Coexisting Th1 and Th2 cytokines in patients with collagenous gastritis and implications for its pathogenesis.

OBJECTIVES: Collagenous gastritis (CG) is a rare cause of refractory dyspepsia and anemia that frequently affects children and young adults and whose histological hallmark is chronic mucosal inflammation with a subepithelial collagen band. The etiology remains obscure, and no established treatments exist. We investigated the pathogenesis of CG by determining the expression profiles of genes related to immunity and inflammation in index biopsies. METHODS: Gastric biopsies from 10 newly diagnosed patients with CG were evaluated using the NanoString nCounter assay. Gastric biopsies from 14 normal individuals served as controls. The gene expression ratios for CG versus controls were determined in pooled samples and confirmed in individual samples by quantitative reverse transcription polymerase chain reaction. The results were compared with previously reported expression data from a cohort of patients with collagenous colitis, a colonic disorder with similar morphology, including subepithelial collagen band. RESULTS: CG biopsies featured enhanced expression of key genes encoding both Th1 (IFNγ, TNF-α, IL-2, IL-10, IL-12A, IL-12B, and IL-18) and Th2 cytokines (IL-3, IL-4, IL-5, IL-6, and IL-13). In contrast, biopsies from patients with CC exhibited upregulated Th1 cytokines only. CONCLUSIONS: We show in this first published gene expression profiling study that CG involves simultaneous upregulation of Th1 and Th2 cytokines. This finding is unique, contrasting with other types of chronic gastritis as well as with collagenous colitis, which shares the presence of a collagen band. Involvement of Th2 immunity in CG would support further investigation of potential dietary, environmental, or allergic factors to guide future therapeutic trials.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial.

BACKGROUND & AIMS: Histologic evaluation of mucosal healing in Crohn's disease is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. METHODS: Biopsy specimens from 1 ileal and 4 colonic segments were evaluated at weeks 0, 12, and 52 from each of the 170 SERENITY participants. Criteria for the weeks 12 and 52 histologic response were no epithelial neutrophils or epithelial damage, or >50% decrease in either the Robarts Histopathology Index or the active Global Histologic Disease Activity Score, and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsy specimens. Agreement was evaluated between histologic and endoscopic end points. Associations between 1-year outcomes and week 12 histologic and endoscopic response were evaluated. RESULTS: At week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%; P < .001) and remission (26% vs 6%; P < .01) than placebo. Rates were numerically similar at 1 year (mirikizumab pooled response, 46%-69%; remission, 13%-31%). Agreement between week 12 histologic and endoscopic response was 69% (Cohen's kappa coefficient [κ] = 0.40) and remission was 83% (κ = 0.38) in all pooled arms, including placebo. At 1 year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (P = .003). CONCLUSIONS: In a post hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in Crohn's disease over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226).

Aberrant p53 expression is associated with neoplastic progression in Barrett oesophagus diagnosed as indefinite for dysplasia.

The aim of this study was to investigate the role of immunohistochemical (IHC) expression of p53 and other potential clinical parameters as prognostic markers for predicting neoplastic progression in Barrett oesophagus (BE) patients diagnosed as indefinite for dysplasia (IND). The study included patients with established BE of any extent who had a diagnosis of IND accompanied by concurrent p53 immunohistochemistry (IHC) stain at the index endoscopic procedure and at least one follow-up examination between 2000 and 2021. Correlation between disease progression from IND to higher-grade dysplasia [low-grade dysplasia (LGD), high-grade dysplasia (HGD) and oesophageal adenocarcinoma (EAC)] and clinicopathological parameters were analysed. A total of 149 patients (99 males; mean age 63.3 ± 10.0 years, range = 35-89) were included in the final analysis. Median follow-up was 37.1 months [interquartile range (IQR) = 20.5-59.1 months]. Progression rates from IND to LGD and HGD were 12.1% (18 of 149) and 2.7% (four of 149), respectively. On multivariate analysis, the number of IND diagnoses was significantly associated with progression to both LGD and HGD (P = 0.016 and P < 0.001, respectively). Cox regression analysis showed that aberrant p53 expression was significantly associated with progression to LGD [hazard ratio (HR) = 4.87, 95% confidence interval (CI) = 1.91-12.45, P = 0.001] and HGD (HR = 21.81, 95% CI = 1.88-253.70, P = 0.014). Kaplan-Meier survival analysis also demonstrated that aberrant p53 expression was significantly associated with progression to LGD (P < 0.001) and HGD (P = 0.001). Our results suggest that frequency of IND diagnoses and status of p53 expression can help to stratify risk of neoplastic progression in BE patients with IND.

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

OBJECTIVE: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Constrictive and Hypertrophic Strictures in Ileal Crohn's Disease.

