Page 1. Is the Risk This High? Dysplasia in the IBD Patient. Dysplasia in the Non IBD Patient. Increased Risk of CRC in Ulcerative Colitis

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1 Screening for Colorectal Neoplasia in Inflammatory Bowel Disease Francis A. Farraye MD, MSc Clinical Director, Section of Gastroenterology Co-Director, Center for Digestive Disorders Boston Medical Center Professor of Medicine Boston University School of Medicine Increased Risk of CRC in Ulcerative Colitis Meta-analysis of 116 worldwide studies assessing the risk of CRC in UC patients Cumulative risk of developing CRC: 2% at 10 yrs, 8% at 20 yrs and 18% at 30 yrs Risk of CRC higher in extensive colitis patients Eaden JA, et al. Gut 2001;48: Dysplasia in the Non IBD Patient Is the Risk This High? 600 patients with extensive UC followed for 5932 person-years at St. Marks in London 30 CRCs detected (annual risk: 0.5% or 1/200) Cumulative probability of CRC was 2.5% at 20 years, 7.6% at 30 years and 10.8% at 40 years Rutter MD, et al. Gastroenterology 2006;130: Dysplasia in the IBD Patient Comprehensive meta-analysis of the risk of colorectal cancer in UC and CD 48 studies included in the meta-analysis Included both population based and referral centers Included 131,743 personsyears 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. Gastro 2008;134:48 Cumulative probability (%) Cumulative risk in IBD patients Overall Population based 50 Referral center >20 Years from diagnosis 6 Page 1

2 No increase in proctitis patients, intermediate risk in left Page 2

3 Surveillance Colonoscopy in IBD Premise that dysplasia antecedes cancer Marker of malignancy risk Present in 75-80% (close and distant) of patients with carcinomas Any portion of colon (single, multifocal, diffuse) Flat or elevated (DALM) No RCTs proving value of colonoscopy have ever been conducted Accepted as standard of care Bernstein CN. Gastroenterology 2003;124: sided UC and highest risk in pancolitis Dysplasia Classification Negative for dysplasia Indefinite for dysplasia (probably negative, unknown and probably positive) Positive for low-grade dysplasia, high-grade dysplasia or invasive cancer Pathologists should not be grading dysplasia as mild, moderate or severe Riddell RH, et al. Hum Pathol 1983;14: Histological Inflammation is a Risk for Neoplasia in UC Author (Year) Rutter UK (2004) Gupta NY (2007) Rubin Chicago (2006) Design Cohort Casecontrol Casecontrol Patients 68 cases 136 controls 418 pts 65 neoplasia 15 advanced neoplasia 59 cases 141 controls Histologic inflammation (retrospective) Inflammation (pathology reports) Inflammation (pathology reports, without polypectomy) Average Histologic Inflammation (re-graded) Risk (OR or HR) OR 4.69 ( ) p-value < neoplasia advanced HR 2.2 p<0.05 any neoplasia HR 1.3 p=0.03 neoplasia advanced HR 2.4 p=0.03 any neoplasia HR 2.0 p=0.01 OR 4.9 ( ) 7.1 ( ) Interobserver variation Several studies demonstrated only moderate levels of agreement Agreement better for HGD/Negative than LGD/Indefinite Confirm diagnosis by expert GI pathologist Scope when IBD quiescent Need for patient compliance with colonoscopy Dysplasia may be absent in 25-30% of colectomy specimens in patients with cancer Courtesy of David Rubin, MD Page 3

4 Interobserver variation Several studies demonstrated only moderate levels of agreement Agreement better for HGD/Negative than LGD/Indefinite Confirm diagnosis by expert GI pathologist Scope when IBD quiescent Need for patient compliance with colonoscopy Dysplasia may be absent in 25-30% of colectomy specimens in patients with cancer Sampling error Multiple biopsies needed 33 biopsies needed to achieve 90% confidence to detect dysplasia if it is present At least half of all CRC in UC develop in the rectum or sigmoid colon Surveillance offers a reasonable chance of detecting dysplasia or early stage cancer Interobserver variation Several studies demonstrated only moderate levels of agreement Agreement better for HGD/Negative than LGD/Indefinite Confirm diagnosis by expert GI pathologist Scope when IBD quiescent Need for patient compliance with colonoscopy Dysplasia may be absent in 25-30% of colectomy specimens in patients with cancer Sampling error Multiple biopsies needed 33 biopsies needed to achieve 90% confidence to detect dysplasia if it is present At least half of all CRC in UC develop in the rectum or sigmoid colon Surveillance offers a reasonable chance of detecting dysplasia or early stage cancer Interobserver variation Several studies demonstrated only moderate levels of agreement Agreement better for HGD/Negative than LGD/Indefinite Confirm diagnosis by expert GI pathologist Scope when IBD quiescent Need for patient compliance with colonoscopy Dysplasia may be absent in 25-30% of colectomy specimens in patients with cancer High Grade Dysplasia (HGD) Review of Ten Prospective Surveillance Trials of 1225 patients 42% (10 of 24) of patients with HGD who underwent immediate colectomy had synchronous CRC 32% (15 of 47) of patients with HGD who underwent colectomy at a later date had CRC Bernstein CN, et al. Lancet 1994;343:71-74 Page 4

