Dysplasia In Inflammatory Bowel Disease Patients Research Articles

Management of Dysplasia in Inflammatory Bowel Disease.

Given the chronic nature of mucosal inflammation present in patients with inflammatory bowel disease (IBD), there is a high risk of dysplastic lesions progressing to cancer, in addition to a high risk of synchronous and/or metachronous cancers developing in those diagnosed with dysplasia. Due to this, consensus guidelines recommend regular surveillance. When visible dysplasia is encountered, options include endoscopic or surgical resection depending on characteristics of the lesion. Advancements in endoscopic tools increasingly allow for endoscopic removal when appropriate. Invisible dysplasia discovered on random biopsy should prompt referral to physicians who specialize in IBD. While surgical resection with proctocolectomy significantly decreases the risk of colorectal cancer, the risk must be balanced against the morbidity of surgery and quality-of-life concerns. Management of dysplasia in IBD patients requires complex decision-making that requires balance of patient values and goals of care with cancer-related risk factors.

S831 Obesity Is Associated With an Increased Risk of Colorectal Neoplasia in Patients With Inflammatory Bowel Disease

Introduction: Obesity is associated with an increased risk of colorectal neoplasia, but this relationship has not been studied in patients with inflammatory bowel disease (IBD). Both IBD and obesity induce a chronic inflammatory state, so the combination of the two could have an additive or synergistic effect on risk of colorectal neoplasia. Given the increased baseline incidence of dysplasia among IBD patients, identifying modifiable risk factors, such as obesity, could have a significant impact on long term cancer-related outcomes. Methods: We performed a retrospective case-control study of IBD colitis patients at an academic IBD Center between January 2006 and February 2022. Demographic and disease-related data, known risk factors for dysplasia, and median BMI during the follow-up period were obtained. Only patients with at least 5 years of colonoscopy reports were included. A case was defined as any patient with biopsy proven dysplasia—indefinite, low-grade, or high-grade—during the study period. A control was defined as any patient with absence of biopsy-proven dysplasia. Obesity was defined as BMI of 30 or greater. Univariate analysis was performed using T-test for continuous variables and chi-square for categorical variables. Multivariate analysis was performed using logistic regression to model dysplasia risk. Results: 106 cases had biopsy-proven colorectal dysplasia (64 IND, 36 LGD, 10 HGD); 125 controls had no dysplasia. Number of colonoscopies (p < 0.001) IBD subtype ulcerative colitis (p = 0.016), maximum histologic severity (p = 0.127), pseudopolyps (p = 0.162), IBD duration (p = 0.098), sex (p = 0.18), age (p < 0.001), smoking history (p = 0.048), prior dysplasia (p < 0.001), and obesity (p < 0.001) were associated with dysplasia on univariate analysis. On multivariable regression, number of colonoscopies (OR 1.26, 95% CI 1.08 - 1.48, p = 0.004), prior dysplasia (OR 3.98, 95% CI 1.23 - 12.86, p = 0.021), and obesity (OR 2.90, 95% CI 1.21 - 6.95, p = 0.017) were each independently associated with increased dysplasia risk. (Figure) Conclusion: Patients with IBD have an increased risk of colorectal neoplasia, but a variety of comorbid states may exacerbate this risk. Notably, we identified obesity as an independent risk factor for dysplasia. Further research is needed to determine whether this risk functions synergistically with IBD or just as an independent risk factor. Furthermore, targeted weight-loss interventions may reduce the incidence of dysplasia among patients with IBD.Figure 1.: Univariate Analysis and Multivariable Regression of Risk Factors for Dysplasia in IBD Patients.

Prevalence of Anal Intraepithelial Lesions in Patients with Inflammatory Bowel Disease

Abstract Introduction Anal intraepithelial neoplasia (AIN) is a premalignant lesion of the anal canal associated with HPV, with a higher prevalence in immunosuppressed individuals. Patients with inflammatory bowel disease (IBD) are at potential risk for their development, due to the use of immunosuppressants and certain characteristics of the disease. Method This is a prospective, cross-sectional, and interventional study that included 53 patients with IBD treated at a tertiary outpatient clinic, who underwent anal smear for cytology in order to assess the prevalence of AIN and associated risk factors. Results Forty-eight samples were negative for dysplasia and 2 were positive (4%). Both positive samples occurred in women, with Crohn's disease (CD), who were immunosuppressed and had a history of receptive anal intercourse. Discussion The prevalence of anal dysplasia in IBD patients in this study is similar to that described in low-risk populations. Literature data are scarce and conflicting and there is no evidence to recommend screening with routine anal cytology in patients with IBD. Female gender, history of receptive anal intercourse, immunosuppression and CD seem to be risk factors.

