Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) associated with multiple colonic and extraintestinal complications, the most severe being the development of colorectal cancer (CRC). Compared to the general population, there is an increased risk of CRC associated with UC. Although the pathogenesis of CRC in UC is unknown, most studies have linked it to long-standing inflammation as well as other risk factors such as duration of disease, extent of inflammation, family history of CRC, and coexisting conditions such as primary sclerosing cholangitis (PSC). UC is a life-long disease for which patients enter a vigilant screening program which includes surveillance colonoscopy to promote early detection of CRC yet some controversies exist regarding the cost effectiveness of surveillance colonoscopy and improving survival. Newer modalities such as chromoendoscopy, narrow band imaging, high definition colonoscopy, and confocal microscopy have aided in developing a more targeted approach for early detection of dysplasia in surveillance colonoscopy. This review focuses on the role of chronic colonic inflammation and dysplasia in development of UC-associated CRC and current methods of screening, detection, chemoprevention, and treatment of UC-associated CRC. 1. Introduction Ulcerative Colitis (UC) is one of two types of inflammatory bowel disease (IBD) with disease limited to the colonic mucosa. The disease is associated with episodic periods of debilitating symptoms such as abdominal pain, rectal bleeding, fecal urgency, diarrhea, incontinence, and weight loss followed by asymptomatic intervals of remission. UC also is associated with extraintestinal manifestations such as uveitis, ankylosing spondylitis, erythema nodosum, and primary sclerosing cholangitis (PSC). The disease course in UC may be severe, but main contributors to morbidity and mortality is due to the increased risk of developing colorectal cancer (CRC) [1]. The incidence of CRC in the UC is approximately 4/1000 per person year duration with an average prevalence of 3.5% [2]. Currently, UC ranks third only behind familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) as a high-risk condition for CRC [3]. While the exact pathogenesis behind the development of colitis related CRC has not been identified, studies have shown it is most likely a result of chronic inflammation that leads to progressive dysplasia and eventually adenocarcinoma. This neoplastic process typically begins after a long duration of disease of 8 to 10 years and it can occur
References
[1]
D. K. Podolsky, “Inflammatory bowel disease,” The New England Journal of Medicine, vol. 347, no. 6, pp. 417–429, 2002.
[2]
J. A. Eaden, K. R. Abrams, and J. F. Mayberry, “The risk of colorectal cancer in ulcerative colitis: a meta-analysis,” Gut, vol. 48, no. 4, pp. 526–535, 2001.
[3]
S. H. Itzkowitz and X. Yio, “Inflammation and cancer. IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation,” American Journal of Physiology, vol. 287, no. 1, pp. G7–G17, 2004.
[4]
C. Mathy, K. Schneider, Y. Y. Chen, M. Varma, J. P. Terdiman, and U. Mahadevan, “Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis,” Inflammatory Bowel Diseases, vol. 9, no. 6, pp. 351–355, 2003.
[5]
M. N. Kulaylat and M. T. Dayton, “Ulcerative colitis and cancer,” Journal of Surgical Oncology, vol. 101, no. 8, pp. 706–712, 2010.
[6]
R. H. Riddell, H. Goldman, and D. F. Ransohoff, “Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications,” Human Pathology, vol. 14, no. 11, pp. 931–966, 1983.
[7]
A. Von Herbay, C. Herfarth, and H. F. Otto, “Cancer and dysplasia in ulcerative colitis: a histologic study of 301 surgical specimen,” Zeitschrift für Gastroenterologie, vol. 32, no. 7, pp. 382–388, 1994.
[8]
J. Potack and S. H. Itzkowitz, “Colorectal cancer in inflammatory bowel disease,” Gut and Liver, pp. 61–73, 2008.
[9]
V. J. Croog, T. A. Ullman, and S. H. Itzkowitz, “Chemoprevention of colorectal cancer in ulcerative colitis,” International Journal of Colorectal Disease, vol. 18, no. 5, pp. 392–400, 2003.
