Risk for Colorectal Neoplasia in Patients With Colonic Crohn s Disease and Concomitant Primary Sclerosing Cholangitis

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Risk for Colorectal Neoplasia in Patients With Colonic Crohn s Disease and Concomitant Primary Sclerosing Cholangitis BARBARA BRADEN,* JOHNNY HALLIDAY,* SANJEEWA ARYASINGHA,* YALDA SHARIFI,* DAVIDE CHECCHIN,* BRYAN F. WARREN, TAYA KITIYAKARA,* SIMON P.L. TRAVIS,* and ROGER W. CHAPMAN* *Translational Gastroenterology Unit, and Department of Cellular Pathology, John Radcliffe Hospital, Oxford, United Kingdom This article has an accompanying continuing medical education activity on page e31. Learning Objective At the end of this activity, the learner will identify the risk for the development of colorectal neoplasia in patients with colonic Crohn s disease and concomitant primary sclerosing cholangitis compared to patients with ulcerative colitis and concomitant primary sclerosing cholangitis. Podcast interview: Also available on itunes. BACKGROUND & AIMS: Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn s disease of the colon. METHODS: We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn s disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn s disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. RE- SULTS: Only 1 patient with colonic Crohn s disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7 16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8 16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn s disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn s disease (P 1.00). CONCLUSIONS: PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn s disease. Keywords: Inflammatory Bowel Syndrome; Colonoscopy; IBD; Screening. Patients with ulcerative colitis or colonic Crohn s disease are at increased risk of colorectal cancer. The classical risk factors include the extent and duration of inflammatory bowel disease, but a family history of sporadic colorectal cancer, the severity of histologic bowel inflammation over time, and coincidental colonic adenomas also seem to be independent risk factors. 1 Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a significantly higher risk of developing colorectal intraepithelial neoplasia or invasive cancer than ulcerative colitis patients without PSC. The adjusted relative risk is reported to be from 3.1 to ,3 In a metaanalysis of 11 studies the risk for colorectal cancer was approximately fourfold increased in patients with ulcerative colitis and PSC compared with those with ulcerative colitis alone. 4 This is in spite of a clinical course of colitis in patients with ulcerative colitis and PSC that is commonly characterized by a quiescent colitis with relative rectal sparing and backwash ileitis. 5 It is unknown whether PSC also increases the risk of developing colorectal (pre)cancerous lesions in patients with colonic Crohn s disease. The lack of studies is explained by the rarity of PSC in the general population and the fact that ulcerative colitis is more commonly associated with PSC than Crohn s disease with colonic involvement, which is found in only 1% to 14% of all patients with PSC. 6 Dysplasia in inflammatory bowel disease is associated with concurrent or future colorectal cancer in ulcerative colitis and, although less investigated, also in Crohn s disease. 7 Therefore, dysplasia (intraepithelial neoplasia) is considered a marker of cancer risk in inflammatory bowel disease. Current colonoscopy surveillance programs in patients with longstanding inflammatory bowel syndrome of the colon aim to detect dysplasia in flat mucosa, or protruding lesions through random biopsies or by targeted biopsies after chromoendoscopy. Annual colonoscopy from the time of diagnosis of ulcerative colitis or Crohn s disease is recommended in patients with concomitant PSC. 8 In this retrospective study we investigated the occurrence of colorectal dysplasia or cancer in patients with colonic Crohn s disease with and without PSC and in patients with ulcerative colitis with and without PSC. Abbreviations used in this paper: CD, Crohn s disease; CI, confidence interval; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis; UC, ulcerative colitis by the AGA Institute /$36.00 doi: /j.cgh