Epithelial TLR4 Signaling Activates DUOX2 to Induce Microbiota-Driven Tumorigenesis

Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease. We have described the critical role of innate immune signaling via Toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitis-associated neoplasia. Inflammatory bowel disease and colorectal cancer data sets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (H2O2) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-knockout mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice. Activation of epithelial TLR4 was associated with up-regulation of DUOX2 and NOX1 in inflammatory bowel disease and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H2O2. Epithelial H2O2 was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased H2O2 production and tumorigenesis. Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of H2O2. The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial reactive oxygen species and increased development of colitis-associated tumors. The inter-relationship between epithelial reactive oxygen species and tumor-promoting microbiota requires a 2-pronged strategy to reduce the risk of dysplasia in colitis patients.

Dysplasia Surveillance in Inflammatory Bowel Disease: A Cohort Study

Introduction: Patients with colonic inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer (CRC), whereby surveillance colonoscopy is recommended. Aim: To study the clinical and endoscopic variables associated with dysplasia in IBD patients. Methods: A cohort study was conducted on IBD patients who were part of a colonoscopy surveillance program between 2011 and 2016. Results: A total of 342 colonoscopies were performed on 162 patients (105 with ulcerative colitis [UC] and 57 with Crohn’s disease). Random biopsies were performed at least once on 81.5% of patients; 33.3% of the patients underwent chromoendoscopy (CE) at least once. Endoscopically resectable lesions were detected in 55 patients (34%), and visible lesions deemed unfit for endoscopic resection were found in 5 patients (3.1%). Overall, 62 dysplastic visible lesions (58 with low-grade dysplasia and 3 with high-grade dysplasia) and 1 adenocarcinoma were found in 34 patients. Dysplasia in random biopsies was present in 3 patients, the yield of random biopsies for dysplasia being 1.85%/patient (3/162), 1.75%/colonoscopy (6/342), and 0.25%/biopsy (9/3,637). Dysplasia detected in random biopsies was significantly associated with a personal history of visible dysplasia (p = 0.006). Upon univariate analysis, dysplasia was significantly associated with the type of IBD, the performance of random biopsies, and CE (p = 0.016/0.009/0.05, respectively). On multivariate analysis, dysplasia was associated with duration of disease. Conclusion: Our data confirm that patients with long-standing IBD, in particular UC, should be enrolled in dysplasia surveillance programs, and that performing CE and random biopsies seems to help in the detection of colonic neoplastic lesions.

Significance of serrated epithelial change in inflammatory bowel disease

ABSTRACT Objectives The clinical significance of hyperplastic polyp-like histologic changes in random biopsy samples (‘serrated epithelial change’ or SEC) from patients with inflammatory bowel disease (IBD) remains uncertain, with some studies suggesting an increased risk of dysplasia and even carcinoma. Controlled studies are few. We studied the significance of SEC on the development of dysplasia in follow-up surveillance of IBD patients in our system. Methods We identified 94 IBD patients with SEC and 187 IBD patients without SEC identified in index biopsy samples, and retrospectively collated results of follow-up surveillance samples in each group, with the development of dysplasia and/or adenocarcinoma as study endpoints. Results IBD patients with SEC had a 12.8% likelihood of developing dysplasia of any type within IBD-affected areas vs a 4.3% likelihood in non-SEC patients (follow-up in the 1–4 year range for each group). This was significant in univariate analysis (p = 0.013) but not in multivariate analysis, likely due to increased frequency of follow-up sampling in the SEC patients. One cancer developed in each group (p = NS). Conclusion Our data, in the context of other studies, neither prove nor conclusively exclude an increased risk of dysplasia in IBD patients with SEC. But cancer risk appears low and continued surveillance at usual intervals seems reasonable.

