Patients with chronic ulcerative colitis (UC) have a. Backwash Ileitis Is Strongly Associated With Colorectal Carcinoma in Ulcerative Colitis

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1 GASTROENTEROLOGY 2001;120: Backwash Ileitis Is Strongly Associated With Colorectal Carcinoma in Ulcerative Colitis UDO A. HEUSCHEN,* ULF HINZ, ERIK H. ALLEMEYER,* JOSEF STERN, MATTHIAS LUCAS,* FRANK AUTSCHBACH, CHRISTIAN HERFARTH,* and GUNDI HEUSCHEN* *Department of Surgery, Unit for Documentation and Statistics of the Department of Surgery, and Department of Pathology, University of Heidelberg; and St. Josefs-Hospital, Dortmund, Germany Background & Aims: Commonly accepted risk factors for colorectal carcinoma (CRC) in ulcerative colitis are duration and extent of disease. By identifying still unknown risk factors, surveillance strategies may be improved further. We investigated whether backwash ileitis is also a factor associated with CRC in ulcerative colitis. Methods: Five hundred ninety consecutive patients with ulcerative colitis who received restorative proctocolectomy were classified into 3 groups: (1) pancolitis with backwash ileitis, (2) pancolitis without backwash ileitis, and (3) left-sided colitis. The association with CRC was analyzed in these 3 groups of patients. As further risk factors, we investigated disease duration, dysplasia, primary sclerosing cholangitis, age at diagnosis of disease, disease activity, and gender. Univariate and multivariate logistic regression were used for analysis. Results: CRC was diagnosed in 11.2% of all patients. CRC was found in 29.0% of 107 patients in group 1, compared with 9.0% of 369 patients in group 2, and in 1.8% of 114 patients in group 3 (P < 0.001). Cancer patients in group 1 showed significantly more multiple tumor growth (45.2%) than patients in group 2 (24.2%) and group 3 (0%) (P 0.041). Estimating the relative risk for CRC in the multivariate analysis, patients in group 1 showed a significantly higher odds ratio than patients in groups 2 and 3 (odds ratio: vs vs. 1; P < 0.001). High-grade dysplasia, low-grade dysplasia, disease duration of more than 10 years, and disease duration of less than 10 years in patients older than 45 years were further factors with significantly increased risk (odds ratios: 21.69, 6.36, 3.63, 4.37), but primary sclerosing cholangitis was not (P 0.080). However, primary sclerosing cholangitis was strongly associated with backwash ileitis. Conclusions: There is a strong association of backwash ileitis with CRC in patients with ulcerative colitis who undergo proctocolectomy. The predictive value of backwash ileitis for CRC and premalignant dysplasia in patients with ulcerative colitis should be investigated in future studies based on colonoscopic surveillance. Patients with chronic ulcerative colitis (UC) have a higher risk of developing colorectal carcinoma (CRC). 1 4 Moreover, it is presumed that this risk increases within the range of 0.5% 1.0% per year after 8 10 years of disease in patients with extensive UC, 5 so that, according to different studies, the risk of CRC increases from 1% to 3% 10 years after diagnosis, to approximately 10% after 20 years, and to 25% after 35 years in patients with pancolitis. 6 8 The effects of long duration and extent of disease as risk factors for malignant transformation have been confirmed in several studies. 5,6,9,10 Recent publications also suggest that patients with UC with primary sclerosing cholangitis (PSC) are at higher risk for CRC, relative risks ranging between 1.2 and 10.4, with most of the results being statistically significant By identifying and validating still unknown factors associated with CRC in patients with UC, risk assessment, surveillance strategies, and timing of indications for prophylactic surgery may be improved further. We observed a markedly increased frequency of CRC in patients with UC in whom the mucosal inflammation involved the terminal ileum. The presence of mucosal inflammation proximal to the ileocolic valve was first observed as early as 1949 and termed backwash ileitis (BWI). 