BACKGROUND & AIMS: Strictures in Crohn's disease (CD) are classically attributed to fibromuscular hypertrophy of the intestinal wall. We have identified and characterized CD-related ileal strictures that result instead from mural constriction (ie, reduced external circumference). METHODS: Twenty-four strictures and internal controls from 17 adults with obstructive CD were analyzed by cross-sectional morphometry. RESULTS: The stricture-to-control circumference ratios (CRs) ranged from 0.53 to 1.7. Six strictures with CR ≥1.0, designated hypertrophic, had concentrically thickened walls, mean 3-fold increases in cross-sectional area and stainable fibromucular tissue, and high transmural inflammation scores. In contrast, 18 strictures with CR <1.0, designated constrictive, had thin, pliant walls, cross-sectional areas and stainable fibromuscular tissue comparable with control values, and low transmural inflammation scores. Eight mildly constrictive strictures also showed mild fibromuscular mural expansion that fell short of statistical significance. Twelve of 18 constrictive strictures (67%) occurred multiply (2-4 strictures per specimen) in contrast with hypertrophic strictures, all of which occurred singly (P = .01). Constriction correlated quantitatively with circumferential serosal fat wrapping (P = .003) and was associated with myenteric lymphocytic plexitis (P = .02). Disease duration was shortest among subjects with constrictive strictures and correlated with increasing circumference (CR ≤0.8, 6.3 ± 6.2 years; CR >0.8, 8.7 ± 6.4 years; and CR ≥1.00, 13.7 ± 5.0 years, respectively; P = .03). CONCLUSIONS: Constrictive ileal strictures in CD differ pathologically and clinically from hypertrophic strictures, featuring little or no fibromuscular mural expansion, frequent multiplicity, and earlier onset. Mesenteric fat wrapping and myenteric plexitis may contribute to their pathogenesis. Pathologic manifestations of constriction and hypertrophy can coexist, suggesting that stricture heterogeneity may be shaped in part by the dynamics of constrictive and hypertrophic processes.

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

BACKGROUND AND AIMS: Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension. METHODS: We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments. RESULTS: Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended. CONCLUSION: Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2-related Disease.

BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124.

Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms.

BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.

The association between pre-colectomy thiopurine use and risk of neoplasia after ileal pouch anal anastomosis in patients with ulcerative colitis or indeterminate colitis: a propensity score analysis.

BACKGROUND: The risk of neoplasia of the pouch or residual rectum in patients with ulcerative colitis (UC) who undergo total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is incompletely investigated. Thiopurine use is associated with a reduced risk of colorectal neoplasia in patients with UC. We tested the hypothesis that thiopurine use prior to TPC may be associated with a reduced risk of primary neoplasia after IPAA. METHODS: We conducted a retrospective cohort analysis of patients from a tertiary referral center from January 2008 to December 2017. Eligible patients with UC or IC underwent TPC with IPAA and had at least two pouchoscopies with biopsies ≥ 6 months after surgery. Propensity score analysis was conducted to match thiopurine exposed vs unexposed groups based on clinical covariates. Multivariable Cox regression analysis estimated the risk of neoplasia. RESULTS: A total of 284 patients with UC or IC (57.4% male, median age 35.6 years) were analyzed. Ninety-seven patients (34.2%) were confirmed to have thiopurine exposure ≥ 12 weeks immediately prior to TPC ("exposed") and 187 (65.8%) were confirmed to have no thiopurine exposure for at least 365 days prior to TPC ("non-exposed"). Compared to non-exposed patients, patients with thiopurine exposure less often had dysplasia (7.2% vs 23.0%, p = 0.001) and had lower grades of dysplasia before colectomy. After IPAA, patients with neoplasia were older (44.0 vs 34.8 years, p = 0.03), more likely to have had dysplasia as colectomy indication (44.4% vs 15.4%, p = 0.007), and more likely to require pouch excision (55.6% vs 10.2%, p < 0.0001), compared to patients without neoplasia. On propensity-matched cohort analysis, no factors were significantly associated with risk of primary neoplasia. CONCLUSION: Thiopurine exposure for at least the 12 weeks prior to TPC in patients with UC or IC does not appear to be independently associated with risk of primary neoplasia following IPAA.

Baseline Histological Findings Do Not Predict the Risk of Subsequent Extension in Patients with Limited Ulcerative Colitis.

BACKGROUND: Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. AIMS: We sought to determine whether histologic features correlate with disease extension. METHODS: The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. RESULTS: Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r = - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). CONCLUSIONS: Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.

Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD. METHODS: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system. RESULTS: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed. CONCLUSIONS: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Association Between Indefinite Dysplasia and Advanced Neoplasia in Patients With Inflammatory Bowel Diseases Undergoing Surveillance.