Endoscopic resection of colon dysplasia in patients with inflammatory bowel disease: a systematic review and meta-analysis

Inflammatory bowel disease (IBD) is a well-known risk factor for colorectal cancer (CRC). Current guidelines propose complete endoscopic resection of dysplasia in IBD patients with close endoscopic follow-up. Current data on the risk of neoplasia after endoscopic resection of dysplasia in IBD patients are limited. Multiple databases were searched from inception through August 2019 to identify studies that reported on incidence and/or recurrence of neoplasia after resection of dysplasia in patients with IBD. Outcomes from the included studies were pooled to estimate the risk of neoplasia after dysplasia resection in IBD patients. From 18 studies, 1037 IBD patients underwent endoscopic resection for a total of 1428 colonic lesions. After lesion resection, the pooled risk (rate per 1000 person-years of follow-up) of CRC was 2 (95% confidence interval [CI], 0-3), the pooled risk of high-grade dysplasia was 2 (95% CI, 1-3), and the pooled risk of any lesion was 43 (95% CI, 30-57). Meta-regression analysis based on lesion location (right, left), lesion size (mean and/or median size inmm), lesion type (Paris type I, Paris type II), endoscopic resection technique (EMR, endoscopic submucosal dissection, or polypectomy), and lesion histology (low-grade dysplasia, high-grade dysplasia) did not influence the reported outcomes. Risk of CRC after dysplasia resection in IBD patients appears to be low, supporting the current strategy of resection and surveillance.

Methylation patterns in dysplasia in inflammatory bowel disease patients

Background and aims: Inflammatory Bowel Disease (IBD) with colonic involvement increases colorectal cancer risk. However, the distinction between IBD related and sporadic dysplasia in IBD patients is difficult. Some data favors the importance of abnormal DNA methylation in IBD-related carcinogenesis. We aimed to define methylation patterns in patients with colonic cancer or dysplasia diagnosis following an IBD diagnosis.Methods: Multicentric cross-sectional study-91 samples from colonic mucosa with/without dysplasia from 9 patients with IBD-related dysplasia/cancer and 26 patients with IBD and sporadic dysplasia/cancer were included. Methylation patterns of CpG islands in the promoter regions of 67 genes were studied by Methylation-specific Multiplex Ligation-dependent Probe Amplification.Results: Mean age at IBD diagnosis: 42 ± 16 years;at dysplasia diagnosis: 56 ± 14 years. Twenty-ninepatients had ulcerative colitis. Twenty-five patients had at least 1 lesion endoscopically described as adenoma-like, 4 at least 1 non-adenoma like, 3 had cancer and 3 had dysplasia in flat mucosa. No patient had both adenoma-like and non-adenoma-like lesions. Patients with an IBD-related lesion were significantly younger at IBD diagnosis (p = .003) and at dysplasia/cancer diagnosis (p = .039). Promoter methylation of IGF2, RARB, ESR1, CHFR, CDH13, WT1, GATA5, WIF1genes was significantly associated to dysplasia/cancer; methylation of MSH6, TIMP3 was significantly associated to IBD-related dysplasia/cancer. Promoter methylation of MSH6, MSH3, RUNX3, CRABP1, TP73, RARB, CDH13, PAX5, WT1, THBS1, TP53, SFRP1, WIF1, APAF1, BCL2 genes was significantly associated to active IBD.Conclusions: Methylation analysis, namely of MSH6, may contribute to the classification of dysplastic lesions in IBD– to be further tested in prospective studies.

Importance of Screening Colonoscopy for Colorectal Cancer among Inflammatory Bowel Disease Patients in Qatar

Since 1920, inflammatory bowel disease (IBD) has been linked to increased incidence and mortality from colorectal adenocarcinoma (CRC). Several studies have found that screening colonoscopy reduced CRC mortality and improved survival in IBD patients. However, there are little or no data about the prevalence of CRC/Dysplasia in Qatar detected by screening colonoscopy and weather the Qatar gastroenterologists adhere to the international guidelines. Thus, the focus of the present study was to examine the rate of CRC and dysplasia in IBD patients who underwent a screening colonoscopy. The sample consisted of 153 patients who were diagnosed and treated for IBD. The results of the study showed high incidence rate of CRC/Dysplasia among IBD patients and it was also found that the gastroenterologists in Qatar did not strictly adhere to the international guidelines in relation to the time of first screening colonoscopy of IBD patients.

