Compared to standard control population.

Normal

Hyperplastic Dysplasia Tubular adenoma Villous adenoma Cancer Cancer

Results: Dysplasia detection

• Non targeted biopsies: 0.16% • Targeted biopsies by white light alone: 1.6% • Targeted biopsies by indigo carmine/magnification: 8% • Overall 53 flat lesions (369 patients) indigo carmine magnification compared to 14 in control group (366 patients) (p<0.001).

Current Practice

• Use Pan-colonic dye spray with targeted biopsy - 0.2% indigocarmine in high volume pump is very convenient • Random biopsy still performed, but likely to change soon • Endoscopic equipment advances appear highly promising to target biopsy among “detected” lesions

CCFA Consensus Recommendations: How to Perform Surveillance

• Initiate at 8 years of disease for patients with 1/3 or more of their colon involved • Start immediately for patients with IBD/PSC • 4 quadrant biopsies every 10 cm for minimum of 32 biopsies per exam • Separate jar for all suspicious lesions • Each quartet goes in single specimen jar • Perform every 1-2 years

Itzkowitz/Present, IBD 2005

Can We Alter the Development of Cancer in IBD?

Risk of CRC in IBD: Factors that Increase Risk

• Duration >8-10 years - Extent of colitis: - Extensive disease • Backwash ileitis • Family history of colon cancer • Primary sclerosing cholangitis • Early age at onset of colitis • Histologic activity • Pseudopolyps • Dysplasia at surveillance

Risk of CRC in IBD: Factors that Decrease Risk

• Prophylactic Colectomy • Surveillance colonoscopy • Regular doctor visits • Chemoprevention?

- 5-ASA - Ursodeoxycholic Acid (PSC patients) - Folate - Purine Analogs ?

Yes ?

No

Chemoprevention

• Pharmacologic interruption of the sequence to neoplasia • 5ASA’s • Purine analogs Yes/?

No • Folic Acid • Urso (in PSC) • Anti-TNF’s Yes/?

Yes ?

Possible Dysplasia/CRC Chemopreventive Agents in IBD Agent

Folic acid

Evidence in IBD

Rationale, safety good; not significant 1 Calcium and vitamin D Rationale 6-mercaptopurine azathioprine Ursodeoxycholic acid 5-aminosalicylic acid Statins 1Lashner BA et al.

Gastroenterology

. 1997.

3Matula et al.

Clin Gastro and Hep,

2005.

Case-control suggests not 3 New evidence suggest possible 4 In PSC with UC, yes 2 ; other UC, unknown Studied retrospectively; case control, cohort, population Limited, registry, population-based 2 Pardi D et al.

Gastroenterology

. 2003.

4 Rubin et al. DDW 2006.

Ullman, Clin Gastro Hep, 2008

5-ASA Use After IND

Ullman, Clin Gastro Hep, 2008

Chemopreventive Effect of 5-ASA: Small if at All

Any Use 5ASA Exposure >2 g/day Avg Dose Any Neoplasia HR (95% CI) Advanced Neoplasia HR (95% CI) 0.86

(0.40-1.82) 0.70

(0.20-2.44)

Ullman, CGH 6:1225-30, 2008

0.91

(0.47-1.77) 0.77

(0.22-2.67) 1.01

(0.80-1.28) 0.92

(0.58-1.47)

Purine Analogs: Surveillance Cohort (n=315) 6MP Exposure Any Neoplasia HR (CI) Advanced Neoplasia HR (CI) Any Exposure 1.30

(0.45-3.75) ≥25mg/d 0.88

(0.47-1.65) Avg Daily Dose 1.01

(0.80-1.28) 0.88

(0.48-1.59) 1.46

(0.51-4.21) 1.95

(0.82-4.60)

Matula, CGH 2005

Urso Protects Against Neoplasia in PSC Patients

Pardi, et al. Gastro 2003

Mucosal Healing Reduces Colectomy Rate in UC

Froslie KF et al

Gastroenterology

133 (2007) 412-422.

