Colonoscopic surveillance and management of dysplasia in inflammatory bowel disease (IBD): Introduction
Colorectal cancer (CRC) is one of the most serious complications of chronic colitis in patients with inflammatory bowel disease (IBD).
Current strategies for risk reduction and management of colitis-associated CRC are chemoprophylaxis, colonoscopic surveillance of at-risk individuals, endoscopic removal of dysplastic lesions, and proctocolectomy, which is a potentially curative treatment for those with precancerous dysplasia or early cancer.
Maintaining mucosal healing may reduce colorectal carcinogenesis. Chemoprophylaxis using mesalazine, thiopurines and ursodeoxycholic acid has also been proposed in the management of IBD with and without primary sclerosing cholangitis (PSC).
Observational data suggest colonoscopy is associated with a reduced risk of CRC and mortality in patients with IBD. Guidelines based on case series suggest that IBD surveillance may permit earlier detection of cancers and improve prognosis. In Australia, there is increasing acceptance that improved endoscopic technologies have resulted in improved identification of dysplasia and have permitted resection of dysplastic lesions before resorting to proctocolectomy.
Since IBD was first recognised in 1925, substantial variation in the incidence of CRC in patients with IBD has been reported in the literature. This variation is thought to be due to referral centre bias, heterogeneity in study design and possibly also to environmental or geographical factors. Furthermore, changes in the surveillance and management of dysplasia, including improved endoscopic technologies that enable earlier identification of pre-cancerous dysplasia, have undoubtedly affected both the reported rates and outcomes of dysplasia and CRC.
Initial data suggested a difference in risk of CRC between those with ulcerative colitis (UC) and Crohn’s disease, but it is now generally accepted that the risks are approximately equivalent, when patients are stratified according to the extent of colonic involvement. A meta-analysis of 116 studies including 54,478 patients, reported the overall prevalence of CRC in any patient with UC to be 3.7%, and an overall incidence of 3 cases per 1,000 person-years duration (PYD). When stratified for disease duration, the incidence increased from 2 per 1000 PYD (cumulative probability 2%) for the first decade, to 7 per 1000 PYD (cumulative probability 8%) for the second decade, and 12 per 1000 PYD (cumulative probability 18%) for the third decade.
Another study from Australia reported that the cumulative incidences of CRC among patients with UC for the first, second and third decades were 1% (95% confidence interval [CI]: 0–2), 3% (95% CI: 1–5) and 7% (95% CI: 4–10), respectively. Similar findings have recently been described in a large Korean multicentre study indicating that the cumulative incidence of CRC in IBD patients in low-prevalence countries might be similar to that of Western countries. The incidence of CRC in patients with IBD may continue to fall with regular surveillance colonoscopy, improvements in imaging and adenoma detection and aggressive use of maintenance therapies to achieve mucosal healing.
Pathological characteristics[edit source]
Intraepithelial dysplasia (superficial to the lamina propria) is the premalignant lesion in IBD-associated CRC, and is classified as low grade or high grade according to histopathological features. The differentiation of low-grade dysplasia (LGD) from high-grade dysplasia (HGD) is based on the degree and extent of nuclear stratification, haphazardness and loss of nuclear polarity, nuclear atypia, nucleolar size, nuclear clumping and presence of atypical mitotic figures.
Low-grade dysplasia needs to be differentiated from reactive changes due to inflammation. The presence of neoplastic invasion is diagnostic of CRC. For the most part, IBD-associated CRC is histologically similar to sporadic CRC, although it exhibits several different pathobiological features.
Colorectal cancer in IBD, like its sporadic counterpart, is most commonly adenocarcinoma. Dysplasia in IBD is typically multifocal, and variously described as flat, indistinct, ulcerated, plaque-like, nodular, velvety, stricturing or mass-like, whereas sporadic dysplasia is more classically unifocal and associated with discrete polyp formation.
Lesions arise from currently or previously inflamed areas of the colon, but may occur in areas of microscopic inflammation rather than macroscopic involvement. Being associated with chronic inflammation, colitis-associated dysplasia is most commonly located in the distal colon. The mean age at diagnosis of CRC is lower for IBD patients than for sporadic CRC patients, and synchronous tumours have been historically reported more commonly in IBD, occurring in up to 12%. This finding might be explained by the subtlety of dysplastic lesions, but might also be partly accounted for by the failure of inferior, older generation colonoscopes to identify lesions.
Colorectal cancer and dysplasia risk[edit source]
Modern IBD surveillance strategy is underpinned by risk stratification. Compared with healed mucosal inflammation, the presence of objective mucosal inflammation (endoscopic or histologic) is associated with a greater risk of subsequent colorectal dysplasia. A meta-analysis reported that the odds ratio (OR) for colorectal dysplasia was 3.5 (95% CI: 2.6–4.8) in those with any endoscopic mucosal inflammation and 2.6 (95% CI: 1.5–4.5) in those with histologic inflammation.
Increased duration of IBD increases CRC risk. The risk of CRC increases markedly after 10 years of disease duration in patients with extensive colitis, and somewhat later in those with limited left-sided colitis.
