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• W1964102710 abstract "Background & Aims: Although inflammation is presumed to contribute to colonic neoplasia in ulcerative colitis (UC), few studies have directly examined this relationship. Our aim was to determine whether severity of microscopic inflammation over time is an independent risk factor for neoplastic progression in UC. Methods: A cohort of patients with UC undergoing regular endoscopic surveillance for dysplasia was studied. Degree of inflammation at each biopsy site had been graded as part of routine clinical care using a highly reproducible histologic activity index. Progression to neoplasia was analyzed in proportional hazards models with inflammation summarized in 3 different ways and each included as a time-changing covariate: (1) mean inflammatory score (IS-mean), (2) binary inflammatory score (IS-bin), and (3) maximum inflammatory score (IS-max). Potential confounders were analyzed in univariate testing and, when significant, in a multivariable model. Results: Of 418 patients who met inclusion criteria, 15 progressed to advanced neoplasia (high-grade dysplasia or colorectal cancer), and 65 progressed to any neoplasia (low-grade dysplasia, high-grade dysplasia, or colorectal cancer). Univariate analysis demonstrated significant relationships between histologic inflammation over time and progression to advanced neoplasia (hazard ration (HR), 3.0; 95% CI: 1.4–6.3 for IS-mean; HR, 3.4; 95% CI: 1.1–10.4 for IS-bin; and HR, 2.2; 95% CI: 1.2–4.2 for IS-max). This association was maintained in multivariable proportional hazards analysis. Conclusions: The severity of microscopic inflammation over time is an independent risk factor for developing advanced colorectal neoplasia among patients with long-standing UC. Background & Aims: Although inflammation is presumed to contribute to colonic neoplasia in ulcerative colitis (UC), few studies have directly examined this relationship. Our aim was to determine whether severity of microscopic inflammation over time is an independent risk factor for neoplastic progression in UC. Methods: A cohort of patients with UC undergoing regular endoscopic surveillance for dysplasia was studied. Degree of inflammation at each biopsy site had been graded as part of routine clinical care using a highly reproducible histologic activity index. Progression to neoplasia was analyzed in proportional hazards models with inflammation summarized in 3 different ways and each included as a time-changing covariate: (1) mean inflammatory score (IS-mean), (2) binary inflammatory score (IS-bin), and (3) maximum inflammatory score (IS-max). Potential confounders were analyzed in univariate testing and, when significant, in a multivariable model. Results: Of 418 patients who met inclusion criteria, 15 progressed to advanced neoplasia (high-grade dysplasia or colorectal cancer), and 65 progressed to any neoplasia (low-grade dysplasia, high-grade dysplasia, or colorectal cancer). Univariate analysis demonstrated significant relationships between histologic inflammation over time and progression to advanced neoplasia (hazard ration (HR), 3.0; 95% CI: 1.4–6.3 for IS-mean; HR, 3.4; 95% CI: 1.1–10.4 for IS-bin; and HR, 2.2; 95% CI: 1.2–4.2 for IS-max). This association was maintained in multivariable proportional hazards analysis. Conclusions: The severity of microscopic inflammation over time is an independent risk factor for developing advanced colorectal neoplasia among patients with long-standing UC. CME quiz on page 1340. CME quiz on page 1340. Patients with ulcerative colitis (UC) face an increased risk for developing colorectal cancer (CRC).1Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Google Scholar, 2Eaden J.A. Abrams K.R. Mayberry J.F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis.Gut. 2001; 48: 526-535Google Scholar, 3Ekbom A. Helmick C. Zack M. et al.Ulcerative colitis and colorectal cancer A population-based study.N Engl J Med. 1990; 323: 1228-1233Google Scholar Established risk factors include prolonged disease duration (>7–8 years), extensive colonic involvement, family history of CRC, coexistence of primary sclerosing cholangitis, and, in some studies, young age at disease onset.1Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Google Scholar To lower this risk, patients are typically enrolled in colonoscopic surveillance programs. This serves to diminish the risk of CRC morbidity and mortality while also minimizing the use of prophylactic