Adenomatous polyps in ulcerative colitis and colonic Crohn’s disease: less frequent, but does this change surveillance strategy?

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) has been known for several decades, with CRC remaining one of the most feared complications. Early studies reported an excess risk of CRC in ulcerative colitis patients; however, in these reports, which were published from tertiary referral centers, patients with severe disease were over-represented. In the meta-analysis by Eaden et al. from 2001 [1], the cumulative probability of CRC in ulcerative colitis was 2 % by 10 years, 8 % by 20 years, and 18 % by 30 years. Chronic inflammation is thought to be one of the key factors in the pathogenesis, together with genetic predisposition [2].

More recently, a lower risk of CRC was reported in a meta-analysis of population-based studies, with an average of 1.6 % of ulcerative colitis patients diagnosed with CRC during the first 14 years of follow-up. The pooled standardized incidence ratio (SIR) was 2.4 (95 % confidence interval [CI] 2.1 – 2.7) [3]. However, the interpretation of SIRs has to be adjusted for sporadic CRC rates in the background population and these may show large geographic variation.

In contrast, until recently few data were available on the prevalence of sporadic adenomas in patients with ulcerative colitis or Crohn’s disease. Adenomas are mainly sharply delineated, with or without a stalk, and often show a smooth surface; the differentiation from IBD/colitis-associated neoplasms, especially in affected areas, is sometimes troublesome. The distinction between lesions is also important because of possible differences in the molecular pathogenesis and risk factors [4].

In the current issue of Endoscopy, Ben-Horin et al.[5] report on the prevalence of adenomatous polyps in patients with ulcerative colitis aged 50 years or older compared with a matched control population at the Gastroenterology Department of Sheba Medical Center. The major findings of this retrospective study were that the rate and number of adenomatous polyps in non-affected areas were significantly lower in ulcerative colitis patients (6.3 % vs. 25.9 %; odds ratio [OR]_{any adenoma} = 0.15, 95 %CI 0.09 – 0.44) compared with controls during index colonoscopies performed between 2006 and 2012. The difference between ulcerative colitis patients and controls remained significant when ever-adenoma rates were analyzed (14.1 % vs. 25.9 %; OR = 0.47, 95 %CI 0.3 – 0.72).

A clear strength of the paper is the very detailed data collection and statistical analysis. The authors were able to perform multiple adjustments and sensitivity analyses to control for possible confounders. As an example, screening colonoscopies for all controls were performed during 2011 – 2012, but an adjustment for the potential differences in colonoscopy techniques confirmed the lower adenoma rate in ulcerative colitis (OR = 0.24, 95 %CI 0.1 – 0.53; P = 0.0005).

The authors also studied the possible risk factors, including sex, age, body mass index (BMI), smoking, alcohol consumption, family history of CRC, and aspirin or statin use. While ulcerative colitis-associated CRC was reported to be associated with young age at diagnosis [6], disease extent [7], disease duration [6], primary sclerosing cholangitis (PSC) [8], and family history of IBD [9] in previous studies, ulcerative colitis diagnosis, male sex, age, and BMI were identified as being associated with adenoma risk in the present cohort. In addition, patients with colonic, but not ileal, Crohn’s disease also had a significantly lower rate of adenomas compared with controls (3.9 % vs. 25.9 %; P = 0.002). In contrast, the overall rate of any polyp did not differ between the two groups, mostly because of the high frequency of inflammatory polyps (18 %) in ulcerative colitis patients.

The finding from the study by Ben-Horin et al. [5] of a low prevalence of adenomatous polyps in ulcerative colitis patients is in line with some earlier reports [10] [11]. However, these studies had important methodological limitations, including the selection of controls, the age groups, and the lack of possible adjustment for age, sex, and drug use. In addition, a very recent publication by Sonnenberg et al. [12], published around the same time as the present study, came to similar conclusions based on histopathology records in a case – control study among 130 204 patients undergoing colonoscopy. They reported lower risks of hyperplastic polyps, serrated adenomas, and tubular adenomas in patients with microscopic colitis (n = 11 176; OR = 0.46, 95 %CI 0.43 – 0.49; OR = 0.24, 95 %CI 0.19 – 0.30; and OR = 0.35, 95 %CI 0.33 – 0.38, respectively) and IBD (n = 4435; OR = 0.18, 95 %CI 0.15 – 0.21; OR = 0.24, 95 %CI 0.16 – 0.35; and OR = 0.18, 95 %CI 0.15 – 0.21, respectively), but not in patients with diverticulitis or ischemic colitis after adjustment for sex and age. Adjustments for family history of CRC, BMI, medication use, size of affected area, and prior colonoscopy results were however not possible because of the nature of the study.

One important question is how the lower frequency of adenomas in ulcerative colitis can be explained, knowing the association between chronic inflammation and the risk of carcinogenesis. A possible explanation could be that, although chronic colonic inflammation increases the risk of field cancerization in the affected area, the same chronic inflammation may prevent development through the “conventional” adenoma to carcinoma sequence [13] [14]. In other words, the overall risk of colorectal carcinoma is not decreased, but the primary molecular pathway is different in patients with chronic colonic inflammation. This is also supported by genetic studies that show differences in the early genetic changes between sporadic carcinogenesis (APC, KRAS, and methylation pathways) and ulcerative colitis-associated carcinogenesis (p53 and loss of heterozygosity) [14]. It is further supported by the findings from the present study by Ben-Horin et al. [5], where a trend for higher rates of carcinoma in ulcerative colitis patients was identified, although this difference was not significant.

Another question relates to the clinical implication of the above findings. On the one hand, it is reassuring that gastroenterologist performing surveillance colonoscopy in ulcerative colitis can expect to find fewer colorectal adenomas. However, the colonoscopy surveillance strategy will not be affected in older ulcerative colitis patients. Furthermore, interpreting the implications of this data for clinical practice is even more controversial. Adenoma-like lesions are known to be less common in the area affected by ulcerative colitis, as confirmed also by the present study. However, the calculation of the “expected frequency” of adenomas on the basis of rates in the non-affected area is challenging. Therefore, the risk may be underestimated in patients with more extensive disease. Nonetheless, the rate of ever finding right-sided adenomas in ulcerative colitis patients in the present study was not different to finding right-sided adenomas in controls (13.1 % vs 13.4 %), which suggests that the ever-adenoma rate and the risk in non-affected areas are unaffected and are not different from normal subjects; this is probably the main take-home message for everyday clinical practice.

The endoscopic management of ulcerative colitis/Crohn’s disease patients with sporadic adenomas or an adenoma-like dysplasia-associated lesion or mass (DALM) will also not be changed [15]. Polypectomy with complete excision and continued close endoscopic surveillance are the methods of choice for both entities in ulcerative colitis patients. Of note, the prevalence of polyp formation during follow-up was found to be similar in both groups (51 % – 62 % during an average follow-up of 42 months). Close follow-up is however mandatory, because the cumulative probability of subsequent colorectal neoplasia in those who have undergone polypectomy may be as high as 18 % at 1 year and 69 % at 5 years in ulcerative colitis patients with polypoid dysplasia, as reported from Olmstead county [16]. In addition, the cumulative incidence of cancer or flat dysplasia was reported to be 2 % at 1 year and 13 % at 5 years.

Finally, in a recent meta-analysis [17], patients with polypoid dysplasia had a pooled incidence of cancer of 5.3 cases/1000 years (95 %CI 2.7 – 10.1) and a pooled rate of any recurrent dysplasia of 65 cases/1000 patient-years (95 %CI 54 – 78).

In conclusion, the present study by Ben-Horin et al. [5] and a few additional papers suggest that the prevalence of adenomatous polyps may be lower in ulcerative colitis and colonic Crohn’s disease. Because the ulcerative colitis-associated CRC risk remains increased, these together suggest that the primary pathway of carcinogenesis is different where there is chronic colonic inflammation and patients are more prone to develop ulcerative colitis-associated CRCs rather than conventional “adenoma to carcinoma sequence” CRCs. Although these findings are interesting and novel, the conclusions from this study do not change the surveillance strategies and management or follow-up of IBD patients with sporadic adenomas.

• References

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