ColorectalReferring to the large bowel, comprising the colon and rectum. cancer (CRCColorectal cancer) is one of the most serious complications of chronic colitis in patients with inflammatory bowel disease (IBDInflammatory bowel disease).
Current strategies for risk reduction and management of colitis-associated CRCColorectal cancer 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. ChemoprophylaxisAdministration of a medication or drug to prevent disease. using mesalazine, thiopurines and ursodeoxycholic acid has also been proposed in the management of IBDInflammatory bowel disease with and without primary sclerosing cholangitis (PSCPrimary sclerosing cholangitis).
Observational data suggest colonoscopy is associated with a reduced risk of CRCColorectal cancer and mortality in patients with IBDInflammatory bowel disease. Guidelines based on case series suggest that IBDInflammatory bowel disease 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.Back to top
Since IBDInflammatory bowel disease was first recognised in 1925, substantial variation in the incidence of CRCColorectal cancer in patients with IBDInflammatory bowel disease 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 CRCColorectal cancer.
Initial data suggested a difference in risk of CRCColorectal cancer between those with ulcerative colitis (UCUlcerative colitis) 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 CRCColorectal cancer in any patient with UCUlcerative colitis 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 CRCColorectal cancer among patients with UCUlcerative colitis 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 CRCColorectal cancer in IBDInflammatory bowel disease patients in low-prevalence countries might be similar to that of Western countries. The incidence of CRCColorectal cancer in patients with IBDInflammatory bowel disease may continue to fall with regular surveillance colonoscopy, improvements in imaging and adenoma detection and aggressive use of maintenance therapies to achieve mucosal healing.
Intraepithelial dysplasia (superficial to the lamina propria) is the premalignant lesion in IBDInflammatory bowel disease-associated CRCColorectal cancer, and is classified as low grade or high grade according to histopathological features. The differentiation of low-grade dysplasia (LGDLow grade dysplasia) from high-grade dysplasia (HGDHigh grade dysplasia) 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 CRCColorectal cancer. For the most part, IBDInflammatory bowel disease-associated CRCColorectal cancer is histologically similar to sporadic CRCColorectal cancer, although it exhibits several different pathobiological features.
ColorectalReferring to the large bowel, comprising the colon and rectum. cancer in IBDInflammatory bowel disease, like its sporadic counterpart, is most commonly adenocarcinoma. Dysplasia in IBDInflammatory bowel disease 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 CRCColorectal cancer is lower for IBDInflammatory bowel disease patients than for sporadic CRCColorectal cancer patients, and synchronous tumours have been historically reported more commonly in IBDInflammatory bowel disease, 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.
ColorectalReferring to the large bowel, comprising the colon and rectum. cancer and dysplasia risk
Modern IBDInflammatory bowel disease 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 IBDInflammatory bowel disease increases CRCColorectal cancer risk. The risk of CRCColorectal cancer 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 CRCColorectal cancer, 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 IBDInflammatory bowel disease 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 CRCColorectal cancer risk seen in those with extensive colitis or pancolitis. An Australian UCUlcerative colitis cohort study identified CRCColorectal cancer 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 CRCColorectal cancer in patients with IBDInflammatory bowel disease.
The risk of developing colitis-associated CRCColorectal cancer is increased in the presence of PSCPrimary sclerosing cholangitis. A meta-analysis of studies that compared the risk of CRCColorectal cancer in patients with UCUlcerative colitis with and without PSCPrimary sclerosing cholangitis confirmed the CRCColorectal cancer risk to be 4.8-fold higher in patients with PSCPrimary sclerosing cholangitis. Australian data demonstrated a trend towards increased CRCColorectal cancer risk in the presence of PSCPrimary sclerosing cholangitis with IBDInflammatory bowel disease (6%), compared with PSCPrimary sclerosing cholangitis without IBDInflammatory bowel disease (0%, P=0.08). Interestingly cancers associated with PSCPrimary sclerosing cholangitis and IBDInflammatory bowel disease tend to be located predominantly in the proximal colon (as distinct from UCUlcerative colitis patients without PSCPrimary sclerosing cholangitis).The risk of CRCColorectal cancer remains elevated following orthotopic liver transplant and ongoing yearly surveillance is recommended.
As with sporadic CRCColorectal cancer, a family history of CRCColorectal cancer is associated with a greater risk of developing dysplasia in patients with IBDInflammatory bowel disease. For patients with IBDInflammatory bowel disease and a first-degree relative with CRCColorectal cancer, the risk is at least two times baseline.
For patients with UCUlcerative colitis treated with proctocolectomy and ileal pouch-anal anastomosis, the risk of pouch cancer is very rare, questioning the need for selective surveillance.Back to top
Characterisation of lesions and implications for management
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 (WLEWhite light endoscopy) 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 CRCColorectal cancer 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. ProctocolectomyA surgical procedure to remove the colon and rectum. 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 WLEWhite light endoscopy.
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, PSCPrimary sclerosing cholangitis or foreshortened tubular colon).
Ultimately, the primary goal of IBDInflammatory bowel disease management should be prevention of IBDInflammatory bowel disease 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.Back to top
- 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
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