17,18 The frequency of BWI in patients with pancolitis ranges from 10% 20% Nevertheless, the clinical implications of BWI have not yet been examined and the underlying pathomechanism is still poorly understood. We conducted the present study to verify the validity of commonly accepted risk factors for CRC and to investigate whether BWI, as the maximum extent of inflammation, as compared with left-sided colitis and pancolitis is associated with CRC in patients with UC. Materials and Methods A total of 609 consecutive patients with UC underwent restorative proctocolectomy at the Department of Sur- Abbreviations used in this paper: BWI, backwash ileitis; CRC, colorectal carcinoma; HGD, high-grade dysplasia; LGD, low-grade dysplasia; PSC, primary sclerosing cholangitis by the American Gastroenterological Association /01/$35.00 doi: /gast

2 842 HEUSCHEN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 gery, University of Heidelberg, between 1982 and 1998 and were included in this study. Data were entered into a clinical registry at the time of surgery and documented prospectively. The registry was maintained and statistical analysis of the data was performed by a biostatistician. Data regarding the clinical course of UC before surgery were obtained directly from the patient s gastroenterologist and the patients themselves. Patients were defined as eligible if UC was confirmed in the specimen resected at proctocolectomy. The extent of UC was determined by the most proximal localization of the inflammation according to the pathologic examination of the resected specimen. We defined BWI as inflammation of the terminal ileal mucosa over a minimum length of 5 cm. BWI could not be confounded with an inflammation of the ileocolic valve, which is frequently encountered in total UC. During each operation, the terminal ileum was examined macroscopically by the surgeon. This finding was later compared with the findings from the histologic examination of the terminal ileum, which was performed by an experienced pathologist in all patients included in the study. Only in cases of histologically verified inflammation and macroscopically verified extent of this inflammation over 5 cm of the terminal ileum was BWI diagnosed. According to the extent of inflammation, patients were classified into 3 groups: (1) pancolitis with BWI, (2) pancolitis without BWI, and (3) left-sided colitis with inflammatory manifestations only distal to the hepatic flexure. In no patient was the mucosal inflammation manifested merely as ulcerative proctitis. All patients with elevated laboratory parameters of cholestasis (alkaline phosphatase and -glutamyl transpeptidase) underwent endoscopic retrograde cholangiography 23 to determine whether PSC was present. The outcome of principal interest was the presence of carcinoma in the resected specimen. As possible influencing factors, we studied gender, age at diagnosis, duration of UC, extent of UC, presence and grade of dysplasia (as defined by the Inflammatory Bowel Disease/Dysplasia Morphology Study Group 24 ), disease activity (based on histological classification according to Truelove and Richards 25 ), and PSC. Statistical Methods SAS software (Release 6.12, SAS Institute, Inc., Cary, NC) was used for statistical analysis. Descriptive statistics are presented as median and interquartile range (25% 75%). Subgroups of patients were compared with respect to the extent of disease using the Fisher exact test and 2 test if appropriate. The Cochran Armitrage trend test was used to determine the relationship between the number of carcinomas and the 3 groups. Age at diagnosis and duration of disease were compared among the 3 groups using the Mann Whitney U test. Logistic regressions were performed for univariate and multivariate analysis of factors potentially associated with cancer. The relative risk was described by the estimated odds ratio (OR) with a 95% confidence interval. To adjust statistically for known risk factors and confounders, multiple logistic regressions were performed that included interaction terms. Any significant interactions were included in the final model. Ninety-five percent confidence intervals that exclude one were considered as statistically significant at the 0.05 level. All tests were 2-sided. Results A total of 609 consecutive