colectomy. Such programs call for periodic colonoscopic examinations during which multiple biopsy specimens are taken and evaluated for neoplasia (dysplasia or CRC).1Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Google Scholar Patients with biopsy-proven neoplasia are regarded as being at high risk for the coexistence of or further progression to CRC and, depending on the specific findings, are encouraged to undergo either colectomy or more frequent surveillance examinations. Although acknowledged to be the most effective method of cancer prevention other than prophylactic colectomy, surveillance carries important limitations, including unproven efficacy, incomplete patient enrollment and adherence,4Connell W.R. Lennard-Jones J.E. Williams C.B. et al.Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis.Gastroenterology. 1994; 107: 934-944Google Scholar, 5Lynch D.A. Lobo A.J. Sobala G.M. et al.Failure of colonoscopic surveillance in ulcerative colitis.Gut. 1993; 34: 1075-1080Google Scholar, 6Woolrich A.J. DaSilva M.D. Korelitz B.I. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia.Gastroenterology. 1992; 103: 431-438Crossref Scopus (168) Google Scholar invasiveness, high cost,7Provenzale D. Wong J.B. Onken J.E. et al.Performing a cost-effectiveness analysis: surveillance of patients with ulcerative colitis.Am J Gastroenterol. 1998; 93: 872-880Google Scholar endoscopic sampling variations,8Bernstein C.N. Weinstein W.M. Levine D.S. et al.Physicians’ perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.Am J Gastroenterol. 1995; 90: 2106-2114Google Scholar, 9Eaden J.A. Ward B.A. Mayberry J.F. How gastroenterologists screen for colonic cancer in ulcerative colitis: an analysis of performance.Gastrointest Endosc. 2000; 51: 123-128Google Scholar and poor interobserver agreement in histopathologic interpretation.10Eaden J. Abrams K. McKay H. et al.Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.J Pathol. 2001; 194: 152-157Google Scholar, 11Melville D.M. Jass J.R. Morson B.C. et al.Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome.Hum Pathol. 1989; 20: 1008-1014Scopus (0) Google Scholar One way to improve the effectiveness of surveillance would be to identify additional risk factors for neoplastic progression, thereby permitting closer observation of high-risk patients. Curiously, although inflammation has been assumed to be a key factor contributing to higher risk of colonic neoplasia in UC,12Itzkowitz S.H. Yio X. Inflammation and cancer IV Colorectal cancer in inflammatory bowel disease: the role of inflammation.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G7-G17Google Scholar few studies have examined this issue. One well-conducted, retrospective, case-control study recently reported that histologic inflammation was indeed associated with an increased risk of neoplastic progression.13Rutter M. Saunders B. Wilkinson K. et al.Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.Gastroenterology. 2004; 126: 451-459Google Scholar We reasoned that a cohort study design would better mimic the usual clinical situation of surveillance colonoscopy and would allow us to account for changes in inflammation over time while also considering exposure to surveillance colonoscopies. The aim of the present study was to use such a study design to establish whether the degree of histologic inflammation was an independent risk factor for developing neoplasia in UC. Following approval by The Mount Sinai School of Medicine Institutional Review Board and in accordance with Health Insurance Portability and Accountability Act guidelines, our research group established a UC surveillance database. This database contains all patients in the Mount Sinai Hospital gastrointestinal pathology and surgical pathology registries who had undergone at least 1 surveillance colonoscopy between January 1996 and December 1997, a period chosen to allow for long-term follow-up. The database includes demographic information, data on exposure to inflammatory bowel disease (IBD)-related medications, clinical history, and pathologic findings from colonoscopies and surgeries, including anatomic extent of disease (defined by greatest microscopic extent at any examination based on the findings of Mathy et al),14Mathy C. Schneider K. Chen Y.Y. et al.Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis.Inflamm Bowel Dis. 2003; 9: 351-355Google Scholar number of biopsy specimens per examination, presence and grade of any dysplasia, and presence and severity of inflammation at each biopsied segment of colon. Patients were included if they had (1) a colonoscopic examination in 1996 or 1997; (2) an established clinical diagnosis of UC for ≥7 years based on symptoms, radiology, or endoscopy; (3) no known dysplasia or CRC prior to, or at the time of, their first colonoscopy at our institution; and (4) at least 1 subsequent endoscopic or surgical follow-up examination with biopsies of the colon. Patients were excluded who had undergone prior segmental resection of colitic colon or carried a diagnosis of either Crohn’s disease or indeterminate colitis. The severity of histologic inflammation in each biopsy specimen was extracted from the pathology reports for all available surgical and colonoscopic specimens (surveillance and nonsurveillance) prior to, at, and subsequent to each subject’s inclusion colonoscopy in 1996 or 1997. The histologic criteria for grading severity of inflammation was developed by one of the authors (N.H.) and placed into routine use at The Mount Sinai Hospital in 1988. These criteria have remained unchanged since their introduction. All reports had been issued by one of a small group of gastrointestinal pathologists, trained by N.H., using the narrative equivalent of a standardized histologic activity index (HAI). The degree of inflammation for each biopsy site was scored as follows: 0, inactive/absent; 1, mild; 2, moderate; or 3, severe. Histologic criteria are listed in Table 1, with examples provided in Figure 1. A previous study has verified that the grading of HAI achieves high levels of intra- and interobserver agreement with κ values of approximately 0.9 regardless of level of training.15Fiel M. Qin L. Suriawinita A. et al.Histologic grading of disease activity in chronic IBD: inter- and intra-observer variation among pathologists with different levels of experience.Mod Pathol. 2003; 16: 118AGoogle Scholar By convention, when more than 1 biopsy specimen was taken from a particular segment of the colon, the highest HAI from that segment was recorded. Results of a particular colonoscopy were summarized into a single value, the inflammatory score (IS), which was equal to the sum of HAIs at all sites divided by the number of sites.Table 1Histologic Activity IndexInflammatory activityScoreHistopathologic defining characteristicsInactive/quiescent/normal0No epithelial infiltration by neutrophils.Mildly active1Neutrophil infiltration of <50% of sampled crypts or cross sections, no ulcers or erosions.Moderately active2Neutrophil infiltration of ≥50% of sampled crypts or cross sections, no ulcers or erosions.Severely active3Erosion or ulceration, irrespective of other features. Open table in a new tab Dysplasia, the outcome measure in the present study, was either diagnosed initially or subsequently confirmed as part of routine clinical practice at our institution by one of the authors (N.H.) using the criteria of the IBD Dysplasia Morphology Study Group16Riddell R.H. Goldman H. Ransohoff D.F. et al.Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.Hum Pathol. 1983; 14: 931-968Google Scholar and was recorded as either negative for dysplasia, indefinite for dysplasia, positive for low-grade dysplasia (LGD), positive for high-grade dysplasia (HGD), or positive for CRC. Adenomatous polyps above the proximal-most extent of microscopic disease were excluded. Such polyps were defined as discrete polypoid dysplastic lesions located in segments of endoscopically and histologically normal colon (proximal to diseased colon). Polypoid dysplastic lesions within colitic mucosa were graded according to their histology (LGD, HGD, or CRC). We defined the development of HGD or CRC at follow-up surveillance or colectomy as progression to advanced neoplasia and the development of LGD, HGD, or CRC as progression to any neoplasia. For these outcome events, no distinction was made between flat and polypoid neoplasia. All subjects were followed from their first dysplasia-free colonoscopy (defined as time zero) to 1 of the following end points: (1) neoplastic progression, (2) colectomy, or (3) last recorded colonoscopy without progression. Only 2 colectomies were performed for indications other than dysplasia. The interval between time zero and the end point was termed the follow-up interval. Medians and interquartile ranges were calculated for all continuous variables; proportions were calculated for all binary variables. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using proportional hazards analysis (Cox regression).17Cox D.R. Regression models and life tables.J R Stat Soc Ser B Methods. 1972; 34: 187-220Google Scholar The primary variable of interest, IS (see below), was assessed for its relationships to progression to advanced or any neoplasia both in univariate models and jointly with other suspected risk factors in a multivariable analysis. Univariate analyses were performed initially to test for the influence of known and suspected confounders (duration and extent of disease, primary sclerosing cholangitis, age of onset of disease, exposure to mesalamine-based compounds, and exposure to colonoscopy) on the development of any, or of advanced, neoplasia. Covariates were added, 1 at a time, to a multivariable model with IS-mean if they had a P value < .20 in either the any or advanced neoplasia univariate analyses. In the proportional hazards model, effects of covariates are assessed repeatedly for all patients still under observation at the time of each positive finding in any patient. Typically, values of the covariates are fixed at the time of entry into the study. In this study, 2 variables whose values are known to change over time, IS and exposure to colonoscopy, were coded as time-changing covariates. Use of time-changing covariates allows for values of variables to be updated so that they refer only to values up to and including the time of a particular comparison.18Collett D. Modelling survival data in medical research. Chapman and Hall/CRC, Boca Raton, FL1994Google Scholar The relationship between histologic inflammation and progression to any neoplasia or to advanced neoplasia was assessed 3 ways, each based on the inflammation scores of all colonoscopies up to and including the time of a particular comparison. (As described previously, comparisons were made at the time of each positive outcome according to Cox proportional hazards modeling.)17Cox D.R. Regression models and life tables.J R Stat Soc Ser B Methods. 1972; 34: 187-220Google Scholar (1) IS-mean is the average inflammation score of all of the colonoscopies registered in the model at the time of the comparison. It is a continuous variable, with high values if there are multiple high inflammation scores to date. An occasional high inflammation score will be diluted by a large number of colonoscopies with low scores and vice versa. (2) IS-bin is a binary variable that equals 1 if IS-mean at the time of comparison is ≥1 and is 0 if otherwise. (3) IS-max is a continuous variable whose value equals the maximum inflammation score among colonoscopies up to and including the time of a particular comparison. Exposure to colonoscopy, given its irregular application in this nonprotocolized surveillance cohort, was also evaluated as a time-changing covariate, defined at each time point as the number of colonoscopies to that time divided by the number of years since the first. Exposure to medications was considered positive if there were at least 4 months of consecutive use. All analyses were performed with SAS software (SAS Institute, Cary, NC) on a Windows (Microsoft Corp, Redmond, WA) operating system personal computer. Of 543 UC patients who underwent surveillance colonoscopy between 1996 and 1997, 125 patients were excluded for having dysplasia at their first colonoscopy at our institution, lack of histologic follow-up, or prior colorectal surgery, leaving a cohort of 418 patients with no initial dysplasia. The demographic characteristics of the cohort and their surveillance patterns and medication use are provided in Table 2. Over 90% of patients had extensive colitis, and the median duration of UC was 16 years. Very few patients in this cohort had primary sclerosing cholangitis. Patients were followed for a median of 6.7 years, receiving a median of 5 surveillance colonoscopies at a median interval of 0.8 years. The vast majority was taking mesalamine-based compounds, more than half had used steroids, fewer than one third had taken 6-mercaptopurine or azathioprine, almost one third had taken folic acid, and very few received cyclosporine. Overall, 65 (15.6%) patients progressed to any neoplasia, and 15 (3.6%) progressed to advanced neoplasia. Of these 15 with advanced neoplasia, 5 were adenocarcinomas, 1 was a raised HGD lesion, and 9 were flat HGD.Table 2DemographicsTotalNumber of patients418Male, n224 (54.0%)Age at UC diagnosis; y (IQ-range)26.8 (19.4–36.1]Extensive UC, n324 (92.0%)Duration UC; y (IQ-range)16 (11.1–22.9)PSC, n6 (1.8%)Surveillance patterns Total number of colonoscopies2255 Examinations per patient; median (IQ-range)5 (3–7) Length of follow-up; median (IQ-range)6.7 (4.2–8.8) Frequency of examinations per patient per y; median (IQ-range)0.8 (0.6–1.1)Medication use Mesalamine-based agents, n310 (90.9%aExcludes patients for whom this information was missing.) Steroids, n200 (58.7%aExcludes patients for whom this information was missing.) 