2 304 BRADEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 3 Table 1. Demographic Characteristics of Patients With IBD (and PSC) Diagnosis PSC and CD PSC and UC PSC and indeterminate colitis CD UC n Sex 19 m, 16 f 85 m, 35 f 6 m, 5 f 43 m, 71 f 68 m, 34 f Age (y) a 54 (36 66) 58 (50 69) 57 (25 64) 49 (38 65) 59 (46 68) Body weight (kg) a,b 67 (59 76) 80 (70 91) 66 (63 76) 68 (59 83) 80 (70 91) f, female; m, male. a Median (interquartile range). b At last visit. Methods Patients We studied 166 patients with PSC and colonic inflammatory bowel disease from our database of PSC patients treated in the John Radcliffe Hospital in Oxford. Only PSC patients with established diagnosis of Crohn s disease, ulcerative colitis, or indeterminate colitis were included. Patients with PSC without inflammatory bowel disease or inflammatory bowel disease of less than 5 years were not included in this study. Patients with duration of PSC of less than 3 years were also excluded. The diagnosis of PSC was based on established criteria in all patients (demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography, in the presence of inflammatory bowel disease). The onset of PSC was designated as the date of the first abnormal liver histopathology, or cholangiography (endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography). One hundred twenty of the patients with PSC had concomitant ulcerative colitis, 35 had Crohn s disease with involvement of the colon (defined as at least 1 third of the colon affected by the disease), and 11 had indeterminate colitis. One hundred fourteen patients with colonic Crohn s disease without PSC and 102 patients with ulcerative colitis without PSC served as controls. Patients with duration of inflammatory bowel disease of less than 8 years were not included as controls. Controls were selected in consecutive alphabetical order from patients in the Oxford Inflammatory Bowel Disease (IBD) database. Patients with any pre-existing malignancy at the time of diagnosis of inflammatory bowel disease were not included. Controls with Crohn s colitis were matched according to age and extension of colitis to patients with PSC and Crohn s disease, patients with ulcerative colitis to patients with PSC and ulcerative colitis. All patients with PSC and inflammatory bowel disease were under an annual colonoscopy surveillance program. Patients with longstanding extensive inflammatory bowel disease of the colon without PSC were offered surveillance colonoscopy in 3- to 5-year intervals in accordance with current guidelines of the British Society of Gastroenterology. 8,9 Reasons for discontinuation of the colonoscopy surveillance were advanced age, poor health condition, subtotal or total colectomy, or death. Histopathology The Inflammatory Bowel Disease Dysplasia Study Group has established standard criteria for the diagnosis and grading of dysplasia. Dysplasia is defined as unequivocal neoplastic epithelial changes characterized by cytologic (eg, nuclear alterations, mitoses, mucin depletion) and architectural features (eg, mucosal thickening, crypt elongation and branching, nuclei pseudostratification). Using these criteria, colorectal biopsies were classified as negative, indefinite, or positive for dysplasia, with this latter group subdivided into low-grade and high-grade dysplasia. 10 According to the Vienna classification 11 invasive neoplasia was defined as neoplastic cellular proliferation extending into the lamina propria or muscularis mucosae (intramucosal carcinoma) or into the submucosal layer or beyond to the muscularis propria. Presence of dysplasia or cancer was always confirmed by a second pathologist. All the specimens with dysplastic or cancerous alterations were reviewed by an expert gastrointestinal histopathologist (BFW) with a special interest in inflammatory bowel disease and dysplasia. Statistics Data are shown as mean and standard deviation or median and interquartile range as appropriate. Differences between groups were compared using the Pearson Mantel Haenszel s 2 test. P.05 was considered statistically significant. 95% confidence intervals (CI) are given. Statistic analyses were performed using the program BIAS (version 7.06; epsilon verlag, Hochheim Darmstadt, Germany). Results Demographic characteristics of the patient groups with inflammatory bowel disease with and without PSC are given in Table 1. The majority of patients with PSC and inflammatory bowel disease were being treated with ursodeoxycholic acid at a daily dose of 15 to 20 mg/kg body weight; 74% of the patients with PSC and Crohn s disease, 82% of patients with PSC and indeterminate colitis, and 79% of the patients with PSC and ulcerative colitis received ursodeoxycholic acid (Table 2). Apart from 1 patient who developed a low grade adenomatous polyp in the descending colon and cecum, all other colorectal neoplastic lesions were observed in PSC patients taking ursodeoxycholic acid (P.28). Eighty-two percent of the patients with PSC and Crohn s disease had macroscopically a pancolitis, while in the patients with PSC and ulcerative colitis and indeterminate colitis, pancolitis was diagnosed in 89% and 73%, respectively. Ninety percent of the controls with ulcerative colitis and 75% of the controls with Crohn s disease had total colitis. From the 120 patients with ulcerative colitis and concomitant PSC, 1 developed a tubular adenoma with low grade dysplasia in the rectum. Seven patients were diagnosed with