patients with UC underwent restorative proctocolectomy at the Department of Surgery at the University of Heidelberg. Of these patients 590 were eligible for the study. One patient had to be excluded from the study because of postoperative diagnosis of Crohn s disease, which had developed in the colon. In all patients with BWI, Crohn s disease was explicitly excluded by histologic examination. Eighteen (3.1%) patients in whom partial colonic resection had previously been performed were excluded because of missing data about the extent of disease. Three groups of patients were distinguished according to the extent of UC and presence of BWI. The frequency of CRC within these 3 groups, potential factors associated with CRC, and indications for proctocolectomy are shown in Table 1. In patients of group 1 with BWI, we found significantly higher values than in the 2 other groups regarding the frequency of CRC (P 0.001), concomitant PSC (P 0.001), and dysplasia (P 0.001). In addition, patients of group 1 were significantly younger at the time of UC diagnosis (P 0.001) and showed a tendency toward longer disease duration (P 0.088), and in this group oncological indications for proctocolectomy were found more often (36.4% vs. 11.7% and 8.8%). Table 2 shows the results of all patients with UC with CRC, differentiating again between patients with pancolitis and BWI, patients with pancolitis but no BWI, and patients with left-sided colitis. The frequency of multiple tumor growth was significantly higher in patients with UC with BWI (P 0.041), and right-sided CRC was found more frequently in patients with BWI than in patients with pancolitis without BWI and patients with left-sided colitis. However, the latter difference was not significant. Univariate Analysis The results of the univariate analysis are presented in Table 3. In patients with a duration of UC of 10 years or longer, the frequency of CRC was significantly higher (OR, 4.51) than in patients with a duration of UC up to 10 years (P 0.001). In relation to the extent of disease, the frequency of CRC was significantly higher in patients of group 1 with BWI or group 2 without BWI than in

3 March 2001 BACKWASH ILEITIS IN UC 843 Table 1. Frequency of CRC in Specimens of 590 UC Patients who Underwent Restorative Proctocolectomy Total no. of UC patients (590) Group 1 (107) Group 2 (369) Group 3 (114) P value CRC 66 (11.2%) 31 (29%) 33 (8.9%) 2 (1.8%) Females 251 (43.9%) 50 (46.7%) 164 (44.4%) 45 (39.5%) 0.52 Age at diagnosis of UC (yr) (IQR ) (IQR ) (IQR ) (IQR ) Disease duration (yr) (IQR ) (IQR ) (IQR ) (IQR ) PSC 44 (7.5%) 28 (26.7%) 12 (3.3%) 4 (3.5%) Dysplasia 101 (17.2%) 37 (34.5%) 48 (13%) 16 (14%) LGD 40 (6.8%) 10 (9.3%) 22 (6%) 8 (7%) HGD 61 (10.4%) 27 (25.2%) 26 (7%) 8 (7%) Disease activity Mild 163 (30.6%) 30 (32.6%) 91 (27.2%) 42 (40%) Severe 369 (69.4%) 62 (67.4%) 244 (72.8%) 63 (60%) Indications for colectomy a Cancer 58 (9.8%) 27 (25.2%) 29 (7.9%) 2 (1.8%) Dysplasia 34 (5.8%) 12 (11.2%) 14 (3.8%) 8 (7.0%) Failed medical treatment 407 (69.0%) 60 (56.1%) 266 (72.5%) 81 (71.1%) Toxic colitis, perforation, hemorrhage 55 (9.3%) 11 (10.3%) 38 (10.4%) 6 (5.3%) Other 62 (10.5%) 10 (9.4%) 35 (9.5%) 17 (14.9%) NOTE. The frequency of potentially associated factors in the 3 groups of patients: (1) pancolitis with BWI (n 107, 18.2%), (2) pancolitis without BWI (n 369, 62.5%), and (3) left-sided colitis (n 114, 19.3%). Total numbers of patients are given, with their relative proportion in parentheses (%). Age and disease duration are described as median and interquartile range (IQR). a More than one indication existed for some of the patients. patients with left-sided colitis (P and 0.021, respectively, with corresponding ORs of 22.8 and 5.5). Patients with high-grade dysplasia (HGD) showed the highest frequency of CRC and the highest OR vs. lowgrade dysplasia (LGD) and vs. no dysplasia (P 0.001). The relative risk of CRC was increased in patients with UC with associated PSC (OR, 8.39; P 0.001). Regarding age at diagnosis of UC, no statistically significant difference was found between the groups examined. Regarding duration of UC combined with the age at diagnosis of UC, we identified a subgroup