* Oral 5-ASA, topical 5-ASA, sulfasalazine, antibiotics, corticosteroids, azathioprine, and/or metronidazole

Histologic Inflammation Is Associated with Progression to HGD or CRC in UC

Gupta, Gastro 2007

Questions?

Increased Inflammation Leads to Increased Risk of Colectomy

• UC surveillance database of 561 patients • Median follow up of 21.4 years Hefti M

et al. Dis Col Rectum

2009; 52: 193-197

Cumulative Risk of CRC Among 376 UC Patients From Olmsted County, Minnesota, 1940-2001

Jess T, et al, Gastroenterology 2006; 130:1039-46.

Colonoscopy Surveillance Guidelines

• Pancolitis (or Left (or Left-sided) : Every 1-2 years after 8-10 years.

• Proctitis: Risk not greater than non-IBD • Begin surveillance immediately in PSC patients • Recommendations also apply to Chrohn's disease.

Limitations of Surveillance

1. Poor levels of agreement among pathologists 2. Dysplasia is patchy/Poor detection 3. Natural history of dysplasia poorly understood 4. Cancers can arise without any apparent prior dysplasia 5. Incomplete patient follow-up

“Natural” History of Dysplasia in IBD

• Diagnosis

Endoscopy in IBD

- IBD versus non-IBD diagnosis Distinguish UC from Crohn’s • Assess Activity - Change therapy - Effect of therapy - Prognosis • Dysplasia Surveillance • Therapeutics - Stricture - Polypectomy

Issues in Diagnosis

• Endoscopist: messenger boy/girl • Pathologist: makes diagnosis based on features of chronicity • Architectural distortion • Basal plasmacytosis • Increased lamina propria cellularity • Pyloric gland +/- Paneth cell metaplasia • Granulomata (15-35%)

Differential

• Infectious and other “acute-selflimited” colitis • NSAID and other drug-induced colitis • Ischemic colitis • Radiation changes • Diverticular colitis (SCAD) • Neoplasia

Ileocolonoscopy Preferred Single Test Even for Small Bowel CD Diagnosis

Solem et al, Gastrointest Endosc 2008;68:255-66

Historic Endoscopic Features Distinguishing UC from CD

• Rectal sparing • “Patchiness” • Small bowel involvement • Discrete and aphthous ulcers • Serpiginous ulcers • Cobblestoning

Rectal Sparing: Not your father’s IBD?

• Treated UC 1 - Rectal sparing in 13% - Endoscopic patchiness in 44% • Untreated UC later leading to surgery 2 - Rectal attenuation in 31% 1 Bernstein et al, Gastrointest Endoscop 1995; 42:232-7 2 Robert et al, Am J Clin Pathol. 2004; 122:94-9

Mayo Scoring

0= Normal or inactive disease 1= Mild disease: erythema, decreased vascular pattern, mild friability 2= Moderate disease: marked erythema, absent vascular pattern, friability, erosions 3= Severe disease: spontaneous bleeding, ulceration

Mucosal Healing

Nested Case Control Uppsala, SWE

Karlen et al, Gut 1998

CRC Risk Reduction in UC: Colonoscopy

Eaden et al, Aliment Pharmacol Ther 14:145, 2000

CRC Risk Reduction in UC: Colonoscopy

Velayos et al, Gastroenterology 130:1941, 2006

Mount Sinai: Is the Curve Changing?

Ullman, CGH 6:1225-30, 2008

Number of Biopsies Needed Per Site

• To detect dysplasia with 95% confidence: 56 biopsies * • To detect dysplasia with 90% confidence: 33 biopsies * *Rubin et al, Gastroenterol 1992

Biopsy Practices: Mount Sinai

Ullman, ACG 2007

Low Rate of Breakthrough CRC with current practices

Ullman, ACG 2007