6-MP/AZA, n117 (28.0%aExcludes patients for whom this information was missing.) Cyclosporine, n21 (6.1%aExcludes patients for whom this information was missing.) Folate, n105 (30.8%aExcludes patients for whom this information was missing.)NOTE. Median and interquartile range (IQ-range) given for continuous variables.PSC, primary sclerosing cholangitis; 6MP/AZA, 6-mercaptopurine or azathioprine.a Excludes patients for whom this information was missing. Open table in a new tab NOTE. Median and interquartile range (IQ-range) given for continuous variables. PSC, primary sclerosing cholangitis; 6MP/AZA, 6-mercaptopurine or azathioprine. Of the 2255 surveillance examinations, most exhibited little histologic inflammation in the colon. As seen in Table 3, only 83 of these examinations resulted in an IS-mean of ≥2, with 1832 showing values of <1. Overall, the median IS was 0.33 with an interquartile range from 0 to 0.75.Table 3Inflammatory Score for the 2255 Colonoscopies PerformedISNumber0591>0 to <112411 to <23402 to <359>324 Open table in a new tab On univariate analysis, a significant relationship was found between inflammation and progression to advanced neoplasia (Table 4). Measuring inflammation as the mean over the length of surveillance (IS-mean), a 3-fold increased risk for advanced neoplasia was observed (HR, 3.0; 95% CI: 1.4–6.3). Thus, for every unit increase in cumulative mean histologic inflammation score, there was a 3-fold increase in risk of advanced neoplasia. Likewise, when scored as the maximal inflammation score ever during surveillance (IS-max), a 2-fold increase in risk was observed (HR, 2.2; 95% CI: 1.2–4.2). When the cumulative mean inflammation score was ≥1 (IS-bin), we found the highest point estimate (HR, 3.4, 95% CI: 1.1–10.4) for inflammation predicting advanced neoplasia. When the end point of any neoplasia was used, there was a trend toward increased risk of neoplasia, with HR values ranging between 1.0 and 1.7 for the 3 IS measures, but these did not achieve statistical significance. To ensure that the effects of inflammation prior to surveillance were not somehow biasing our results, we removed the 34 patients in whom such examinations were available for analysis and found that there was no change in risk to progression to advanced neoplasia, with IS-mean yielding an HR of 2.8 (95% CI: 1.2–6.2).Table 4Univariate Association Between Predictors and End PointEnd point, HR (95% CI)Any neoplasia (n = 65)Advanced neoplasia (n = 15)Inflammation score IS-mean1.4 (0.9–2.3)3.0 (1.4–6.3) IS-bin1.7 (0.9–3.1)3.4 (1.1–10.4) IS-max1.0 (0.7–1.5)2.2 (1.2–4.2)Other factors One or more colonoscopies/y1.7 (0.9–3.0)3.9 (1.3–11.4) Extent of disease1.1 (0.4–3.5)HRaNonextensive disease group, among patients with PSC, and those who received cyclosporine. Duration of disease >15 y1.6 (0.9–2.8)2.0 (0.6–6.3) Age at diagnosis ≤25 y0.7 (0.4–1.2)1.6 (0.6–4.5) PSC1.1 (0.2–8.0)HRaNonextensive disease group, among patients with PSC, and those who received cyclosporine. Mesalamine-based agents0.6 (0.3–1.2)0.5 (0.1–2.4) 6MP/AZA1.0 (0.6–1.6)0.8 (0.3–2.7) Steroids0.6 (0.4–1.1)0.6 (0.2–1.7) Cyclosporine0.8 (0.3–2.6)HRaNonextensive disease group, among patients with PSC, and those who received cyclosporine. Folate0.9 (0.5–1.6)1.3 (0.4–3.7) Male1.5 (0.9–2.4)2.5 (0.8–7.8)PSC, primary sclerosing cholangitis; 6MP/AZA, 6-mercaptopurine or azathioprine.a Nonextensive disease group, among patients with PSC, and those who received cyclosporine. Open table in a new tab PSC, primary sclerosing cholangitis; 6MP/AZA, 6-mercaptopurine or azathioprine. As shown in Table 4, the relationship between most suspected clinical variables and neoplastic progression was not significant in univariate testing, including disease extent, duration, age at diagnosis, or presence of primary sclerosing cholangitis or the use of aminosalicylates, purine analogue immunomodulators, corticosteroids, or folic acid. Because it met the predefined threshold of P < .20 for progression to any neoplasia in univariate testing, mesalamine was included in the multivariable model, but it was neither independently significant (P = .12 for any neoplasia and P = .60 for advanced neoplasia) nor did it alter the relationship between inflammation and either any neoplasia or advanced neoplasia. There was a significant relationship between exposure to surveillance colonoscopy and the subsequent detection of advanced neoplasia. IS-mean and frequency of colonoscopy were therefore considered together in multivariable analyses (Table 5). The modest changes in the IS-mean odds ratios and their CIs as compared with their univariate counterparts indicate that the effect of inflammation remains significant or near significant when controlling for the frequency of colonoscopy. The results of the multivariable analysis were similar when inflammation score was characterized as IS-bin or IS-max.Table 5Association Between Mean Inflammation Score and End Point After Adjusting for Frequency of Scopes per Year ≥1End point, HR (95% CI)Any neoplasia (n = 65)Advanced neoplasia (n = 15)IS-mean1.4 (0.9–2.3)3.8 (1.7–8.6)One or more colonoscopies per year1.7 (0.9–3.1)5.4 (1.7–17.0)NOTE. IS-mean and frequency of colonoscopy were both modeled as time-changing covariates. Open table in a new tab NOTE. IS-mean and frequency of colonoscopy were both modeled as time-changing covariates. Few studies have addressed the severity of colonic inflammation over time as an independent risk factor for progression to neoplasia. Two attempts to determine whether the risk of CRC was associated with frequency of clinical exacerbations found no such relationship.19Eaden J. Abrams K. Ekbom A. et al.Colorectal cancer prevention in ulcerative colitis: a case-control study.Aliment Pharmacol Ther. 2000; 14: 145-153Google Scholar, 20Pinczowski D. Ekbom A. Baron J. et al.Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study.Gastroenterology. 1994; 107: 117-120Crossref Scopus (344) Google Scholar Rutter et al, however, successfully demonstrated a correlation between histologic inflammation and neoplastic progression in a case-control study involving 68 cases and 136 matched controls.13Rutter M. Saunders B. Wilkinson K. et al.Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.Gastroenterology. 2004; 126: 451-459Google Scholar They also showed that endoscopic disease activity correlated with neoplastic progression, although this relationship did not hold up in multivariable testing.13Rutter M. Saunders B. Wilkinson K. et al.Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.Gastroenterology. 2004; 126: 451-459Google Scholar Although that study strongly supports the hypothesis that inflammation contributes to neoplasia, there were potential limitations based on its design: the authors’ use of a single value of inflammation for each subject’s history does not account for changes in inflammation status over the course of disease; their inflammation scoring system has not been measured for interobserver agreement, and case-control methodology is known to be susceptible to unidentified biases.21Feinstein A.R. Clinical epidemiology. W. B. Saunders Company, Philadelphia1985Google Scholar The present study attempted to overcome some of these potential biases. We used a cohort study design based on our UC surveillance database, which permitted us to determine the effect of changes in inflammation over time. Thus, inflammation scores (measured 3 ways) were continuously updated as they changed with the passage of time. In addition, we used a highly reproducible histologic scoring system to determine the severity of inflammation. In our cohort of 418 patients, all of whom entered surveillance without known dysplasia, we found a significant relationship between the severity of histologic inflammation over time and subsequent neoplastic progression to HGD or CRC. Although it did not reach statistical significance, a similar trend toward increased risk for any neoplasia was observed. An additional strength is our use of a relatively simple histologic activity index to grade inflammation. In contrast to other histologic grading systems, the HAI is assessed primarily on the basis of neutrophil infiltration of the colonic epithelium. It disregards a variety of secondary cumulative changes in IBD that are indicative of disease chronicity but not necessarily activity. HAI therefore limits the number of histologic variables considered and affords both ease of application and high levels of interobserver agreement.15Fiel M. Qin L. Suriawinita A. et al.Histologic grading of disease activity in chronic IBD: inter- and intra-observer variation among pathologists with different levels of experience.Mod Pathol. 