showing a marked association of these factors with CRC. Among the patients with a duration of colitis of up to 10 years, those patients who were older than 45 years at diagnosis of UC were at a significantly higher relative risk of developing CRC than younger patients (OR, 4.60; P 0.001). Men and women did not show different ORs. In patients with severe UC at the time of restorative proctocolectomy, the relative risk of CRC decreased significantly (OR, 0.52) compared with patients with mild UC. Multivariate Analysis We studied the simultaneous effects of epithelial dysplasia (HGD and LGD), extent of disease (pancolitis with BWI and pancolitis without BWI), duration of UC Table 2. Patients With CRC CRC in UC Group 1 Group 2 Group 3 P value CRC No. of carcinomas Singular 44 (66.6%) 17 (54.8%) 25 (75.8%) 2 (100%) Multiple 22 (33.4%) 14 (45.2%) 8 (24.2%) 0 (0%) Localization a Right 15 (22.7%) 7 (22.6%) 8 (24.2%) 0 (0%) 0.29 Right and left 9 (13.6%) 7 (22.6%) 2 (6.1%) 0 (0%) Left 42 (63.6%) 17 (54.8%) 23 (69.7%) 2 (100%) PSC 19 (28.8%) 11 (35.5%) 7 (21.2%) 1 (50%) 0.36 NOTE. CRC, n 66. Total number of patients is given, with their relative proportion in parentheses (%). Number of carcinomas, localization, and presence of PSC are shown in relation to the 3 groups of patients. Malignancies proximal to the splenic flexure were considered as being located in the right, distal to the splenic flexure in the left hemicolon. a Localization of the tumor proximal or distal to the splenic flexure.

4 844 HEUSCHEN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 Table 3. Univariate Analysis of Potential Risk Factors for CRC in UC Variable Total CRC OR 95% CI P value Duration 10 yr (5.5%) 1 10 yr (20.6%) Extent Group (29.0%) Group (8.9%) Group (1.8%) 1 Dysplasia No (3.9%) 1 LGD (25%) HGD (59%) PSC No (8.2%) 1 Yes (43.2%) Age at diagnosis of UC 15 to 45 yr (10.5%) 1 15 yr 56 8 (14.3%) yr (12.8%) Duration and age at diagnosis of UC 10 yr age 45 yr (3.4%) 1 10 yr age 45 yr (13.9%) yr (20.6%) Gender Male (10.6%) 1 1 Female (12%) Disease activity at time of colectomy a Mild UC (12.3%) 1 1 Severe UC (6.8%) NOTE. n 590. Total numbers of patients are given, with their relative proportion in parentheses (%). a Disease activity measured with the Truelove Witts index (mild: 1 2 pts; severe: 3 4 pts). CI, confidence interval. for more than 10 years, duration of less than 10 years in patients older than 45 years, and of PSC. The results of the multivariate analysis are listed in Table 4. We found that patients with HGD had the highest relative risk of CRC, followed by group 1 patients who suffered from pancolitis with BWI and group 2 patients with pancolitis but without BWI. The relative risk of CRC in patients with pancolitis and BWI was more than twice as high (OR, vs. 9.58) as in patients with pancolitis but without BWI. The differences relative to Table 4. The Final Model of Multiple Logistic Regression Analysis of Risk Factors Independently Associated With CRC Risk factor OR 95% CI P value HGD LGD Pancolitis with BWI Pancolitis without BWI Duration 10 yr Duration 10 yr and patients older than 45 yr PSC NOTE. n 584; missing values, n 6. left-sided colitis again were highly significant. Patients with a disease duration of 10 years or more had an OR of 3.63 (P 0.003). However, patients with a duration of less than 10 years who were older than 45 years even showed an OR of 4.37 (P 0.007). The increase in the relative risk was no longer significant in patients with UC with associated PSC, reflecting the strong association between PSC, BWI, and CRC. The addition of gender, severity of disease, and age at diagnosis of UC under 15 years did not significantly improve any of the logistic regression models examined. Discussion It is generally recognized that there is an increased risk of CRC in patients with UC This threat is particularly high in patients with certain risk factors. For these patients, intensified surveillance programs including coloscopy and random biopsies have been recommended with the aim of detecting dysplasia as a malignant transformation at an early stage of carcinogenesis. This would make it possible to time prophylactic surgery more appropriately. Nevertheless, there is controversy about the effectiveness of surveillance, 1,29 31 and