3 March 2012 PSC AS A RISK FACTOR IN CROHN S DISEASE 305 Table 2. Follow-up in Patients With IBD and PSC Diagnosis PSC and CD PSC and UC PSC and indeterminate colitis Crohn s colitis UC n Patients receiving ursodeoxycholic 26 (74.3%) 95 (79.2%) 9 (81.8%) 0 0 acid Years of follow-up a For IBD 16 (9 25) 17 (11 27) 9 (8 15) 19 (12 26) 20 (14 29) For PSC 10 (7 16) 11 (8 16) 8 (5 10) NA NA Total years of follow-up For IBD For PSC NA NA Number of colonoscopies 3 (2 5) 4 (2 6) 2 (1.5 4) 3 (2 4) 4.5 (3 6) (Sub-)total colectomy Death PSC related NA NA Other causes Adenoma-like dysplastic lesion Nonadenoma-like dysplastic lesion 0 7 (2 indefinite) 0 (1 indefinite) 2 Colon cancer a Median (interquartile range). nonadenoma-like dysplastic lesions; 2 of these patients had dysplasia on 2 clearly separated biopsy areas. Two patients with ulcerative colitis and PSC developed cancer during the median follow up of 11 years (Table 2). The cumulative incidence rate of developing nonadenoma-like dysplasia or colorectal carcinoma was 7.5% (9/120) in patients with PSC and ulcerative colitis (Table 2). The crude annual incidence rate of dysplasia or colorectal cancer was 1 in 150 patients with PSC and ulcerative colitis. Among the 102 patients with ulcerative colitis alone, 1 was diagnosed with rectal cancer; in 2 others low grade dysplasia was detected. The odds ratio for PSC as risk factor for developing nonadenoma-like dysplastic lesions or colorectal cancer was 2.7 (95% CI, ) in patients with ulcerative colitis. Patients with adenoma-like dysplastic lesions were older (64 years, 54 71) than patients in whom nonadenoma-like dysplasia was found (38 years, 37 49; P.01). The only dysplasia observed during a median follow-up of 10 years in the 35 PSC patients with colonic involvement of Crohn s was an adenomatous polyp with dysplasia (Table 2). A 1-cm sized pedunculated polyp in the descending colon was removed using snare polypectomy in this patient. Histologically, it showed a tubular adenoma with low-grade dysplasia. In the 114 patients with Crohn s disease without PSC, 2 cancer, in the sigmoid colon and in the ascending colon, were diagnosed. A further case, indefinite dysplasia, was described in a biopsy from the anastomosis in a patient with previous ileocecal resection for complex Crohn s disease. Therefore, regarding PSC as an additional risk factor for developing dysplasia or colorectal cancer in patients with Crohn s colitis gives an odds ratio of 1.64 (95% CI, ). The characteristics of the patients with inflammatory bowel disease and concomitant PSC who developed colorectal cancer or dysplasia are given in Table 3. None of these patients had had liver transplantation. Only 5 of all 13 neoplastic lesions detected in patients with PSC were on the right side of the colon. Nonadenoma-like dysplastic lesions and colorectal cancer occurred more frequently in patients with ulcerative colitis and PSC (9/120) than in patients with Crohn s disease and PSC (0/35; P.07). Thirty of 120 (33%) patients with ulcerative colitis and PSC died during the follow-up time compared with 6 of 35 (17%) patients with Crohn s disease and PSC (P.33). PSC-related mortality occurred more frequently in patients with ulcerative colitis and PSC, but the difference was not significant (P.41; Table 2). In the control group of patients with Crohn s colitis without PSC, 2 patients died during the follow-up period, 1 from lung cancer, the other from myocardial infarction, none from cholangiocarcinoma. Discussion Despite evidence showing that PSC is a risk factor for colorectal cancer in patients with ulcerative colitis 4 and that there is increased risk of colorectal cancer in patients with Crohn s disease similar to longstanding ulcerative colitis, 12 it is unclear whether PSC is an additional risk factor for colorectal cancer in patients with Crohn s colitis. We have investigated this in the current study by comparing the prevalence