Development of Neoplasia in IBD-nonadenoma Patients During Follow-up
Within the IBD-nonadenoma cohort 15 patients (12%) developed adenomas during follow-up, which were endoscopically classified as typical adenomas in 10 patients and atypical adenomas in five. Two patients developed flat LGD and four developed both flat and raised dysplasia.
A total of seven patients (7%) developed AN after a median duration of follow-up of 80 months (range 18-91 months; Fig. 1). Three patients developed HGD in a typical adenoma. Of these, two were treat by polypectomy. None of these during follow-up. Four patients developed CRC. One of these developed CRC 4 years after an endoscopically resected flat adenoma, whereas three developed CRC without evidence of prior LGD or HGD. The 5-year cumulative incidence of AN was 3% in the IBD-nonadenoma cohort (Fig. 2). This was significantly lower compared to the IBD + adenoma cohort (P <0.01). No differences were found between CD and UC patients regarding development of AN (P = 0.12). The 5-year cumulative incidence of CRC alone was not significantly different between the IBD-nonadenoma and IBD + adenoma groups (2% vs. 4%, respectively, P = 0.23; Fig. 2b).
Factors Associated with Development of AN
The presence of an adenoma in patients with IBD was associated with an increased risk of developing AN during follow-up (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.5–8.7) (Table 3). In the multivariate analysis, this effect remained borderline significant after adjustment for duration and type of IBD, extent of inflammation, age, gender, concomitant diagnosis of PSC, and medication use (HR 2.8, 95% CI 1.0–8.2). A diagnosis of UC (compared to CD) was associated with an increased risk of developing AN as well (unadjusted HR 6.1, 95% CI 1.4–26.4), which remained significant in the multivariate analysis (adjusted HR 4.5, 95% CI 1.0–25.4). Medication use, including 5-aminosalicylate (5-ASA) and thiopurines, was not associated with the development of AN.
Development of Neoplasia in NonIBD + Adenoma Patients During Follow-up
In 77 nonIBD + adenoma patients (42%) adenomas were detected during follow-up. A total of eight patients (4%) developed AN after a median follow-up of 53 months (range 17-99 months, Fig. 1). In five patients HGD was detected in an adenoma that was treated endoscopically in all five patients. None of these patients developed CRC during follow-up. Three nonIBD + adenoma patients developed CRC, which were all treated by surgical resection.
The 5-year cumulative incidence of AN in the non-IBD + adenoma cohort was 5% (Fig. 2). This was significantly lower compared to the IBD + adenoma cohort (P <0.01), as well as to the subset of IBD + adenoma patients with a typical adenoma resembling sporadic adenomas (P = 0.03). The 5-year cumulative incidence of CRC alone in the nonIBD + adenoma cohort did not differ from the IBD + adenoma cohort (1% vs. 3% respectively, P = 0.06, Fig. 2b).
This study demonstrates an increased risk of AN in IBD patients with an adenoma when compared with non-IBD patients with adenomas and IBD patients without adenomas. Notably, atypical as well as typical adenomas in patients with IBD were found to be associated with an increased risk of AN. This finding is in contrast with most previously published studies, which consistently reported a low risk of AN in IBD patients with polypoid dysplasia.8,10,13,14
The high incidence of AN among IBD + adenoma patients during follow-up in our study was mainly caused by the development of HGD rather than the development of CRC. HGD developed in 12% of IBD + adenoma patients as compared to 2% and 3% of IBD-nonadenoma and nonIBD + adenoma patients, whereas CRC developed in 6% of IBD + adenoma patients compared to 3% and 2% of IBD-nonadenoma and nonIBD + adenoma patients, respectively. Although previous studies primarily focused on CRC incidence, the reported incidences of HGD after a diagnosis of adenoma were low in these studies and varied between 0% and 5%.8–10,15 Since HGD will undoubtedly progress to CRC when left untreated, we opted to use a composite endpoint including both HGD and CRC.16–18 Furthermore, we report a substantially higher CRC incidence in IBD + adenoma patients than reported in several previous studies.8,10,13
One might assume that the inclusion of both patients treated by polypectomy and patients in whom adenomas were not endoscopically removed accounts for the higher risk of AN in our cohort. Eighty-one percent of all nonIBD + adenoma patients were treated by polypectomy, compared to only 62% of IBD + adenoma patients. An explanation for the relatively low polypectomy rate in the IBD + adenoma cohort might be that postinflammatory-like and small flat lesions are more frequently encountered and not deemed serious enough for polypectomy. Our rates are in line with recent data from Vieth et al,9 who found a polypectomy rate of 59% in IBD patients with adenomas, although we could not confirm the higher incidence of neoplasia and CRC among patients in whom no polypectomy was performed as reported in that study. It is therefore conceivable that AN developed either as a result of field cancerization or due to residual dysplastic tissue.