The age of onset might be an independent predictor for the development of CRC, but this effect appears to be attenuated after adjusting for disease duration. The commencement of surveillance is therefore calculated based upon disease duration, not patient age. Nevertheless, a nationwide cohort study showed that childhood-onset IBD was associated with an increased risk of gastrointestinal cancers (hazard ratio 18.0; 95% CI: 14.4–22.7).
Greater extent of disease also equates to an increase in cumulative inflammatory insults, reflected in the corresponding increase in CRC risk seen in those with extensive colitis or pancolitis. An Australian UC cohort study identified CRC in 24 patients, of whom 1 (1.6%) had proctitis, 8 (3.8%) had left-sided colitis, 12 (6.1%) had extensive colitis and 3 (8.8%) had an unknown extent of colitis at study entry.
Evidence of chronic intestinal damage is also associated with the risk of developing colorectal neoplasia. Colonic strictures, a foreshortened colon, and pseudopolyps represent healing of severe inflammation. These endoscopic features have been shown to be associated with a higher rate of CRC in patients with IBD.
The risk of developing colitis-associated CRC is increased in the presence of PSC. A meta-analysis of studies that compared the risk of CRC in patients with UC with and without PSC confirmed the CRC risk to be 4.8-fold higher in patients with PSC. Australian data demonstrated a trend towards increased CRC risk in the presence of PSC with IBD (6%), compared with PSC without IBD (0%, P=0.08). Interestingly cancers associated with PSC and IBD tend to be located predominantly in the proximal colon (as distinct from UC patients without PSC).The risk of CRC remains elevated following orthotopic liver transplant and ongoing yearly surveillance is recommended.
As with sporadic CRC, a family history of CRC is associated with a greater risk of developing dysplasia in patients with IBD. For patients with IBD and a first-degree relative with CRC, the risk is at least two times baseline.
For patients with UC treated with proctocolectomy and ileal pouch-anal anastomosis, the risk of pouch cancer is very rare, questioning the need for selective surveillance.
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Characterisation of lesions and implications for management[edit source]
New consensus in the nomenclature used to describe dysplasia in IBDs has been developed. Modern descriptors classify lesions based on (i) the Paris classification of endoscopically-detected lesions and (ii) whether they are endoscopically resectable
The use of high-definition white-light endoscopy (WLE) and chromoendoscopy (see Advances in technique) has resulted in greater appreciation of flat and indistinct dysplastic lesions that were previously missed on standard-definition colonoscopy. The inability to visually identify subtle lesions in previous decades led to the approach of random biopsies every 10 cm in the colon in an attempt to identify dysplasia. The finding of dysplasia through random biopsies was often a late event signifying the presence of widespread multifocal dysplasia. As such, many of these patients were treated by proctocolectomy, due to the high likelihood of missed synchronous invasive CRC or the risk of developing metachronous cancer.
The modern surveillance paradigm is to manage endoscopically-identified lesions by endoscopic removal where possible. High-quality colonoscopy and the use of high-definition colonoscopes are pre-requisites for identifying dysplasia, which is often subtle. When confirmed as dysplasia without invasion, such lesions can be dealt with by endoscopic resection or polypectomy withclose follow-up colonoscopic surveillance. Proctocolectomy is advised if there is evidence of invasion, if dysplastic lesions cannot be removed endoscopically, or if dysplasia is multifocal.
Individualisation of treatment is also important. The new surveillance paradigm accepts the move away from taking random biopsies towards targeted biopsies based on high-definition colonoscopy with other image-enhancement technologies. The most established image enhancement technology remains dye-spray chromoendoscopy, for which there is high-level evidence for superiority of yield of dysplasia compared with standard WLE.
Random biopsies typically have a low yield of dysplasia identification, but are still advocated in those with a high risk of invisible dysplasia (those with prior dysplasia, PSC or foreshortened tubular colon).
Ultimately, the primary goal of IBD management should be prevention of IBD dysplasia through improved medical management and achievement of mucosal healing. Achieving histological remission might be an emerging treatment paradigm in the prevention of dysplasia development.
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- Initiation of surveillance in IBD (SUR1)
- Surveillance interval for IBD patients (SUR2)
- Recommended surveillance techniques in IBD patients (SUR3)
- Management of elevated dysplasia (MNG1)
- High grade dysplasia in IBD (MNG2)
- Low grade dysplasia in IBD (MNG3)
- Indefinite dysplasia in IBD (MNG4)
- Management of dysplasia in IBD: Discussion
- ↑ Leong RW, Koo JH. Colorectal cancer in inflammatory bowel disease. J Gastroenterol Hepatol 2009 Apr;24(4):503-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19368629.
- ↑ Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, et al. Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2015 Feb;13(2):322-329.e1 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25041865.
- ↑ Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis 2017 Jun 1;11(6):649-670 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28158501.
- ↑ Leong RW, Perry J, Campbell B, Koo J, Turner IB, Corte C, et al. Knowledge and predictors of dysplasia surveillance performance in inflammatory bowel diseases in Australia. Gastrointest Endosc 2015 Oct;82(4):708-714.e4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26007222.