BACKGROUND & AIMS: Little is known about the clinical significance of indefinite dysplasia (IND) in patients with inflammatory bowel diseases (IBD) undergoing colonoscopic surveillance for colorectal neoplasia. METHODS: We conducted a retrospective cohort analysis of 492 patients with colonic IBD for 8 or more years or concomitant primary sclerosing cholangitis, with no history of advanced colorectal neoplasia (high-grade dysplasia or colorectal cancer) or colectomy, undergoing colorectal neoplasia surveillance at a tertiary IBD referral center from 2001 through 2017. Subjects received consistent histopathologic grading of dysplasia. We collected data on time to development of (advanced) colorectal neoplasia or colectomy using Kaplan Meier methods. We identified factors independently associated with (advanced) colorectal neoplasia with multivariable Cox regression analysis. RESULTS: After 2149 person-years of follow-up, 53 patients (10.8%) received a diagnosis of IND without prior or synchronous low-grade dysplasia (LGD). Compared to patients without dysplasia, patients with IND had a significantly higher risk of advanced colorectal neoplasia (adjusted hazard ratio, 6.85; 95% CI, 1.78-26.4) and colorectal neoplasia (adjusted hazard ratio, 3.25; 95% CI, 1.50-7.05), but not colectomy (P = .78). Compared to IND, LGD was associated with a significantly higher risk of advanced colorectal neoplasia (P = .05). Following a diagnosis of no dysplasia, IND only, or LGD, the incidence rates of advanced colorectal neoplasia were 0.4% per patient-year, 3.1% per patient-year, and 8.4% per patient-year, respectively. CONCLUSIONS: In a retrospective analysis of patients with IBD undergoing colorectal neoplasia surveillance with consistent histopathologic grading of dysplasia, IND was independently associated with a significant increase in risk of advanced colorectal neoplasia. These findings require validation and if confirmed, a reappraisal of the colorectal neoplasia surveillance guidelines.

Nonconventional dysplasia in patients with inflammatory bowel disease and colorectal carcinoma: a multicenter clinicopathologic study.

Several types of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). However, strict morphologic criteria are lacking, and their clinicopathologic features (including potential association with conventional dysplasia and/or colorectal cancer [CRC]) are poorly understood. A total of 106 dysplastic or serrated lesions in 58 IBD patients with CRC were retrospectively identified from five institutions. Thirty-six cases of nonconventional dysplasia were identified in 26 (45%) of the 58 patients and occurred with similar frequency in men and women (58% and 42%, respectively), with a mean age of 54 years (range: 24-73) and a long history of IBD (mean: 17 years, range: 2-43). Six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a 'pure type' (n = 5; 14%) or a 'mixed type' with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare. Twelve (46%) of the 26 patients had only nonconventional dysplasia, whereas the remaining 14 patients (54%) had both nonconventional and conventional dysplasias. Nonconventional dysplasia was most often graded as low-grade dysplasia (81%), which was less common in conventional dysplasia (37%) (p = 0.003). When present alone, nonconventional dysplasia was predominantly found in the left colon (81%, p = 0.006) as a polypoid or raised lesion (75%, p < 0.001) compared with when it occurred simultaneously with conventional dysplasia (35% and 50%, respectively). When both nonconventional and conventional dysplasias occurred simultaneously, they were found in the same colonic segment in all but 3 patients (79%). Nonconventional dysplasia was also commonly detected in the same colonic segment as CRC or immediately adjacent to the CRC at a rate (85%) similar to conventional dysplasia (96%). CRC occurring in patients with only nonconventional dysplasia was more likely to be high-grade (poorly differentiated; 36%) than CRC that occurred in association with conventional dysplasia (10%) (p = 0.026). In conclusion, nonconventional dysplasia is common in IBD patients with CRC. It appears to develop in the same field of carcinomatous development, and it is not uncommonly associated with conventional dysplasia.

Mutation profile of high-grade appendiceal mucinous neoplasm.