[10]
B. Crohn and H. Rosenberg, “The sigmoidoscopic picture of chronic ulcerative colitis (non-specific),” The American Journal of the Medical Sciences, vol. 170, pp. 220–228, 1925.
[11]
D. Palli, G. Trallori, S. Bagnoli et al., “Hodgkin's disease risk is increased in patients with ulcerative colitis,” Gastroenterology, vol. 119, no. 3, pp. 647–653, 2000.
[12]
C. N. Bernstein, J. F. Blanchard, E. Kliewer, and A. Wajda, “Cancer risk in patients with inflammatory bowel disease: a population-based study,” Cancer, vol. 91, no. 4, pp. 854–862, 2001.
[13]
K. V. Winther, T. Jess, E. Langholz, P. Munkholm, and V. Binder, “Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County,” Gastroenterology, vol. 125, no. 6, pp. 1576–1582, 2003.
[14]
J. Kewenter, H. Ahlman, and L. Hultén, “Cancer risk in extensive ulcerative colitis,” Annals of Surgery, vol. 188, no. 6, pp. 824–828, 1978.
[15]
S. N. Gyde, P. Prior, R. N. Allan et al., “Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres,” Gut, vol. 29, no. 2, pp. 206–217, 1988.
[16]
U. Broomé and A. Bergquist, “Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer,” Seminars in Liver Disease, vol. 26, no. 1, pp. 31–41, 2006.
[17]
E. Langholz, P. Munkholm, M. Davidsen, and V. Binder, “Course of ulcerative colitis: analysis of changes in disease activity over years,” Gastroenterology, vol. 107, no. 1, pp. 3–11, 1994.
[18]
C. J. Karvellas, R. N. Fedorak, J. Hanson, and C. K. W. Wong, “Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age,” Canadian Journal of Gastroenterology, vol. 21, no. 7, pp. 443–446, 2007.
[19]
A. Sugita, D. B. Sachar, C. Bodian, M. B. Ribeiro, A. H. Aufses, and A. J. Greenstein, “Colorectal cancer in ulcerative colitis. Influence of anatomical extent and age at onset on colitis-cancer interval,” Gut, vol. 32, no. 2, pp. 167–169, 1991.
[20]
A. Ekbom, C. Helmick, M. Zack, and H. O. Adami, “Ulcerative colitis and colorectal cancer: a population-based study,” The New England Journal of Medicine, vol. 323, no. 18, pp. 1228–1233, 1990.
[21]
U. A. Heuschen, U. Hinz, E. H. Allemeyer et al., “Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis,” Gastroenterology, vol. 120, no. 4, pp. 841–847, 2001.
[22]
J. P. J. Issa, N. Ahuja, M. Toyota, M. P. Bronner, and T. A. Brentnall, “Accelerated age-related CpG island methylation in ulcerative colitis,” Cancer Research, vol. 61, no. 9, pp. 3573–3577, 2001.
[23]
S. Itzkowitz, “Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice,” Journal of Clinical Gastroenterology, vol. 36, no. 5, pp. S70–S74, 2003.
[24]
S. P. Hussain, P. Amstad, K. Raja, et al., “Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease,” Cancer Research, vol. 60, no. 13, pp. 3333–3337, 2000.
[25]
S. H. Itzkowitz, “Molecular biology of dysplasia and cancer in inflammatory bowel disease,” Gastroenterology Clinics of North America, vol. 35, no. 3, pp. 553–571, 2006.
[26]
M. O. Blackstone, R. H. Riddell, B. H. G. Rodgers, and B. Levin, “Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy,” Gastroenterology, vol. 80, no. 2, pp. 366–374, 1981.
[27]
C. N. Bernstein, F. Shanahan, and W. M. Weinstein, “Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis?” The Lancet, vol. 343, no. 8889, pp. 71–74, 1994.
[28]
R. D. Odze, F. A. Farraye, J. L. Hecht, and J. L. Hornick, “Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis,” Clinical Gastroenterology and Hepatology, vol. 2, no. 7, pp. 534–541, 2004.
