Interim Analysis of a Trial Evaluating the Utility of Non-Targeted Biopsies for Colorectal Neoplasia Detection in Inflammatory Bowel Disease.

Persons with inflammatory bowel disease (IBD) affecting the colorectum (cIBD) have a 1.5- to 2-fold higher risk of developing colorectal cancer (CRC) relative to age- and sex-matched members of the general population.1 Intensive surveillance colonoscopy is recommended in this population to detect and treat early neoplastic lesions before they evolve to incurable cancers.2 Some societies advocate for widespread non-targeted ("random") biopsies throughout the colorectum to screen for "invisible" neoplastic lesions, in addition to targeted biopsies and/or resection of visible lesions.2 Despite the theoretical value of non-targeted biopsies in this setting, there are no high-quality, controlled data to support this practice. In addition to adding significant time and costs to colonoscopy screening, extensive biopsy sampling may also increase the risk of colorectal bleeding and bowel perforation, particularly in elderly patients and those receiving anticoagulant/antiplatelet therapies. With the widespread adoption of disease-modifying biologic and small molecule therapies,3 mucosal healing as a treatment end point,4 high-definition endoscopes,5 and endoscopy quality standards,6 as well as reports of very low neoplasia yield for non-targeted biopsies (0.1%-0.2% of biopsies),7 many experts have started to question the value of non-targeted biopsies as an adjunct for neoplasia surveillance in persons with cIBD.8 However, a recent large French cohort study reported that non-targeted biopsies still identify up to 20% of all neoplastic foci in persons with cIBD,9 albeit primarily in individuals with other major CRC risk factors.

Early Change in Epithelial Neutrophilic Infiltrate Predicts Long-Term Response to Biologics in Ulcerative Colitis.

BACKGROUND & AIMS: The prognostic value of histologic scores, grades, and individual histologic subcomponents, alone or in combination with endoscopy, for predicting endoscopic improvement (EI) and histoendoscopic mucosal improvement (HEMI) during maintenance therapy in ulcerative colitis remains uncertain. METHODS: We performed a post hoc analysis of participants from the VARSITY trial (n = 734 with histology). Receiver operating characteristic and multivariate logistic regression analyses were performed to assess whether baseline and/or week 14 assessments for the Robarts Histopathology Index, Geboes score, individual histologic subcomponents, and baseline disease characteristics, including endoscopic severity and biomarkers, could predict the achievement of EI and HEMI at week 52. RESULTS: Changes in epithelial neutrophil involvement from baseline to week 14 had the best performance for predicting week 52 EI (area under the curve, 0.83; 95 % confidence interval [CI], 0.74-0.91) and HEMI (area under the curve, 0.85; 95 % CI, 0.76-0.94). On multivariate analyses, improvement of neutrophils in the epithelium was the only histologic parameter associated with increased odds of week 52 EI (odds ratio, 3.63; 95 % CI, 1.45-9.08; P = .0059) and HEMI (odds ratio, 6.88; 95 % CI, 3.29-14.36; P < .0001). Patients with more than 50 % of crypts involved with neutrophils at week 14 were significantly less likely to achieve week 52 HEMI irrespective of week 14 Mayo endoscopic scores (week 14 Mayo endoscopic score of 2-3: 9.9 % vs 22.4 %; P = .001; week 14 Mayo endoscopic score of 0-1: 33 % vs 62.4 %; P = .044). CONCLUSIONS: Our results on epithelial neutrophilic infiltrate after induction therapy as the only independent predictor for achievement of maintenance EI or HEMI helps clarify the clinical relevance of measuring histologic disease activity in ulcerative colitis. Epithelial neutrophilic infiltrate poses a means to stratify patients according to their likelihood of response to biologic treatment.

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.

Active Margins, Plexitis, and Granulomas Increase Postoperative Crohn's Recurrence: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Rates of postoperative Crohn's disease recurrence remain high, although the ability to predict this risk of recurrence remains limited. As such, we aimed to determine the association of histologic features at the time of resection with postoperative recurrence. METHODS: Electronic databases were searched through February 2020 for studies that reported risk of clinical, endoscopic, or surgical postoperative recurrence in patients with positive resection margins, plexitis, or granulomas in the index specimen. Pooled risk ratios (RRs) with 95% CIs were calculated for this risk in patients with and without these histologic features. RESULTS: Twenty-one studies (2481 patients) assessed positive resection margins, 10 studies (808 patients) assessed plexitis, and 19 studies (1777 patients) assessed granulomas. Positive resection margins increased the risk of clinical (RR, 1.26; 95% CI, 1.06-1.49; I2 = 41%) and surgical (RR, 1.87; 95% CI, 1.14-3.08; I2 = 71%) recurrence, with a trend toward endoscopic recurrence (RR, 1.56; 95% CI, 0.79-3.05; I2 = 85%). Granulomas increased the risk of clinical (RR, 1.31; 95% CI, 1.05-1.64; I2 = 36%) and endoscopic (RR, 1.37; 95% CI, 1.00-1.87; I2 = 49%) recurrence, with a trend toward surgical recurrence (RR, 1.58; 95% CI, 0.89-2.80; I2 = 75%). Plexitis increased the risk of endoscopic recurrence (RR, 1.31; 95% CI, 1.00-1.72; I2 = 20%), with a trend toward clinical recurrence (RR, 1.34; 95% CI, 0.95-1.91; I2 = 46%). CONCLUSIONS: Positive resection margins, granulomas, and plexitis are predictive of postoperative Crohn's disease recurrence and should be recorded at the time of index resection.

Beyond Helicobacter: dealing with other variants of gastritis-an algorithmic approach.

In daily practice, the presence of inflammation in gastric biopsies prompts a mental algorithm, an early question being whether the lesion present is Helicobacter-associated. If Helicobacter organisms are not found, then there is a further algorithm, governed by the predominant type of inflammatory cells present, and the presence of other features such as intraepithelial lymphocytosis, a subepithelial collagen band, granulomas, coexisting chronic inflammation, focality, and superimposed reactive changes including erosions and ulcers. Each of these generates its own differential diagnosis. If no inflammation is present, then the two major changes specifically looked for are the changes associated with hypergastrinaemia, by far the most common cause of which is treatment with proton pump inhibitors, and reactive changes. These may be present with and without accompanying inflammation, and, when the epithelial changes dominate, the term gastropathy is preferred. In this article, we present an approach to non-Helicobacter inflammation and gastropathies.

Most colitis associated carcinomas lack expression of LGR5: a preliminary study with implications for unique pathways of carcinogenesis compared to sporadic colorectal carcinoma.

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a component of the Wnt receptor complex, is thought to lineage label gastric and intestinal stem cells. LGR5 expression is increased in colorectal carcinoma (CRC) compared to normal tissue. Colitis associated colorectal adenocarcinoma (CAC) often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the expression profile of LGR5, and by extension the potential role of an intestinal stem cell phenotype, has not been well described in a series of human CAC. METHOD: RNA in situ hybridization (ISH) for LGR5 expression on 30 CACs (12 cases with conventional morphology and 18 cases with non-conventional type morphology) from 29 inflammatory bowel disease (IBD) patients was performed and compared the expression profile to a control group of 10 sporadic CRCs. Immunohistochemistry for beta-catenin and SATB2 was performed on the 30 CACs. RESULT: LGR5 was positive in 30% (9/30) of CAC cases and 90% (9/10) of sporadic CRCs (p = 0.002). A large majority (89%) of LGR5 positive CACs were of the conventional histologic type, and conventional type CAC showed a significantly higher LGR5 score (median 3.0; interquartile range 1.75-3.25) than non-conventional type CAC (median 1.5; interquartile range 1.00-2.00) (p = 0.034). CAC with conventional morphology did have a lower level of LGR5 expression than sporadic CRC. Sporadic CRCs showed a significantly higher LGR5 level score than non-conventional type CACs (p < 0.001). Nuclear translocation of beta-catenin was strongly associated with LGR5 expression (p = 0.003), however no significant association was identified between SATB2 expression and LGR5 expression status in CACs. CONCLUSION: These findings suggest that the wider spectrum of tumor morphology in CAC may be associated with absence of a LGR5-expressing intestinal stem cell phenotype.

Colitis-associated colorectal adenocarcinomas are frequently associated with non-intestinal mucin profiles and loss of SATB2 expression.

The special AT-rich sequence binding protein 2 (SATB2) is a sensitive and specific diagnostic marker for colorectal adenocarcinoma and reduced expression of SATB2 is associated with a poor prognosis. Colitis-associated colorectal adenocarcinoma often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the SATB2 expression profile in colitis-associated carcinoma has not been defined. We performed immunohistochemistry for SATB2 as well as CDX2, MUC5AC, MUC6 and mismatch repair proteins on 60 consecutive colitis-associated carcinomas from 58 inflammatory bowel disease patients and compared the expression profile to a control group of 32 sporadic colorectal carcinomas. Only 26 (43%) colitis-associated carcinomas expressed SATB2, compared to 29 (91%) sporadic colorectal carcinomas (p < 0.0001). MUC5AC expression was more frequently observed in colitis-associated carcinomas than sporadic colorectal caracinomas (52% and 25% respectively; p = 0.013). Eight (13%) cases of colitis-associated carcinoma showed loss of CDX2 expression, which was retained in all of the sporadic controls (p = 0.047). In colitis-associated carcinoma, 50% of SATB2 negative cases had lymph node metastasis compared to only 15% of SATB2 positive cases (p = 0.007). Loss of SATB2 was particularly frequent in mucinous-type tumors, occurring in 83% of these cases. There was no significant association between SATB2 expression and mismatch repair protein status. These data show that the immunoprofile of colitis-associated carcinoma is different than that seen in sporadic cases. In particular, SATB2 is significantly less sensitive in colitis-associated carcinoma and it should be interpreted cautiously as a marker of colorectal origin in colitis patients. The association between loss of SATB2 and lymph node metastasis suggests that it may have similar prognostic value in the setting of inflammatory bowel disease as in sporadic cases.