P268 Systematic review and meta-analysis: Inflammatory bowel disease (IBD) associated colonic dysplasia prognosis in the video-endoscopic era

Abstract Background Management of dysplasia in IBD patients is largely based on outcomes reported by a small number of observational studies, most of which include data from the pre-videoendoscopic era (before 1990). The impact of recent advances in dysplasia detection e.g. high definition chromoendoscopy (HDCE) and endoscopic resection techniques on colorectal cancer (CRC) risk needs to be better understood to inform management decision-making. We conducted an updated review of dysplasia prognosis in the videoendoscopic (VE) era according to lesion morphology, grading and endoscopic resectability. Methods The search strategy is described in Figure 1. The inclusion criteria were studies of (1) IBD colitis patients with dysplasia, (2) who had a colectomy or at least one colonoscopy on follow-up, and (3) reported on the incidence of CRC, according to the endoscopic visibility, morphology and grade of the index dysplasia. The primary outcomes were: (a) the ‘prevalent CRC rate’ (incidental CRC found on colectomy undertaken within 6 months of a dysplasia diagnosis and may represent missed cancers on colonoscopy) and (b) the incidence of metachronous CRC found on follow-up of more than 6 months after a dysplasia diagnosis. Meta-analyses were performed to obtain pooled estimates of the outcomes as appropriate. Quality of the evidence was assessed using GRADE criteria. Results Thirty studies met criteria for inclusion. The pooled estimated prevalent cancer rate for visible and invisible high-grade dysplasia (HGD) patients were 14% (95% CI 0–54; I2=92) and 11% (95% CI 5–20) respectively; for visible and invisible low-grade dysplasia (LGD) patients it was 3% in both groups (95% CI 0–8; I2=19–45); and for indefinite dysplasia it was 1% (95% CI 0–7). Risk of metachronous CRC, 2 years after endoscopic resection of polypoid or non-polypoid LGD were 0–5% and 0–22%, respectively. Risk of metachronous CRC, 2 years after a diagnosis of invisible LGD or indefinite dysplasia were 0–28% and 0–1%, respectively. The lowest rates for both primary outcomes were noted for dysplasia detected during HDCE surveillance and resected en bloc with clear histological resection margins.GRADE assessment of the quality of evidence was low or very low due to the inclusion of mainly case series or small cohort studies with heterogeneous populations and limited follow-up. Conclusion The results from this review suggest that the recent advances in endoscopic techniques are reducing the rates of prevalent and metachronous CRC. However, the evidence-base informing dysplasia prognosis from the VE era remains of low quality. More long-term data on the risk of metachronous CRC, particularly after the resection of non-polypoid dysplasia, is required to inform decision making.

Endoscopic Therapeutic Approach for Dysplasia in Inflammatory Bowel Disease.

Long-standing intestinal inflammation in patients with inflammatory bowel disease (IBD) induces dysplastic change in the intestinal mucosa and increases the risk of subsequent colorectal cancer. The evolving endoscopic techniques and technologies, including dye spraying methods and high-definition images, have been replacing random biopsies and have been revealed as more practical and efficient for detection of dysplasia in IBD patients. In addition, they have potential usefulness in detailed characterization of lesions and in the assessment of endoscopic resectability. Most dysplastic lesions without an unclear margin, definite ulceration, non-lifting sign, and high index of malignant change with suspicion for lymph node or distant metastases can be removed endoscopically. However, endoscopic resection of dysplasia in chronic IBD patients is usually difficult because it is often complicated by submucosal fibrosis. In patients with dysplasias that demonstrate submucosa fibrosis or a large size (≥20 mm), endoscopic submucosal dissection (ESD) or ESD with snaring (simplified or hybrid ESD) is an alternative option and may avoid a colectomy. However, a standardized endoscopic therapeutic approach for dysplasia in IBD has not been established yet, and dedicated specialized endoscopists with interest in IBD are needed to fully investigate recent emerging techniques and technologies.

Abstract IA13: Stool DNA detection of colorectal neoplasia

Abstract IA13: Stool DNA detection of colorectal neoplasia

Association between serrated epithelial changes and colorectal dysplasia in inflammatory bowel disease

Serrated epithelial change (SEC) is a histologic finding in longstanding colitis that maybe associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC. A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia. There were 187 patients with confirmed IBD and 1 or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first-degree relative with CRC were associated with dysplasia in IBD patients with SEC. This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive endoscopic examinations further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a precancerous lesion in IBD patients and if SEC can be endoscopically identified.