[29]
J. B. J. Fozard and M. F. Dixon, “Colonoscopic surveillance in ulcerative colitis—dysplasia through the looking glass,” Gut, vol. 30, no. 3, pp. 285–292, 1989.
[30]
J. Onkin, “Is colorectal cancer surveillance cost-effective in patients with ulcerative colitis?” Inflammatory Bowel Disease, vol. 14, pp. 196–197, 2008.
[31]
T. Byers, B. Levin, D. Rothenberger, G. D. Dodd, and R. A. Smith, “American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997,” Ca: A Cancer Journal for Clinicians, vol. 47, no. 3, pp. 154–160, 1997.
[32]
S. H. Itzkowitz, D. H. Present, V. Binder et al., “Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 11, no. 3, pp. 314–321, 2005.
[33]
R. C. Thomas, C. Selinger, and M. D. Rutter, “Adherence to BSG adenoma surveillance guidelines will reduce colonoscopic workload,” Gut, vol. 54, no. 1, p. 173, 2005.
[34]
T. L. Zisman and D. T. Rubin, “Colorectal cancer and dysplasia in inflammatory bowel disease,” World Journal of Gastroenterology, vol. 14, no. 17, pp. 2662–2669, 2008.
[35]
D. A. F. Lynch, A. J. Lobo, G. M. Sobala, M. F. Dixon, and A. T. R. Axon, “Failure of colonoscopic surveillance in ulcerative colitis,” Gut, vol. 34, no. 8, pp. 1075–1080, 1993.
[36]
M. J. Carter, A. J. Lobo, and S. P. L. Travis, “Guidelines for the management of inflammatory bowel disease in adults,” Gut, vol. 53, no. 5, pp. v1–v16, 2004.
[37]
A. Kornbluth and D. B. Sachar, “Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee,” American Journal of Gastroenterology, vol. 99, no. 7, pp. 1371–1385, 2004.
[38]
T. Ullman, R. Odze, and F. A. Farraye, “Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn's disease of the colon,” Inflammatory Bowel Diseases, vol. 15, no. 4, pp. 630–638, 2009.
[39]
P. D. Collins, C. Mpofu, A. J. Watson, and J. M. Rhodes, “Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD000279, 2006.
[40]
G. N. J. Tytgat, V. Dhir, and N. Gopinath, “Endoscopic appearance of dysplasia and cancer in inflammatory bowel disease,” European Journal of Cancer Part A, vol. 31, no. 7-8, pp. 1174–1177, 1995.
[41]
M. Rutter, C. Bernstein, T. Matsumoto, R. Kiesslich, and M. Neurath, “Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining,” Endoscopy, vol. 36, no. 12, pp. 1109–1114, 2004.
[42]
R. Kiesslich, J. Fritsch, M. Holtmann et al., “Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis,” Gastroenterology, vol. 124, no. 4, pp. 880–888, 2003.
[43]
S. E. Kudo, S. Tamura, T. Nakajima, H. O. Yamano, H. Kusaka, and H. Watanabe, “Diagnosis of colorectal tumorous lesions by magnifying endoscopy,” Gastrointestinal Endoscopy, vol. 44, no. 1, pp. 8–14, 1996.
[44]
S. Winawer, R. Fletcher, D. Rex et al., “Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence,” Gastroenterology, vol. 124, no. 2, pp. 544–560, 2003.
[45]
D. P. Hurlstone, D. S. Sanders, A. J. Lobo, M. E. McAlindon, and S. S. Cross, “Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation,” Endoscopy, vol. 37, no. 12, pp. 1186–1192, 2005.
[46]
J. E. East, N. Suzuki, A. Von Herbay, and B. P. Saunders, “Narrow band imaging with magnification for dysplasia detection and pit pattern assessment in ulcerative colitis surveillance: a case with multiple dysplasia associated lesions or masses,” Gut, vol. 55, no. 10, pp. 1432–1435, 2006.