of colorectal neoplasia in 5 groups of patients; patients with Crohn s colitis and PSC, patients with ulcerative colitis and PSC, patients with indeterminate colitis and PSC, and patients with Crohn s colitis or ulcerative pancolitis alone. Our data demonstrate no increased risk of colorectal neoplasia in patients with PSC and Crohn s colitis, in contrast to that found in patients with PSC and ulcerative colitis. The pathogenesis of the increased risk for colorectal cancer in patients with ulcerative colitis and PSC is unclear. Bile acids may be involved, as in patients with ulcerative colitis/psc, colorectal cancer is reported to occur predominantly in the right colon, 13 or associated with backwash ileitis, 14 where concentrations of secondary bile acids are thought to be highest. In addition, studies have demonstrated abnormal levels of fecal secondary bile acids in patients with colonic polyps and cancers

4 306 BRADEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 3 Table 3. Characteristics of Patients With PSC and UC or CD Who Developed Dysplasia or Colorectal Cancer Patient Age a (y), sex Follow-up in IBD a (y) UDCA intake Number of colonoscopies a Localization Extension of disease (Sub-)total colectomy Type of dysplasia or colorectal cancer UC 31 m 13 Yes 4 Rectum Pancolitis 2007 Adenocarcinoma UC 49 m 8 Yes 2 Rectum Left sided 1979 Low grade UC 72 m 4 Yes 2 Rectum Pancolitis No Low grade UC 35 m 2 Yes 2 Rectosigmoid Left sided 1989 Low grade UC 53 f 12 Yes 3 Sigmoid Pancolitis 2000 Adenocarcinoma (T3N2M0) UC 37 m 1 No 6 Descending Pancolitis No Low grade 57 m 20 Cecum Low grade UC 45 m 15 Yes 5 Cecum Pancolitis 1999 Low grade UC 24 m 3 Yes 4 Cecum Pancolitis 2004 Low grade 25 m 4 Rectosigmoid Low grade UC 37 f 15 Yes 4 Both in ascending Pancolitis 1997 Low and high grade UC 72 m 3 Yes 1 Rectum Pancolitis No Low grade in tubular adenomatous polyp Total UC 45 (35 56) 6 (3 14) 3.5 (2 4) 8 Left-sided 5 Right-sided 2 Cancer 10 Low grade 1 High grade CD 62 m 2 Yes 1 Descending Pancolitis No Low grade in tubular adenomatous polyp f, female; m, male; UDCA, ursodeoxycholic acid. a At time of detection of neoplasia. with 15 and without 16 inflammatory bowel disease. Moreover, studies 17 have shown ursodeoxycholic acid to be chemoprotective for colorectal neoplasia in patients with PSC and ulcerative colitis, while ursodeoxycholic acid has been shown to affect the bile salt pool composition by decreasing secondary bile salt levels. 18 However, interestingly in the present study, the dysplasia and cancer was predominantly left-sided, with only a minority of right-sided neoplasia in patients with PSC (5/14 cases). In a recent study by Thackeray et al, the colonic neoplasms that developed in patients with inflammatory bowel disease and PSC were spread throughout the colon. 19 Furthermore, if bile salts were that important, a higher incidence of colorectal cancer in patients with bile salt malabsorption (such as might occur after ileocaecal resection for Crohn s disease) might be expected. Ongoing genome-wide association studies in patients with PSC might find out whether genetic factors play a role and might shed some light on the special cancer risk observed in patients with PSC. Risk factors for the development of colorectal cancer in patients with ulcerative colitis, other than PSC, include long duration and extent of disease, 1 as well as severity of disease, 20 family history of colorectal cancer, 21 coincidental adenomas, and lack of regular mesalamine therapy. 22 Case reports describing colorectal cancer in Crohn s disease have historically compared risk factors and characteristics with those found in ulcerative colitis. 12 These series suggest similar risk factors in Crohn s disease for colorectal cancer development including long duration and extent of the disease. More recent evidence from studies of colorectal surveillance in patients with Crohn s colitis, 23 where the criteria for surveillance include involvement of more than a third of the colon, appear to confirm the increased risk in patients with Crohn s colitis. In contrast to ulcerative colitis, no previous studies have investigated the risk of additional PSC in colonic Crohn s disease. Rasmussen et al reported the development of 2 colorectal cancers in 9 patients with PSC and colonic Crohn s disease over a period of 15 years 24 which seems strikingly high compared with our data. In our study, only 1 of our 35 patients with PSC and Crohn s colitis developed a low-grade dysplastic tubular adenoma, which may itself have been