Importance of Nonpolypoid (Flat and Depressed) Colorectal Neoplasms in Screening for CRC in Patients with IBD

Matthew D. Rutter, MBBS, MD, FRCP (London, Edinburgh)ab∗Matt.rutter@nth.nhs.uk,     aDepartment of Gastroenterology, University Hospital of North Tees, Hardwick, Stockton-on-Tees, Cleveland TS19 8PE, UK; bDurham University School of Medicine, Pharmacy and Health Queen’s Campus, University Boulevard, Stockton-on-Tees, TS17 6BH, UK

∗Department of Gastroenterology, University Hospital of North Tees, Hardwick, Stockton-on-Tees, Cleveland TS19 8PE, UK.

Patients with inflammatory bowel disease colitis have an increased risk of developing colorectal cancer compared with the general population. Colonoscopic surveillance remains challenging because the cancer precursor (dysplasia) can have a varied and subtle endoscopic appearance. Although historically the dysplasia was often considered endoscopically invisible, today with advanced endoscopic understanding, technique, and imaging, it is almost always visible. The frequency of different dysplasia morphologies and true clinical significance of such lesions are difficult to determine from retrospective series, many of which were performed prior to the current endoscopic era.

Keywords

Cancer

Dysplasia

Surveillance

Colonoscopy

Key points

• Patients with colitis have an increased risk of developing colorectal cancer (CRC), although the excess risk seems to be diminishing.

• Colonoscopic surveillance remains challenging because the cancer precursor (dysplasia) can have a varied endoscopic appearance.

• The vast majority of colitic dysplasia is endoscopically visible.

• The relative frequency of different dysplasia morphologies and true clinical significance of such lesions are difficult to determine from retrospective series, many of which were performed prior to the current era of endoscopic technique and imaging.

Cancer risk

People with long-standing inflammatory bowel disease (IBD) colitis have a higher risk of developing CRC than the general population. The most reliable estimates of this risk come from population-based studies. The first such study, a large Swedish cohort of long-standing ulcerative colitis (UC), found a standardized incidence ratio (SIR) compared with the general population of 5.7 (95% CI, 4.6–7.0).1 In more recent population-based studies of UC, the magnitude of risk seems smaller: an updated Swedish study found an SIR of 2.3 (95% CI, 2.0–2.6),2 and one from Canada found an SIR of 2.75 (95% CI, 1.91–3.97).3 Studies that have found no difference in CRC incidence or morbidity when comparing UC with the general population have in general been limited by selection bias4 and retrospective study design.5 A recent meta-analysis that summarizes the data from only population-based cohort studies found the risk of CRC 2.4-fold higher in UC compared with the general population.6 Recent evidence suggests that the CRC risk in Crohn's colitis seems parallel to that in UC, for the same extent of colonic involvement. In Ekbom and colleagues’ study,7 patients with colonic Crohn had a relative risk (RR) of 5.6 (95% CI, 2.1–12.2) compared with the general population, in contrast to those with terminal ileal Crohn, who had a risk no different from the general population. Subsequent studies have corroborated these findings in Crohn's disease, reporting SIR of 2.1 (95% CI, 1.2–3.4)2 and RR 2.64 (95% CI, 1.69–4.12).3

Various potential reasons for the apparent reduced risk of CRC over time have been postulated, including early study selection bias, differing means of determining colitis extent, timely colectomy, better disease (inflammation) control, a chemopreventive effect of aminosalicylate compounds, and the beneficial effect of surveillance programs.

Additional Risk Factors

Not all people with colitis have the same magnitude of CRC risk—several additional risk factors have been identified.

