Inflammatory Bowel Disease
CI, 1.1–108.7); and (iii) hazardous occupational exposures known to be associated with the development of colorectal cancer (OR 20.3; 95% CI, 2.7–150.5). The second case-control study, by Solem et al. from the Mayo Clinic, involved nine patients with SBA matched to 18 controls on age and sex.8
Although a number of potential risk factors were examined, including presence of fistulae or strictures, history of other malignancies, or use of various medications (including 5-aminosalicylates, corticosteroids, 6-mercaptopurine or azathioprine, methotrexate, cyclosporine, or infliximab), none was significantly associated with the development of SBA.
In this study, cases, defined as CD patients with SBA, were selected from medical records collected between 1986 and 2006 from the various university hospitals affiliated with the GETAID, and controls, defined as CD patients without SBA, were selected from the MICISTA Registry, a tertiary medical database of inflammatory bowel disease patients treated at Rothschild Hospital (in Paris) from 1974 to 2002 and subsequently at the Saint-Antoine Hospital (also in Paris).
The largest case-control study was performed by Piton et al. from the GETAID.9
The authors identified 29 cases and 87 controls matched by age (+ 5 years), sex, location of disease during the first six months after diagnosis, and duration of disease (+ 5 years). A number of both non-treatment and treatment variables were examined as possible risk factors for the development of SBA. Non-treatment variables included history of smoking, cholecystectomy, or appendectomy, family history of inflammatory bowel disease (IBD), date of symptom onset and date of diagnosis of CD, and extra-intestinal manifestations. In addition, the disease behavior was classified according to the Montreal classification (B1 = inflammatory, B2 = stenosing, B3 = penetrating) and examined at three different time points: five years after CD diagnosis, three years before SBA diagnosis, and at SBA diagnosis.10
Treatment variables analyzed in this study
included duration of use of 5-aminosalicylates, corticosteroids, 6-mercaptopurine or azathioprine, methotrexate, or infliximab, date and site of previous small bowel resection as well as disease duration without resection, and history of stricturoplasty or intestinal bypass. Although the median duration of disease prior to SBA diagnosis was 11 years, eight patients developed SBA within one year of diagnosis of CD, and three of these patients did not even have symptoms of CD prior to diagnosis of SBA. Among the non-treatment variables on univariate analysis, only disease behavior at SBA diagnosis seemed to show promise as a potential risk factor, as none of the cases versus 39% of controls had an inflammatory phenotype, while 45% of cases versus 24% of controls had a stenosing phenotype. Thus, although fibrostenotic disease may be a risk factor for the development of SBA, it may not manifest itself until it is too late (i.e. at diagnosis of SBA). Among the treatment variables on univariate analysis, only use of 5-aminosalicylates for more than two years and small bowel resection showed significant associations. 5-aminosalicylate use for more than two years was observed in 29% of cases versus 57% of controls, with an OR of 0.29 (95% CI, 0.10–0.82; p=0.02). Small bowel resection was also less frequent in cases, occurring in 24% versus 73% in controls, with an OR of 0.07 (95% CI, 0.01–0.32; p=0.0007). Not surprisingly, cases had a significantly longer disease duration without resection (15.6 years versus 8.2 years; p=0.02). On multivariate analysis, these
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same two treatment variables remained significantly associated with SBA, with an OR of 0.16 (95% CI, 0.03–0.79; p=0.02) for 5-aminosalicylate use more than two years and an OR of 0.04 (95% CI, 0.01–0.28; p=0.001) for small bowel resection. Finally, since cases and controls were not selected from the same population, a restriction analysis was performed on 11 cases and 33 controls seen at Saint-Antoine Hospital, and similar results were reported.
Even though a recent meta-analysis of nine observational studies demonstrated a protective effect of 5-aminosalicylates in the prevention of colorectal cancer in patients with ulcerative colitis (pooled OR 0.51; 95% CI, 0.37–0.69)11
and another suggested that
regular 5-aminosalicylate use may protect against colorectal cancer in patients with Crohn’s colitis (OR 0.30; 95% CI, 0.05–1.17; p=0.10,12 it remains to be determined whether 5-aminosalicylates are truly protective against the development of SBA, as the efficacy data of 5-aminosalicylates for the treatment of small bowel inflammation in CD have been underwhelming. Also, patients whose small bowel disease is controlled with 5-aminosalicylates are likely to have milder disease and thus a lower risk of SBA.
With respect to small bowel resection, it seems biologically plausible that resection of inflamed tissue would protect against the subsequent development of cancer if SBA in CD develops as a consequence of chronic inflammation, as some studies suggest.3,6,8 Prospective randomized studies evaluating potential risk factors for SBA in CD will almost certainly never be undertaken, as outcomes are so rare and tend to occur after a median of 11–21 years.4–6,8
Pathogenesis
The mechanism by which SBA in CD arises is unclear. Chronic inflammation appears to play a key role in the pathogenesis of SBA in CD, since cancer seems to occur most often in areas of chronic inflammation, as discussed above.3,6,8
Moreover, a number of case
reports have documented the development of SBA within CD strictures or even at sites of prior strictureplasty.13–18
Presumably,
dysplasia and eventually adenocarcinoma may develop as a result of chronic inflammation.
In a study of eight patients with SBA in CD, Sigel et al. reported that six of the eight patients had dysplasia found adjacent to the carcinoma and another had dysplasia adjacent to and distant from the carcinoma.19 Watermeyer et al. reported a case of patient with quiescent CD who had terminal ileal flat dysplasia (discovered on surveillance colonoscopy with biopsy) that progressed to adenocarcinoma within 18 months.20 Mechanistically, a link between microsatellite instability and SBA has also been described, similar to the progression of lesions seen in hereditary non-polyposis colorectal cancer.21
Another factor to consider in the pathogenesis of SBA is the rarity of its occurrence as a whole. A number of hypotheses have been suggested to explain this phenomenon. First, small bowel transit is relatively rapid, thereby limiting exposure time between the mucosa and potential carcinogens.22
Second, the concentration of intraluminal
carcinogens may be substantially reduced due to the large volume of daily small bowel secretions.22
Third, bile salts, which are potentially US GASTROENTEROLOGY & HEPATOLOGY REVIEW
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