[47]
E. Dekker, F. J. C. van den Broek, J. B. Reitsma et al., “Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis,” Endoscopy, vol. 39, no. 3, pp. 216–221, 2007.
[48]
K. Kuznetsov, R. Lambert, and J. F. Rey, “Narrow-band imaging: potential and limitations,” Endoscopy, vol. 38, no. 1, pp. 76–81, 2006.
[49]
M. Goetz, A. Hoffman, P. R. Galle, M. F. Neurath, and R. Kiesslich, “Confocal laser endoscopy: new approach to the early diagnosis of tumors of the esophagus and stomach,” Future Oncology, vol. 2, no. 4, pp. 469–476, 2006.
[50]
R. Kiesslich, M. Goetz, K. Lammersdorf et al., “Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis,” Gastroenterology, vol. 132, no. 3, pp. 874–882, 2007.
[51]
S. R. Ritland, J. A. Leighton, R. E. Hirsch, J. D. Morrow, A. L. Weaver, and S. J. Gendler, “Evaluation of 5-aminosalicylic acid (5-ASA) for cancer chemoprevention: lack of efficacy against nascent adenomatous polyps in the Apc(Min) mouse,” Clinical Cancer Research, vol. 5, no. 4, pp. 855–863, 1999.
[52]
R. N. DuBois, F. M. Giardiello, and W. E. Smalley, “Nonsteroidal antiinflammatory drugs, eicosanoids, and colorectal cancer prevention,” Gastroenterology Clinics of North America, vol. 25, no. 4, pp. 773–791, 1996.
[53]
P. Bansal and A. Sonnenberg, “Risk factors of colorectal cancer in inflammatory bowel disease,” American Journal of Gastroenterology, vol. 91, no. 1, pp. 44–48, 1996.
[54]
A. Farhadi, S. Gundlapalli, M. Shaikh et al., “Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis,” Liver International, vol. 28, no. 7, pp. 1026–1033, 2008.
[55]
N. M. Davies, “Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine,” Diseases of the Colon and Rectum, vol. 38, no. 12, pp. 1311–1321, 1995.
[56]
J. Eaden, “Review article: the data supporting a role for aminosalicylates in the chemoprevention of colorectal cancer in patients with inflammatory bowel disease,” Alimentary Pharmacology and Therapeutics, vol. 18, no. 2, pp. 15–21, 2003.
[57]
S. N. Agoff, T. A. Brentnall, D. A. Crispin et al., “The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia,” American Journal of Pathology, vol. 157, no. 3, pp. 737–745, 2000.
[58]
D. S. Pardi, E. V. Loftus, W. K. Kremers, J. Keach, and K. D. Lindor, “Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis,” Gastroenterology, vol. 124, no. 4, pp. 889–893, 2003.
[59]
I. A. Mouzas, E. Papavassiliou, and I. Koutroubakis, “Chemoprevention of colorectal cancer in inflammatory bowel disease? A potential role for folate,” Italian Journal of Gastroenterology and Hepatology, vol. 30, no. 4, pp. 421–425, 1998.
[60]
J. Carrier, A. Medline, K. J. Sohn et al., “Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2- and β-microglobulin-deficient mice,” Cancer Epidemiology Biomarkers and Prevention, vol. 12, no. 11, pp. 1262–1267, 2003.
[61]
B. A. Lashner, P. A. Heidenreich, G. L. Su, S. V. Kane, and S. B. Hanauer, “Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study,” Gastroenterology, vol. 97, no. 2, pp. 255–259, 1989.
[62]
B. A. Lashner, K. S. Provencher, D. L. Seidner, A. Knesebeck, and A. Brzezinski, “The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis,” Gastroenterology, vol. 112, no. 1, pp. 29–32, 1997.
[63]
S. Matula, V. Croog, S. Itzkowitz et al., “Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine,” Clinical Gastroenterology and Hepatology, vol. 3, no. 10, pp. 1015–1021, 2005.