5 March 2001 BACKWASH ILEITIS IN UC 845 the overall prevalence of manifest CRC in patients with UC is still unacceptably high An improvement in risk assessment, surveillance, and timing of prophylactic proctocolectomy can be achieved by identifying and verifying still unknown factors associated with CRC. Long duration and extent of the inflammation have been established as risk factors in several studies Recently, PSC and early age of onset of UC were discussed as further factors influencing the frequency of CRC. 3,11 16,42,43 The morphology of BWI is similar to that of colitis, 18 but its etiology is poorly understood as yet. The original interpretation of BWI as a reaction to the reflux of colonic content into the terminal ileum, 17,21 which gave rise to the term BWI, but this is no longer considered as the underlying pathomechanism. BWI has recently been discussed as a primary ileal involvement by the mucosal inflammation. 19 The study design that we chose for our investigations has a number of advantages, as well as a few drawbacks. All patients examined in this study were included consecutively. This reduces the risk of selection bias within the total group of patients treated at our hospital. The validity of the results concerning the presence or absence of BWI is supported by the fact that the terminal ileum was macroscopically examined by the surgeon and later histologically examined by an experienced pathologist in all patients included in the study. A possible bias might be introduced by the fact that the study group is composed exclusively of patients with UC who have undergone proctocolectomy. This group of patients represents at most 20% 30% of all patients with UC and has a higher frequency of CRC than patients with UC at medical referral centers. Nevertheless, the frequency of BWI (18.2%) and of PSC (7.5%) in our patients with UC lies within the range observed in the literature. 11,20,22,24 Prophylactic indications for colectomy may introduce a bias into the analysis of factors associated with the endpoint CRC, because the aim of prophylaxis is to avoid CRC. PSC had been suggested to be a potential risk factor for CRC in the last few years Therefore, PSC might have promoted the decision for prophylactic surgery in a number of recent cases, resulting in an imprecise estimation of the predictive value of PSC for CRC. In contrast, up to now BWI was not indicated as being an influencing factor for CRC and therefore did not promote the decision for prophylactic colectomy in any of our patients. As a result of the multivariate analysis, the increase in the relative risk (OR) of CRC was 2-fold higher in patients with pancolitis with BWI than in patients with pancolitis without BWI relative to patients with leftsided colitis. Thus, the strong association of BWI with CRC cannot be attributed to the pancolitis accompanying BWI. In addition to this, multiple tumor growth was found significantly more frequently in patients with pancolitis and BWI than in patients with pancolitis but without BWI. This suggests that some cancerigenic mechanism might be connected with the presence of BWI in patients with UC. No data on BWI as a potential risk factor for CRC have been published to date. We found no case of BWI without concomitant pancolitis, and pancolitis has been shown to imply a greater risk of CRC than colitis of lesser extent. 3,9 Therefore, the risk potential of BWI was presumably assigned to that of pancolitis in a number of patients in earlier studies. The results of our study raise the question of why the frequency of carcinoma is elevated in patients with UC with BWI, and this issue is complicated even further by another interesting finding of our investigation. We found a marked association between the presence of BWI and PSC in patients with UC, which is in line with recent findings published in the literature. 