Another possible explanation for the high incidence of AN might be the design of our study. We selected cases using a pathology database, whereas in previous studies selection was based on the endoscopic identification of solitary polyps.8,10,13 Therefore, our study comprised a heterogeneous group of endoscopic lesions including a large subgroup of “nonadenoma-like” lesions, which have previously been associated with a high risk of synchronous CRC.4,19–21 Current guidelines therefore generally recommend colectomy for these types of lesions.5,6 In our IBD + adenoma cohort, 25% of patients had an atypical adenoma, including both nonadenoma-like lesions and lesions considered to be postinflammatory polyps during endoscopy. The cumulative incidence of AN was substantially higher in these patients: eight patients with an atypical adenoma (29%) developed AN compared to 10 patients (12%) with a typical adenoma. Interestingly, in 15 patients histologically diagnosed adenomas were endoscopically characterized as postinflammatory polyps. Of these, 30% developed AN during follow-up, which highlights the difficulty of differentiation between raised dysplasia and postinflammatory polyps. Inexperience of the endoscopists who assessed the types of polyps may have contributed to this misclassification. Another explanation may be the fact that postinflammatory polyps are proxies for long-standing and severe inflammation and may therefore be associated with an increased risk of CRC.22,23
Of note, IBD + adenoma patients with typical adenomas displayed a significantly increased 5-year cumulative incidence of advanced neoplasia as well: 6% compared to 5% in nonIBD + adenoma patients (P = 0.03, log rank test). This conflicts with data from previous studies that reported no difference in development of subsequent neoplasia between these patient groups.7,13 Our results stress the importance of complete removal and close follow-up of either type of adenoma.
The IBD + adenoma cohort contained patients with adenomas detected both inside and outside colonic areas (previously) involved in inflammation. Since by definition IBD-associated dysplasia only develops in areas of chronic inflammation, one should classify adenomas outside an area of previous inflammation as sporadic. Remarkably, the incidence of AN was not different between IBD patients with adenomas detected within or outside an area of previous inflammation.
The comparison of the IBD + adenoma and IBD-nonadenoma cohorts enabled us to assess the additional risk of adenomas in patients with colitis. IBD + adenoma patients had a higher risk of AN compared to IBD-nonadenoma patients. The presence of an adenoma seemed an independent predictor of AN when corrected for several known risk factors of IBD-associated neoplasia, althoughborderline significance (HR 3.0, 95% CI 1.0–8.5).
Our study has some limitations. First, due to the retrospective design of the study we relied on the descriptions provided in endoscopy reports with regard to endoscopic characteristics and treatment of the adenomas. Second, IBD + adenoma patients and IBD-nonadenoma patients were solely matched on age at inclusion, center, and date of inclusion according to the date of adenoma diagnosis in the IBD + adenoma cohort. We do not think that this introduced important bias, however, since these cohorts were quite well matched with regard to duration and extent of IBD. Third, a significant proportion of patients were excluded due to the lack of follow-up or missing endoscopy or pathology reports. Since patients in the nonIBD + adenoma and IBD-nonadenoma cohort were more frequently excluded than patients in the IBD + adenoma cohort, this might have resulted in a higher risk of AN in these two cohorts, thereby introducing a selection bias. Obviously, this would only strengthen our conclusion that the risk of AN is increased in the IBD + adenoma patients. And last, although patients underwent a complete colonoscopy at inclusion in this study and at least one colonoscopy or a colectomy during follow-up, surveillance colonoscopies with random biopsy sampling were performed in only 52% of IBD + adenoma patients and 55% of IBD-nonadenoma patients. This might have resulted in an underestimation of the presence of AN. However, since most cases of AN can be identified endoscopically, we do not feel that this had a major influence on our results.
In conclusion, this study shows that IBD patients with a histological diagnosis of an adenoma have an increased risk of developing AN compared to nonIBD + adenoma patients and IBD-nonadenoma patients. The presence of atypical adenomas in particular was associated with this increased risk, although patients with typical adenomas were found to carry an additional risk as well. Thus, complete removal of adenomas and subsequent strict surveillance is warranted in IBD patients with atypical as well as typical colonic adenomas.
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
inflammatory bowel disease; adenoma; dysplasia; colorectal cancer