The Value of Immunohistochemical Determination of Topoisomerase IIα and Ki67 as Markers of Cell Proliferation and Malignant Transformation in Colonic Mucosa

Considering the role of topoisomerase IIα in cell division, and its increased expression in the G2/M phase of cell cycle, immunohistochemical staining for topoisomerase IIα might be used as a marker for cell proliferation or malignant transformation and compared with traditional proliferation marker (Ki67). In this study, 215 consecutive patients, who had undergone colonoscopy with biopsy, were included. The biopsy samples were fixed in formaldehyde, embedded in paraffin, cut into 3- to 4-μm sections, stained with hematoxylin-eosin and analyzed under a light microscope for pathologic diagnosis. For determination of topoisomerase IIα and Ki67 expression, paraffin blocks were cut into 4- to 5-μm sections and immunohistochemically stained with antitopoisomerase IIα antibody and Ki67. The dysplasia level was determined in adenomas and inflammatory bowel disease (IBD) samples using standard histologic criteria, whereas the grade of differentiation was determined for all colonic carcinomas. In 27 patients (12.6%) normal colonic mucosa was found, IBD was diagnosed in 72 patients (33.5%), 68 (31.6%) patients had adenomas, and 48 (22.3%) were diagnosed as colon carcinoma. In all samples with epithelial dysplasia, higher topoisomerase IIα expression was related to a higher level of dysplasia grade (P<0.0001). High topoisomerase IIα expression was found in all samples of colorectal carcinomas (low and high grade). There was strong correlation between topoisomerase IIα and Ki67 expression in all levels of epithelial dysplasia as well as tumor grades. The imunohistochemical staining for topoisomerase IIα expression might be useful as additional marker for mucosal dysplasia degree determination, as well as in differentiation of reactive/repair changes from dysplasia in IBD patients, but these findings need further evaluation.

The histological diagnosis of dysplastic and neoplastic lesions in inflammatory bowel disease: A pathological perspective

Patients with inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), are at an increased risk for developing colorectal carcinoma (CRC). The accurate diagnosis of dysplasia in biopsies taken during periodic surveillance of long-standing IBD patients is most important in prevention of UC and CD related cancer. Distinction of low from high grade IBD-related dysplasia and differential diagnosis between IBD-related dysplasia and dysplasia in sporadic adenoma as well as distinction from pseudodysplastic lesions in inflammatory pseudopolyps or reparative lesions is often very subtle and difficult and demands expertise of second experienced gastrointestinal pathologist. Although surveillance colonoscopy with multiple biopsies does not reduce the cancer mortality, it offers a reasonable chance of detecting precancer and performed prophylactic colectomy. Novel methods of detecting dysplasia are continuously being evaluated, including chromoscopy and molecular biology markers. In the future, one may expect, from these new markers to detect the dysplasia in IBD patients before development of histological evidence of neoplastic changes.

Managing the cancer risk in chronic ulcerative colitis. A decision-analytic approach.

Chronic ulcerative colitis is associated with a high risk of colon cancer. The most appropriate management--prophylactic proctocolectomy or medical surveillance--is, at present, unclear. Recent reports suggest that the presence of colonic dysplasia or "precancer" on endoscopic biopsy may be a reliable predictor of concurrent or future colon cancer. To assess the value of colonic dysplasia in managing colitis patients, I applied decision analytic techniques to currently available data regarding the sensitivity and specificity of colonic dysplasia in colitis patients. Such analysis shows that management based on biopsy for colonic dysplasia, rather than prophylactic proctocolectomy for all colitis patients, will maximize 5-year survival. Sensitivity analysis suggests that management is primarily determined by the sensitivity of biopsy-diagnosed dysplasia--elective prophylactic surgery would be preferred only when sensitivity of dysplasia on biopsy is less than or equal to 0.70 at 20 years, or less than or equal to 0.85 at 30 years of colitis, and changing surgical mortality and survival benefit from early diagnosis within a range established by previous studies affects management decisions only when sensitivity of dysplasia is at the lower end of its reported range.