Extent of inflammation

Many studies (including a systematic review) have demonstrated that an increasing extent of mucosal inflammation correlates with increased CRC risk.1,2,5,8,9 The measurement of disease extent has evolved over time: earliest studies used barium enemas, in contrast to more recent studies that have used either endoscopic (macroscopic) or histologic evidence. The original Swedish population-based study by Ekbom calculated a risk in UC for CRC of 1.7 for proctitis (nonsignificant), 2.8 for left-sided colitis, and 14.8 for pancolitis, compared with the general population.1 Soderlund and colleagues'2 updated study also indicated an increased risk, albeit of lower magnitude, with SIR 5.6 for pancolitis, 2.1 for Crohn's colitis, and 1.7 for proctitis—all statistically significantly higher than the general population. The underlying principle sustains—the more colonic mucosa involved, the greater the cancer risk to the patient.

Disease duration

A longer duration of colitis is associated with an increased risk of CRC. Early studies included in 2 meta-analyses indicated an exponentially increasing CRC risk after 10 years of UC,10 with cumulative CRC risk of 2% at 10 years, 8% at 20 years, and 18% after 30 years of disease. More recent population-based studies have indicated, however, a much lower risk, with annual incidences as low as 0.06% to 0.20% and cumulative risk at 30 years as low as 2%.4

A Hungarian population-based study calculated a cumulative risk of 0.6% after 10 years, 5.4% after 20 years, and 7.5% after 30 years,8 and, in the largest single-center study of colitis surveillance colonoscopy, the cumulative incidence of CRC by colitis duration showed a linear rather than exponential increase, from 2.5% at 20 years to 10.8% at 40 years of extensive UC.11 CRC before 8 years of colitis was thought uncommon, although a recent Swedish study calculated that 17% to 22% of patients developed cancer before 8 to 10 years for extensive colitis and 15 to 20 years for left-sided disease.12

Severity of inflammation

IBD-CRC risk is thought to be promoted by inflammation. It is intuitive that more severe inflammation may confer a higher CRC risk, but early studies showed no clear association between colitic symptoms and CRC risk. There is poor correlation, however, between patients’ symptoms and the severity of inflammation, and it was only when studies focused on severity of inflammation at a tissue level that the strong association became apparent. A British case-control study found a significant correlation between both colonoscopic (odds ratio [OR] 2.5, P<.001) and histologic (OR 5.1, P<.001) inflammation and neoplasia risk.9 A second article on the same patient cohort found that macroscopically normal mucosa seemed to return the CRC risk to that of the general population.13 A subsequent American cohort study then found a significant correlation between histologic inflammation and advanced neoplasia (hazard ratio 3.0; 95% CI, 1.4–6.3).14

Previous inflammation

Postinflammatory polyps (PIPs), which arise during healing after severe inflammation, have been associated with an increased CRC risk in 2 case-control studies, with ORs of 2.14 (95% CI, 1.24–3.70)13 and 2.5 (95% CI, 1.4–4.6).15 It is thought that this probably reflects the increased risk relating to previous severe inflammation rather than the PIPs having malignant potential per se.

Family history of CRC

As in noncolitic patients, a family history of CRC contributes to the risk of CRC in patients with colitis. Case-control and population-based studies show a 2- to 4-fold increase.16 An American case-control study found family history of CRC an independent risk factor for UC-CRC (OR 3.7; 95% CI, 1.0–13.2).15 A Swedish population-based study found that a family history of CRC was associated with a 2.5-fold increase in IBD-CRC (95% CI, 1.4–4.4). Where the first-degree relative was diagnosed with CRC before 50 years of age, the risk was even higher (RR 9.2; 95% CI, 3.7–23).17

Primary sclerosing cholangitis

Primary slerosing cholangitis (PSC) seems a particularly important independent risk factor for IBD-CRC. Although patients with PSC often have milder colonic inflammation, a meta-analysis of 11 studies concluded that patients who had both UC and PSC were at increased risk of CRC compared with patients with UC alone (OR 4.09; 95% CI, 2.89–5.76).18 Cancers also often occur earlier in a patient’s disease. Potential explanations include that such patients may have had subclinical inflammation for many years prior to colitis diagnosis, a...