- ↑ Crohn B, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis (non- specific). Am J Med Sci 1925;170:220–8.
- ↑ Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel disease. World J Gastroenterol 2008 May 7;14(17):2662-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18461651.
- ↑ 7.0 7.1 Jess T, Loftus EV Jr, Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from olmsted county, Minnesota. Gastroenterology 2006 Apr;130(4):1039-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16618397.
- ↑ 8.0 8.1 Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 1990 Aug 11;336(8711):357-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1975343.
- ↑ Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN. Ulcerative colitis and Crohn's disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994 Nov;35(11):1590-2 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7828978.
- ↑ 10.0 10.1 Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn's disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 1994 Jul;35(7):950-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8063223.
- ↑ 11.0 11.1 Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001 Apr;48(4):526-35 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11247898.
- ↑ 12.0 12.1 12.2 Selinger CP, Andrews JM, Titman A, Norton I, Jones DB, McDonald C, et al. Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2014 Apr;12(4):644-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23707778.
- ↑ Kim BJ, Yang SK, Kim JS, Jeen YT, Choi H, Han DS, et al. Trends of ulcerative colitis-associated colorectal cancer in Korea: A KASID study. J Gastroenterol Hepatol 2009 Apr;24(4):667-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19378391.
- ↑ Mathy C, Schneider K, Chen YY, Varma M, Terdiman JP, Mahadevan U. Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflamm Bowel Dis 2003 Nov;9(6):351-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14671483.
- ↑ Itzkowitz SH. Inflammatory bowel disease and cancer. Gastroenterol Clin North Am 1997 Mar;26(1):129-39 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9119437.
- ↑ Flores BM, OʼConnor A, Moss AC. Impact of Mucosal Inflammation on Risk of Colorectal Neoplasia in Patients with Ulcerative Colitis: A Systematic Review and Meta-Analysis. Gastrointest Endosc 2017 Jul 24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28750838.
- ↑ 17.0 17.1 Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990 Nov 1;323(18):1228-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2215606.
- ↑ Olén O, Askling J, Sachs MC, Frumento P, Neovius M, Smedby KE, et al. Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014. BMJ 2017 Sep 20;358:j3951 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28931512.
- ↑ 19.0 19.1 19.2 Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004 Dec;53(12):1813-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15542520.
- ↑ Reiser JR, Waye JD, Janowitz HD, Harpaz N. Adenocarcinoma in strictures of ulcerative colitis without antecedent dysplasia by colonoscopy. Am J Gastroenterol 1994 Jan;89(1):119-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8273779.
- ↑ Rutter M, Bernstein C, Matsumoto T, Kiesslich R, Neurath M. Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining. Endoscopy 2004 Dec;36(12):1109-14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15578305.
- ↑ Velayos FS, Loftus EV Jr, Jess T, Harmsen WS, Bida J, Zinsmeister AR, et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: A case-control study. Gastroenterology 2006 Jun;130(7):1941-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16762617.
- ↑ 23.0 23.1 Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002 Jul;56(1):48-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12085034.
- ↑ Liu K, Wang R, Kariyawasam V, Wells M, Strasser SI, McCaughan G, et al. Epidemiology and outcomes of primary sclerosing cholangitis with and without inflammatory bowel disease in an Australian cohort. Liver Int 2017 Mar;37(3):442-448 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27891750.
- ↑ Claessen MM, Lutgens MW, van Buuren HR, Oldenburg B, Stokkers PC, van der Woude CJ, et al. More right-sided IBD-associated colorectal cancer in patients with primary sclerosing cholangitis. Inflamm Bowel Dis 2009 Sep;15(9):1331-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19229982.
- ↑ Nuako KW, Ahlquist DA, Mahoney DW, Schaid DJ, Siems DM, Lindor NM. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 1998 Nov;115(5):1079-83 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9797361.
- ↑ Askling J, Dickman PW, Karlén P, Broström O, Lapidus A, Löfberg R, et al. Colorectal cancer rates among first-degree relatives of patients with inflammatory bowel disease: a population-based cohort study. Lancet 2001 Jan 27;357(9252):262-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11214128.
- ↑ Mark-Christensen A, Erichsen R, Brandsborg S, Rosenberg J, Qvist N, Thorlacius-Ussing O, et al. Long-term Risk of Cancer Following Ileal Pouch-anal Anastomosis for Ulcerative Colitis. J Crohns Colitis 2018 Jan 5;12(1):57-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28981638.
- ↑ The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003 Dec;58(6 Suppl):S3-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14652541.
- ↑ Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, Soetikno R, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastroenterology 2015 Mar;148(3):639-651.e28 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25702852.
- ↑ Leong RW, Ooi M, Corte C, Yau Y, Kermeen M, Katelaris PH, et al. Full-Spectrum Endoscopy Improves Surveillance for Dysplasia in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017 May;152(6):1337-1344.e3 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28126349.
- ↑ Moussata D, Allez M, Cazals-Hatem D, Treton X, Laharie D, Reimund JM, et al. Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy? Gut 2017 Jan 23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28115492.
- ↑ Bryant RV, Winer S, Travis SP, Riddell RH. Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis 2014 Dec;8(12):1582-97 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25267173.