2003; 16: 118AGoogle Scholar Furthermore, to account for variations in inflammation and endoscopic sampling, we utilized the mean of the HAI values to define an inflammation score to describe the overall inflammation at each colonoscopy and 3 different summaries of accumulated inflammation scores to assess the cumulative history of disease activity: IS-mean, IS-bin, and IS-max. Although it remains to be seen which of these measures best correlates with an individual’s cancer risk, our results suggest that histologic severity of inflammation should be considered an independent risk factor for neoplastic progression in UC. Such a relationship is indeed supported by current concepts relating inflammation to molecular mechanisms of neoplasia.12Itzkowitz S.H. Yio X. Inflammation and cancer IV Colorectal cancer in inflammatory bowel disease: the role of inflammation.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G7-G17Google Scholar There are several potential limitations to this study. First, despite being a cohort study, it is retrospective. A corresponding prospective investigation would be difficult if not unfeasible because of the long time intervals required for patients with no initial dysplasia to progress to cancer. Second, inflammation in IBD may be regional or patchy and can change with time. Although the time-changing covariate model, the use of 3 measures of histologic activity, and the multiplicity of surveillance examinations and biopsies were intended to compensate as much as possible for these effects, our methodology is nonetheless based on the presumption that the biopsy results captured at each location and time point accurately represent the intensity of inflammation in the colon throughout each interval. Additionally, we were unable to accurately and reliably capture the histologic inflammatory state of our subjects’ colons in the period preceding entrance into a surveillance system, owing in part to the referral nature of many of the practices and the variability with which clinicians perform endoscopic evaluations in the period preceding surveillance. A third point for discussion is the selection of multiple end points to study neoplastic progression. Although LGD, HGD, and CRC have different clinical and prognostic implications, each, by definition, corresponds to unequivocal neoplasia.16Riddell R.H. Goldman H. Ransohoff D.F. et al.Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.Hum Pathol. 1983; 14: 931-968Google Scholar Because so little is known regarding the role of inflammation in the pathogenesis of neoplasia, a comprehensive choice of end points seems justified. Additionally, whereas the diagnosis of dysplasia is less climactic than that of CRC, the current consensus is that it represents an indication for colectomy, certainly in the case of HGD,22Itzkowitz S.H. Present D.H. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 314-321Google Scholar and as recommended by some authorities for flat or unresectable LGD.6Woolrich A.J. DaSilva M.D. Korelitz B.I. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia.Gastroenterology. 1992; 103: 431-438Crossref Scopus (168) Google Scholar, 23Ullman T.A. Loftus Jr, E.V. Kakar S. et al.The fate of low-grade dysplasia in ulcerative colitis.Am J Gastroenterol. 2002; 97: 922-927Google Scholar, 24Ullman T.A. Patients with low-grade dysplasia should be advised to undergo colectomy.Inflamm Bowel Dis. 2003; 9 (discussion 273–275): 267-269Google Scholar, 25Ullman T. Croog V. Harpaz N. et al.Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis.Gastroenterology. 2003; 125: 1311-1319Google Scholar, 26Bernstein C.N. Shanahan F. Weinstein W.M. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis?.Lancet. 1994; 343: 71-74Google Scholar We purposely excluded polypoid dysplastic lesions proximal to areas of colitis because those are considered sporadic adenomas and therefore do not represent an indication for colectomy.1Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Google Scholar We did not attempt to subclassify polypoid dysplastic lesions within the diseased colon into dysplasia-associated lesion or mass and adenomas because the endoscopists generally did not make this distinction themselves or provide sufficient documentation to permit retrospective determinations. It should also be noted that many of the procedures in this study, including that of the patient with polypoid HGD, were carried out prior to publications in 1999 demonstrating the safety of endoscopic resection of polypoid dysplasia in diseased mucosa of UC.27Engelsgjerd M. Farraye F.A. Odze R.D. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis.Gastroenterology. 1999; 117: 1288-1294Google Scholar, 28Rubin P.H. Friedman S. Harpaz N. et al.Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps.Gastroenterology. 1999; 117: 1295-1300Google Scholar However, only 1 of the 15 patients who progressed to advanced neoplasia potentially could have had an adenoma rather than a dysplasia-associated lesion or mass; thus, it is unlikely that misclassification of adenomas as advanced neoplasia has substantially biased the results. Interestingly, although active inflammation has been claimed to interfere with the interpretation of surveillance biopsy specimens and cited as a reason for lower levels of observer agreement when specimens with indefinite for dysplasia and LGD histology have been studied,11Melville D.M. Jass J.R. Morson B.C. et al.Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome.Hum Pathol. 1989; 20: 1008-1014Scopus (0) Google Scholar we found a lesser association with LGD (a constituent of any neoplasia) than with more advanced pathology. Additionally, we noted a strong association between exposure to colonoscopy and the subsequent development of dysplasia and cancer. It is unclear exactly why such patients were more likely to develop neoplasia at a later date (because this variable was measured as a time-changing covariate). The most likely explanation is that a form of detection bias occurred, with a more intensive examination schedule yielding a higher frequency of positive findings. To what extent confounding (unreported endoscopic findings such as incomplete reporting of pseudopolyps, recently noted to be an independent risk factor for neoplasia,29Velayos F.S. Loftus Jr, E.V. Jess T. et al.Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.Gastroenterology. 2006; 130: 1941-9194Abstract Full Text Full Text PDF Scopus (317) Google Scholar for example) may have additionally contributed to the association between colonoscopic frequency and neoplasia is unknown. Nonetheless, more frequent colonoscopy did not alter the association between inflammation and neoplasia in the multivariable analysis. Finally, the system employed to grade histologic activity in this study, although used routinely by gastrointestinal pathologists at The Mount Sinai Hospital for many years, is not standard among pathologists at large. Indeed, no such standard system exists, largely because of issues related to complexity and unproven generalizability.30Xiao L.F. Sutherland L.R. Assessing disease activity and disease activity indices for inflammatory bowel disease.Curr Gastroenterol Rep. 2002; 4: 490-496Google Scholar, 31Geboes K. Is histology useful for the assessment of the efficacy of immunosuppressive agents in IBD and if so, how should it be applied?.Acta Gastroenterol Belg. 2004; 67: 285-289Google Scholar, 32Geboes K. Riddell R. Ost A. et al.A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.Gut. 2000; 47: 404-409Google Scholar The relative simplicity and high rates of intra- and interobserver agreement of the HAI system used in this study15Fiel M. Qin L. Suriawinita A. et al.Histologic grading of disease activity in chronic IBD: inter- and intra-observer variation among pathologists with different levels of experience.Mod Pathol. 2003; 16: 118AGoogle Scholar are therefore advantageous. Whether our results can be extrapolated to other patient populations, surveillance schedules, and pathologists awaits further study. In the meantime, our study supports the concept that severity of histologic inflammation in UC patients is directly related to the likelihood of developing neoplasia and that patient stratification based on this risk may ultimately contribute to modifications in their management and surveillance. Nonetheless, it should be kept in mind that the risk of neoplastic progression in IBD is probably multifactorial. A better understanding of the molecular interplay between inflammation and carcinogenesis and of other potential risk factors offers the hope of decreasing the likelihood of developing colitis-associated CRC. The authors thank the many attending gastroenterologists at Mount Sinai who supported this effort. Continuing Medical Education Exam 1: October 2007GastroenterologyVol. 133Issue 4Preview Full-Text PDF" @default.
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