5 Low Grade Dysplasia IBD Patient with Flat Dysplasia Review of Ten Prospective Surveillance Trials of 1225 patients 19% (3 of 19) patients with LGD who underwent immediate colectomy had synchronous CRC 8% (17/204) of patients with LGD who underwent colectomy at a later date had CRC Bernstein CN, et al. Lancet 1994;343:71-74 Unifocal Colectomy Surveillance Low grade Multifocal Colectomy High grade Colectomy Meta-analysis LGD and Cancer Risk Determine the incidence of CRC and the RR of developing CRC in patients with LGD in chronic UC undergoing surveillance ( ) Twenty surveillance studies with 508 flat LGD or LGD with DALM were reviewed Thomas T, et al. Aliment Pharmacol Ther. 2007;25(6): Dysplasia in IBD Gross Subtypes Flat Endoscopically Invisible Elevated (DALM) Meta-analysis LGD and Cancer Risk Average of 18 biopsies taken per colonoscopy (range: 9 24) 73 advanced lesions detected (CRC or high-grade dysplasia) pre-operatively When LGD is detected on surveillance Nine fold risk of developing cancer (OR: 9.0, 95% CI: ) Twelve-fold risk of developing any advanced lesion (OR: 11.9, 95% CI: ) DALMs (Polypoid or Raised Dysplasia) Adenoma-like Endoscopically resectable Non-adenoma-like Non endoscopically resectable Thomas T, et al. Aliment Pharmacol Ther. 2007;25(6): Page 5

6 Long term Followup of Polypoid Dysplasia Resected Endoscopically Pit Pattern Classification (Kudo) Odze, et al Rubin, et al No further polyps 38% 52% Additional polyps 58% 48% Dysplasia in flat mucosa 4% 0% CRC 4% 0% Rubin PH, et al. Gastroenterology 1999 ;117: Odze RD, et al. Clin Gastro and Hepatol 2004;2: The typical crypt architecture of types I-V are indicated (A). (B) Examples of type I (left) and type IV (right) lesions before and after chromoendoscopy. Kiesslich R, Neurath MF. Gut 2004;53: DALMs (Polypoid or Raised Dysplasia) Adenoma-like Outside colitis Polypectomy Regular surveillance Inside colitis Polypectomy Absence of flat dysplasia? Increase surveillance Non-Adenoma-like (broad-base, irregular) Colectomy Chromoendoscopy Example (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. Gastroenterology 2003;124: Chromoendoscopy Improves the detection of subtle colonic lesions, raising the sensitivity of the endoscopic examination Chromoendoscopy with or without a magnifying colonoscope can improve lesion characterization, increasing the specificity of the examination Crypt architecture can be categorized using the pit pattern, aiding differentiation between neoplastic and non-neoplastic changes, and enabling the performance of targeted biopsies Provides a more accurate diagnosis of the extent of disease and inflammatory activity Controlled Studies on the Use of Chromoendoscopy in Patients with Ulcerative Colitis Study Number of patients Dye MB=methylene blue IC=Indigocarmine Number of lesions Difference (x-fold) Kiesslich et al. (2003) 165 MB 42 (32 vs 10) 3.07 Hurlstone (2004) 324 IC and magnification 93 (69 vs 24) 3.81 Rutter (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 (2008) 102 MB 20 (17 vs 9) 5.66 Farraye FA, Schroy P. Gastroenterology 2006;131: Kiesslich R, et al. Gastroenterology 2007;133: Kiesslich R, et al. Nat Clin Pract Gastroenterol Hepatol Mar;6(3): Page 6

7 The Future of Endoscopic Imaging in Patients with IBD Surveillance Colonoscopy (AGA) 7. Patient with PSC Survey at time of diagnosis and then yearly 8. Ideally, surveillance colonoscopy should be performed when the colonic disease is in remission 9. More frequent surveillance examinations: History of CRC in first-degree relatives Ongoing active endoscopic or histologic inflammation Anatomic abnormalities such as a foreshortened colon, stricture Multiple inflammatory pseudopolyps 10. Same recommendations for patients with Crohn s colitis who have disease involving at least one third of the length of the colon Kiesslich R, et al. Gastroenterology 2007;133: Surveillance Colonoscopy (AGA) 1. All patients should undergo a screening colonoscopy a maximum of 8 years after onset of symptoms Regardless of extent of disease at diagnosis Multiple biopsies to assess microscopic extent of inflammation 2. Ulcerative proctitis or proctosigmoiditis are not considered at increased risk for IBD-related CRC Manage on the basis of average-risk recommendations 3. Patients with extensive or left-sided colitis should begin surveillance within 1 to 2 years after the initial screening colonoscopy Surveillance Colonoscopy (AGA) 4. The optimal surveillance interval has not been clearly defined After 2 negative examinations survey every 1 to 3 years 5. Representative biopsy specimens from each anatomic section of the colon should be obtained Minimum of 33 biopsy specimens be taken in pancolitis patients 6. Chromoendoscopy with targeted biopsies is recommended as an alternative to random biopsies for endoscopists who have expertise with this technique Increased sensitivity for detecting dysplasia BSG Executive Summary All patients with ulcerative colitis or Crohn s colitis should have a screening colonoscopy approximately 10 years after the onset of colitic symptoms to assess disease extent and other endoscopic risk factors Surveillance colonoscopies should be performed, where possible, when the disease is in remission Surveillance procedure should not be unduly delayed if remission cannot be achieved Cairns SR, et al. Gut. 2010;59(5): Page 7

8 BSG Executive Summary Cancer risk factors Duration and extent of disease, primary sclerosing cholangitis, family history of CRC and endoscopic and histological appearances at colonoscopy Screening intervals recommended account for such variables Surveillance colonoscopies should be conducted yearly, 3-yearly or 5-yearly accordingly Cairns SR, et al. Gut. 2010;59(5): BSG Executive Summary Pancolonic dye spraying with targeted biopsy of abnormal areas is recommended If chromoendoscopy is not used, take 2-4 random biopsy specimens every 10cms from the entire colon If a dysplastic polyp is detected within an area of inflammation and can be removed in its entirety, it is not necessary to recommend colectomy Cairns SR, et al. Gut. 2010;59(5): Cairns SR, et al. Gut. 2010;59(5): Page 8