44 This should be considered in light of the fact that PSC has been discussed as a potential risk factor for malignant transformation in patients with UC According to investigations of the pathophysiology of PSC, defects have been detected in the excretion and enterohepatic circulation of cholic acids in these patients It has been speculated that alterations in the enterohepatic circulation of cholic acids are involved in the etiology of CRC. 48,49 Cholic acids are resorbed in the terminal ileum, which suggests that they might also play a role in the genesis of BWI in patients with UC. However, the inflammatory process in the mucosa of patients with BWI might also have implications for the enterohepatic circulation of cholic acids. Other studies have provided evidence that there is an elevated risk of CRC in patients with UC and concomitant PSC In the univariate anlysis, the presence of PSC enhanced the frequency of CRC, but multivariate analysis showed that the impact of concomitant PSC is only small if tested as a risk factor. This is in line with findings of some investigations that question the role of PSC as a risk factor for CRC. 42,43,50,51 Nevertheless, our findings suggest that PSC might be a marker for the presence of BWI. As a means of explaining the simultaneous presence of CRC, BWI, and PSC, one might speculate that some immunologic or genetic defect is the common underlying cause for all 3 pathologic changes. This would mean that we are dealing with a particular subset of patients with UC with a markedly increased risk of CRC.

6 846 HEUSCHEN ET AL. GASTROENTEROLOGY Vol. 120, No. 4 The findings of earlier studies 18,22 suggest that mucosal inflammation involving the terminal ileum may be considered as a maximal extent of UC. It is a commonly accepted theory that CRC develops as the result of an inflammation dysplasia carcinoma sequence in patients with UC. 24,52,53 This explains why the risk of CRC increases if the amount of inflamed mucosal surface increases within the colon, 3 but it certainly does not explain the significant increase in the frequency of CRC when BWI is present. Nor does this explain the increase in multiple tumor growth in patients with pancolitis with BWI. Mucosal inflammation of the terminal ileum, as present in BWI, might mislead the clinician to diagnose Crohn s disease. It is therefore important to emphasize that, in our study, all samples from all patients with UC with and without BWI were examined by a highly experienced pathologist. Crohn s disease was not diagnosed in any of these patients. We also analyzed the implications of conditions that are commonly accepted as risk factors or have been discussed as such in the literature. Our findings concerning the influence of the extent of the inflammation within the colon and of the duration of UC are in line with earlier publications on this issue. 1,3,5,10,29,53,54 In our study, the relative risk of CRC proved to be 5-fold higher in patients with pancolitis than in patients with leftsided colitis and was significantly higher when UC lasted for more than 10 years than in cases of shorter duration. Some investigators reported the predictive value of the age at diagnosis for the risk of CRC. Their findings indicated an increase in the incidence of CRC in patients in whom symptoms of UC began in childhood 3,37,55 or in early adulthood. 9,56 The results of our study are at variance with these findings. Nevertheless, we found a constellation including age at diagnosis and duration of UC, which actually had some impact on carcinoma risk. Patients with a duration of UC of up to 10 years who are older than 45 years at the time of diagnosis of UC are at a significantly higher risk of CRC than younger patients. In conclusion, we showed that there is a high frequency of BWI in patients with UC who undergo restorative proctocolectomy and, furthermore, that a strong association of BWI with CRC is found in these patients. Further studies should investigate the predictive value of BWI in patients with UC for CRC and premalignant dysplasia based on colonoscopic surveillance. If BWI proved to represent a risk factor for CRC in patients with UC, it should be considered to be a criterion for the selection of patients with UC for intensified monitoring, which up to now was based on the known risk factors duration and extent of the colonic inflammation. References 1. 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