AIMS: High-grade appendiceal mucinous neoplasm (HAMN) was recently proposed as a disease entity histologically analogous to low-grade appendiceal mucinous neoplasm (LAMN), but characterised by high-grade cytological atypia. The pathogenesis and clinical features of HAMN have not been fully elucidated. METHODS AND RESULTS: Nine cases of HAMN, eight LAMN, 10 appendiceal mucinous adenocarcinomas (MACA) and five appendiceal serrated polyps resected between 2008 and 2017 contributed by three medical centres underwent targeted next-generation sequencing of 50 cancer-related genes. The patients in each category had similar profiles with respect to gender, age, tumour stage and follow-up intervals. Both LAMN and HAMN harboured mutations of KRAS [nine of nine and eight of eight (100%), respectively] and GNAS [five of eight (63%) and five of nine (56%), respectively] in significantly higher proportions than MACA [KRAS, seven of 10 (70%, P = 0.04); GNAS: one of 10 (10%, P = 0.02)] and serrated polyps [KRAS, one of five (20%, P = 0.0007); GNAS: none of five (0%, P = 0.04)]. Four cases of HAMN, but none of LAMN, harboured mutations of TP53 [four of nine (44%)] and/or ATM [two of nine (22%)]. Three cases of HAMN (33%) showed extra-appendiceal spread with retention of the same mutational profiles in the intra- and extra-appendiceal components. The 10 cases of MACA harboured a similar prevalence of TP53 mutations (n = 5, 50%) as HAMN but, unlike LAMN and HAMN, some harboured mutations in PIK3CA, APC, FBXW7, PTEN and SMAD4. CONCLUSIONS: HAMN and LAMN share high rates of KRAS and GNAS co-mutations supporting a common histogenesis and distinguishing them from MACA. Acquisition of TP53 or ATM mutations by HAMN may drive its progression to a more advanced phenotype.

Ileocolic anastomotic inflammation after resection for Crohn's disease indicates disease recurrence: a histopathologic study.

Objectives: We performed a pathological pilot study to characterize the inflammation at the ileocolic anastomosis as Crohn's disease or ischemia.Methods and materials: Subjects were selected at random from a retrospective database of patients with Crohn's disease and who had undergone an ileocolic resection with subsequent endoscopic assessment of the anastomosis and neo-terminal ileum. Pathology slides from the anastomotic mucosa, either from targeted biopsies or subsequent ileocolic resections, were re-assessed histologically for features of ischemia and of Crohn's disease.Results: Twenty-nine specimens from 8 patients were reviewed, including 12 ileocolic resection specimens and 17 sets of endoscopic biopsies. Twenty-seven of the 29 specimens, accounting for all of the patients, had evidence of CD-like features. In contrast, only 2 specimens, accounting for 2 of 8 patients, had histologic features of ischemia, and both specimens also had Crohn's-like features.Conclusion: To our knowledge this is the first study to specifically evaluate the pathology of ileocolic anastomoses in Crohn's disease. It suggests that anastomotic inflammation is predominantly a manifestation of recurrent Crohn's disease rather than of postoperative ischemia.

High Risk of Advanced Colorectal Neoplasia in Patients With Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC, termed PSC-IBD) are at increased risk for colorectal cancer, but their risk following a diagnosis of low-grade dysplasia (LGD) is not well described. We aimed to determine the rate of advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia and/or colorectal cancer, following a diagnosis of indefinite dysplasia or LGD in this population. METHODS: We performed a retrospective, longitudinal study of 1911 patients with colonic IBD (293 with PSC and 1618 without PSC) who underwent more than 2 surveillance colonoscopies from 2000 through 2015 in The Netherlands or the United States (9265 patient-years of follow-up evaluation). We collected data on clinical and demographic features of patients, as well as data from each surveillance colonoscopy and histologic report. For each surveillance colonoscopy, the severity of active inflammation was documented. The primary outcome was a diagnosis of aCRN during follow-up evaluation. We also investigated factors associated with aCRN in patients with or without a prior diagnosis of indefinite dysplasia or LGD. RESULTS: Patients with PSC-IBD had a 2-fold higher risk of developing aCRN than patients with non-PSC IBD. Mean inflammation scores did not differ significantly between patients with PSC-IBD (0.55) vs patients with non-PSC IBD (0.56) (P = .89), nor did proportions of patients with LGD (21% of patients with PSC-IBD vs 18% of patients with non-PSC IBD) differ significantly (P = .37). However, the rate of aCRN following a diagnosis of LGD was significantly higher in patients with PSC-IBD (8.4 per 100 patient-years) than patients with non-PSC IBD (3.0 per 100 patient-years; P = .01). PSC (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.09-3.71), increasing age (aHR 1.03; 95% CI, 1.01-1.05), and active inflammation (aHR, 2.39; 95% CI, 1.63-3.49) were independent risk factors for aCRN. Dysplasia was more often endoscopically invisible in patients with PSC-IBD than in patients with non-PSC IBD. CONCLUSIONS: In a longitudinal study of almost 2000 patients with colonic IBD, PSC remained a strong independent risk factor for aCRN. Once LGD is detected, aCRN develops at a higher rate in patients with PSC and is more often endoscopically invisible than in patients with only IBD. Our findings support recommendations for careful annual colonoscopic surveillance for patients with IBD and PSC, and consideration of colectomy once LGD is detected.

Chromoendoscopy Is More Effective Than Standard Colonoscopy in Detecting Dysplasia During Long-term Surveillance of Patients With Colitis.

BACKGROUND & AIMS: Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program. METHODS: We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model. RESULTS: In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2). CONCLUSIONS: In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy.