Long-standing inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC).1, 2 This was first shown for ulcerative colitis (UC). Long-term experience of surveillance programs in handling this increased risk is now at hand; most centers employ some form of surveillance program for patients with long-standing (>8–10 years) and extensive UC. The value of this surveillance in terms of decreased mortality is debated, particularly the importance of histopathological low-grade dysplasia as a precancerous indicator.3, 4 There is still more controversy about the value of surveillance in Crohn's colitis. Only one study on colonoscopic surveillance in Crohn's disease (CD) has been performed, and in this study the authors found a cumulative incidence of dysplasia similar to that in UC.5
Apart from histopathological dysplasia, other precancerous markers have been used in surveillance.6 DNA aneuploidy (a numeric chromosomal imbalance) has been used together with histopathology in UC.7–9 Studies using DNA aneuploidy as an additional precancerous marker in Crohn's colitis are few, small, and have so far led to inconclusive results.10–12
At Stockholm Söder Hospital and Karolinska University Hospital, Huddinge patients with long-standing (>8 years duration) extensive Crohn's colitis have been followed with colonoscopic monitoring in the same way as those with UC. In this study, we describe the long-term results from this monitoring of patients with longstanding and extensive Crohn's colitis. In particular, we assessed the incidence of DNA aneuploidy, histopathological dysplasia, and colorectal cancer, and any possible interrelations between them.
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- SUBJECTS AND METHODS
In this study we found that in a cohort of patients with Crohn's and indeterminate colitis the overall occurrence of dysplasia was of similar magnitude as in previous studies of CD as well as of UC.5, 21, 22 The majority of this dysplasia was, however, unifocal, and only a small fraction (4%) had multifocal dysplasia. Besides confirming the occurrence of dysplasia, our study adds important information on the occurrence of DNA aneuploidy in these patients, and the interrelationships between aneuploidy, dysplasia, and CRC. In this regard, our main findings was that: 1) the crude occurrence of DNA aneuploidy was in the same range as in previous studies on UC7, 9; 2) DNA aneuploidy was mostly found in patients with subsequent either low grade or high grade dysplasia; and 3) the finding that DNA aneuploidy with high S-phase values correlated to a subsequent finding of dysplasia.
There are three previous studies on CD-colitis where the occurrence of both DNA aneuploidy and dysplasia has been studied.10–12 The article by McKinley et al10 was a case report of one patient with CD colitis who had concomitant HGD and DNA aneuploidy. Lofberg et al12 studied 24 patients with extensive CD colitis and found no dysplasia but two cases of DNA aneuploidy. Porschen et al11 studied both CD colitis and UC, and found no aneuploidy among 51 patients with CD colitis.
There is one previous study on CD-colitis and surveillance5 in which the frequency of dysplasia paralleled that reported for UC (no other precancerous markers were used). In that study the cumulative incidence of HGD/CRC was 7% after ≈10 years of follow-up, which is in close agreement with our finding of a cumulative CRC incidence 7% after 10 years of follow-up. Further, in a case–control study on possible exposures and CRC risk in Crohn's colitis23 the authors found that previous colonoscopy for an indication of screening or surveillance was associated with a lower risk of CRC.
Based on their findings the authors made the recommendation that patients with extensive CD-colitis should be followed with periodic surveillance colonoscopies. It is tempting to include CD-colitis in similar surveillance programs as for UC. However, the benefit in terms of decreased mortality from such programs is even less certain for CD-colitis, where the absolute and relative risks for colitis associated cancer are uniformly lower than for UC.
A better approach would be to stratify which patients with CD-colitis should be included in such surveillance. Patients with extensive CD-colitis (at least 1/3 of colon), a positive family history for CRC, concomitant PSC, extensive, reproducible DNA aneuploidy with high S-phase values, or any other marker for neoplasia should probably be followed with yearly colonoscopies.
Our study has a several limitations. The lack of a control group, a weakness in common with the earlier studies on CD-colitis and precancerous markers, precluded a direct comparison with the normal population regarding prevalence of dysplasia and DNA aneuploidy. In an earlier study,20 however, we have shown that an unselected normal population without colitis does not have DNA aneuploidy or dysplasia. A further weakness was the incomplete (and hence not included) data on factors such as smoking status, 5-ASA-treatment, and family history of CRC. The anticipated difficulty in definitely separating colonic CD from IC or UC is also a limitation, although particular care was taken to minimize any misclassification of UC as CD. The 25 cases where a firm diagnosis of CD could not be made were retained as IC, since we believed the important factor might be long-standing colitis rather than the diagnosis per se. As always in studies involving histopathology there is the well-described problem of subjectivity in dysplasia grading.24, 25 All our analyses were made by experienced pathologists with a special interest in gastrointestinal pathology. To minimize any ambiguities, only LGD or worse were retained as dysplasia and all cases of indefinite probably dysplastic mucosa were excluded. All cases of dysplasia leading to colectomy were reviewed independently by a second gastrointestinal pathologist.
All patients were surveyed in a similar way, regardless of previous presence of DNA aneuploidy or not, according to the protocol of our local surveillance program. Since we follow this program for every patient undergoing surveillance, there is little risk of bias in real time. The presence of only DNA aneuploidy (without dysplasia) will according to this program not lead to a closer surveillance compared to patients with no DNA aneuploidy. There was no difference in the mean number of colonoscopies between patients with DNA aneuploidy and those without aneuploidy.
A particular difficulty with CD colitis is the occurrence of strictures and complicated anal disease with fistulas. However, in our patient group there were no cases of strictures, fistulas, or by-passed intestinal segments among the neoplasia cases.
Common to all surveillance there is always a risk of sampling error, since only a very small fraction of the entire mucosa can be covered with biopsies. This problem is particularly true for CD colitis, with its often patchy inflammation and possibility of strictures. Brush cytology could be a way to reduce sampling error because of strictures.
Our study also has several strengths: it is based on the largest cohort of patients with extensive CD colitis where information both on histopathological dysplasia as well as DNA aneuploidy were available. All patients were included according to strict diagnostic criteria to minimize the risk for misclassification of patients with UC as Crohn's colitis.
The addition of DNA aneuploidy as a second biological marker for neoplasia adds strength as the histopathological inflammation-dysplasia-carcinoma sequence is not as firmly established for CD as for UC. We increased the precision further by also studying the S-phase fraction and not only the occurrence of DNA aneuploidy per se. It seems that the crucial factor for neoplasia development is the increased S-phase and not just the mere presence of DNA aneuploidy. This seems also to be the case for UC, where high S-phase values correlated well to extensive LGD and HGD. We therefore suggest that in following CD colitis patients in surveillance programs an additional marker for neoplasia such as DNA aneuploidy with S-phase analysis, be used.
In conclusion, the results of our study suggest that although both dysplasia and DNA aneuploidy could be used in the surveillance of CD colitis, the value of merely measuring their crude occurrence may be moderate. By contrast, when additional aspects such as S-phase and extent are considered, the clinical value of both DNA aneuploidy and dysplasia increases. Thus, together with age, duration of disease, CRC heredity, and a recent change in symptoms, S-phase and extent of aneuploidy and dysplasia can help stratify risk and thereby find patients with CD colitis to follow more closely.