coincidental to Crohn s colitis, during a follow-up of 10 years, or a cumulative 424 patient-years of follow-up. Sporadic adenomas (which are by definition dysplastic) can also develop in inflammatory bowel disease. Adenoma-like dysplasia-associated lesions (ALMs) should be distinguished from nonadenoma-like dysplasia-associated lesions or masses (DALMs) because the former are treated adequately by polypectomy with complete excision and continued endoscopic surveillance, 25 while the latter lead to consideration of colectomy. In our study, most dysplastic lesions and the 2 adenocarcinomas in patients with ulcerative colitis and PSC were in the left colon, which is in contrast to previous findings. 13 The predominance of left-sided (pre)malignant lesions in our study (9 of 14) might be due to the fact that most of our patients (78%) were treated with ursodeoxycholic acid whose chemoprotective effect might be greater on the right side of the colon due to pharmacologically higher concentrations. Patients with both inflammatory bowel disease and PSC are mostly endangered by the complications from end-stage liver disease. Whether screening colonoscopy can improve life expectancy is questionable, although this question remains unanswered even for patients with colitis, but without PSC. On the other hand, liver transplantation significantly extends the life expectancy of patients with PSC. However, PSC patients with a long history of pancolitis undergoing liver transplantation have an increased risk of developing colorectal cancer with reduced survival. 26,27 It is conceivable, therefore, that development of colorectal cancer has the potential to become a major cause of mortality in PSC patients. A recent cohort study by Claessen et al 28 reports a cumulative 10-year and 20-year risk of 14% and

5 March 2012 PSC AS A RISK FACTOR IN CROHN S DISEASE % in patients with PSC and concomitant inflammatory bowel disease for colorectal cancer. In contrast to previous studies, the risk was substantially higher than that of cholangiocarcinoma. The retrospective nature of the study does not allow us to confirm or assess other risk factors in our study population. Whether they had a family history of colorectal cancer or were on mesalamine therapy was not determined. There is, however, no evidence for the benefit of sulfasalazine and mesalamine in decreasing the rate of colorectal cancer in patients with PSC. Lindberg et al 13 did not show any chemoprotective effect of sulfasalazine in patients with PSC. Whether sulfasalazine is less effective than other mesalamines 29 or the mechanism of carcinogenesis in patients with PSC predominantly involves toxic bile acids and differs from those in ulcerative colitis alone, is not clear. The incidence of colorectal cancer in ulcerative colitis remains subject to debate, but appears to be lower than previously estimated. In a meta-analysis largely of studies from referral centers, the cumulative incidence of colorectal cancer in ulcerative colitis was 2% at 10-year, 8% at 20-year, and 18% at 30-year follow-up. 30 More recent population-based publications describe a lower cumulative risk of cancer with 1.1%, %, 32 or 5.4% 33 after a disease duration of 20 years which is more consistent with our findings. The lower incidence of colorectal neoplasia in inflammatory bowel disease in the last decade might also be explained by a higher proportion of patients on maintenance therapy with mesalamine, or azathioprine, and biological agents. In the last decade, advances in endoscopic imaging techniques using high definition endoscopes and chromoendoscopy have improved the detection rate for subtle dysplastic lesions. 34,35 The rate of dysplasia found in early colonoscopies may therefore be an underestimate, particularly when compared with those nowadays in patients with PSC undergoing annual colonoscopy using the best imaging techniques. The number of colonoscopies performed in patients with Crohn s colitis did not differ significantly from those with ulcerative colitis. Surveillance in Crohn s colitis has been recommended by many guidelines to match those with ulcerative colitis of a similar extent and duration. Not all gastroenterologists, however, offer surveillance to such patients, indicating that they are unconvinced of the effectiveness of such strategy. No cost-effective analysis on surveillance for patients with Crohn s colitis has been performed and it may be more effective to limit surveillance to those patients with additional risk factors, such as family history of colorectal cancer. In conclusion, the presence of primary sclerosing cholangitis in patients with colonic Crohn s disease does not seem to increase the risk of developing dysplasia of the colon as it does in patients with ulcerative colitis. Prospective studies are needed to confirm our findings. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. Loftus EV Jr. Epidemiology and risk factors for colorectal dysplasia and cancer in ulcerative colitis. Gastroenterol Clin North Am 2006;35: Shetty K, Rybicki L, Brzezinski A, et al. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999;94: Jess T, Loftus EV Jr, Velayos FS, et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota. Am J Gastroenterol 2007;102: Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56: Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54: Broomé U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006;26: Svrcek M, Cosnes J, Beaugerie L, et al. Colorectal neoplasia in Crohn s colitis: a retrospective comparative study with ulcerative colitis. Histopathology 2007;50: Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 2010;59: Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60: Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14: Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47: Friedman S. Cancer in Crohn s disease. Gastroenterol Clin North Am 2006;35: Lindberg BU, Broomé U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001;44: Heuschen UA, Hinz U, Allemeyer EH, et al. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001;120: Hill MJ, Melville DM, Lennard-Jones JE, et al. Faecal bile acids, dysplasia, and carcinoma in ulcerative colitis. Lancet 1987;2: Stadler J, Yeung KS, Furrer R, et al. Proliferative activity of rectal mucosa and soluble fecal bile acids in patients with normal colons and in patients with colonic polyps or cancer. Cancer Lett 1988;38: Pardi DS, Loftus EV Jr, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124: Batta AK, Salen G, Holubec H, et al. Enrichment of the more hydrophilic bile acid ursodeoxycholic acid in the fecal watersoluble fraction after feeding to rats with colon polyps. Cancer Res 1998;58: Thackeray EW, Charatcharoenwitthaya P, Elfaki D, et al. Colon neoplasms develop early in the course of inflammatory bowel disease and primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2011;9: Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004;53: Askling J, Dickman PW, Karlén P, et al. Family history as a risk

6 308 BRADEN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 3 factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001;120: Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005;100: Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn s colitis: results of a surveillance program spanning 25 years. Clin Gastroenterol Hepatol 2008;6: ; Quiz: Rasmussen HH, Fallingborg JF, Mortensen PB, et al. Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn s disease. Scand J Gastroenterol 1997;32: Odze RD, Farraye FA, Hecht JL, et al. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004;2: Ho GT, Seddon AJ, Therapondos G, et al. The clinical course of ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis: further appraisal of immunosuppression post transplantation. Eur J Gastroenterol Hepatol 2005;17: Vera A, Gunson BK, Ussatoff V, et al. Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 2003;75: Claessen MM, Vleggaar FP, Tytgat KM, et al. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009;50: van Staa TP, Card T, Logan RF, et al. 5-aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 2005;54: Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48: Winther KV, Jess T, Langholz E, et al. Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clin Gastroenterol Hepatol 2004;2: Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130: Lakatos L, Mester G, Erdelyi Z, et al. Risk factors for ulcerative colitis-associated colorectal cancer in a Hungarian cohort of patients with ulcerative colitis: results of a population-based study. Inflamm Bowel Dis 2006;12: Hurlstone DP, Kiesslich R, Thomson M, et al. Confocal chromoscopic endomicroscopy is superior to chromoscopy alone for the detection and characterisation of intraepithelial neoplasia in chronic ulcerative colitis. Gut 2008;57: Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: Reprint requests Address requests for reprints to: Roger W. Chapman, MD, Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom. roger.chapman@ndm.ox.ac.uk; fax: (44) Conflicts of interest The authors disclose no conflicts.