Development of an index to define overall disease severity in IBD.

BACKGROUND AND AIM: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. METHODS: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. RESULTS: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. CONCLUSIONS: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.

DALM, rest in peace: a pathologist's perspective on dysplasia in inflammatory bowel disease in the post-DALM era.

There are few abbreviations in surgical pathology that are associated with as much immediate recognition, frustration, and confusion as DALM (dysplasia-associated lesion or mass). DALM is used to describe endoscopically visible dysplastic lesions in the surveillance of patients with inflammatory bowel disease. However, the diagnosis of DALM has been complicated by the inconsistent criteria and use of terminology for describing dysplasia in inflammatory bowel disease, and a tendency to relate DALM with the need for colectomy. Fortunately, advancements in both endoscopic visualization and local excision capability have allowed for a more defined management of dysplasia in inflammatory bowel disease. In 2015, the Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients International Consensus Recommendations (SCENIC) Development Panel, a panel of predominantly expert gastroenterologists and endoscopists in surveillance of inflammatory bowel disease, published a consensus statement. One recommendation was to abandon DALM-related terminology in favor of endoscopic descriptors modified from the Paris endoscopic classification. Recommendations on surveillance and management of dysplastic lesions were also provided. Nevertheless, interval carcinomas and metachronous neoplasia remain persistent issues. This review aims to provide an update on the post-DALM terminology and management recommendations for inflammatory bowel disease-associated dysplasia necessary for a meaningful communication between pathologists and clinicians.

Management of complex polyps of the colon and rectum.

PUPRPOSE: Benign polyps that are technically challenging and unsafe to remove via polypectomy are known as complex polyps. Concerns regarding safety and completeness of resection dictate they undergo advanced endoscopic techniques, such as endoscopic mucosal resection or surgery. We provide a comprehensive overview of complex polyps and current treatment options. METHODS: A review of the English literature was conducted to identifyarticles describing the management of complex polyps of the colon and rectum. RESULTS: Endoscopic mucosal resection is the standard of care for the majority of complex polyps. Only polyps that fail endoscopic mucosal resection or are highly suspicious of invasive cancer but which cannot be removed endoscopically warrant surgery. CONCLUSION: Several factors influence the treatment of a complex polyp; therefore, there cannot be a "one-size-fitsall" approach. Treatment should be tailored to the lesion's characteristics, the risk of adverse events, and the resources available to the treating physician.

Development and validation of a histological index for UC.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016.

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer.

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome.

Observations of different patterns of dysplasia in barretts esophagus - a first step to harmonize grading.

We reviewed a set of cases of early neoplasia (low grade / high grade dysplasia / IEN and mucosal carcinoma) to reach better defined criteria for subtypes of dysplasia/differentiation in the columnar lined (Barretts) esophagus. We discuss criteria that we categorized for recognizing low and high-grade dysplasia and mucosal carcinoma in patterns of neoplasia that we regarded as intestinal, gastric and mixed.

Reproducibility of histological assessments of disease activity in UC.

OBJECTIVE: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. DESIGN: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. RESULTS: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. CONCLUSIONS: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

Progression and Management of Duodenal Neoplasia in Familial Adenomatous Polyposis: A Cohort Study.

OBJECTIVE: To describe the natural history and outcomes of surveillance of duodenal neoplasia in familial adenomatous polyposis (FAP). BACKGROUND: Duodenal cancer is the most common cause of death in FAP. METHODS: Cohort study of patients prospectively enrolled in an upper endoscopic surveillance protocol from 1982 to 2012. The duodenum was assessed by side-viewing endoscopy and classified as stage 1 to 5 disease. Endoscopic and/or operative interventions were performed according to stage. RESULTS: There were 218 patients in the protocol (98 with advanced stage). They had a median of 9 endoscopies (range: 2-25) over a median of 11 years (range: 1-26). Median age at diagnosis of stage 3 disease (adenoma: 2.1-10 mm) was 41 years and stage 4 disease (adenoma >10 mm) was 45 years. Median time from first esophagogastroduodenoscopy to stage 4 disease was 22.4 years. The risk of stage 4 disease was 34.3% [95% confidence interval (CI) 23.8-43.4] at 15 years. In multivariate analysis, sex, type of colorectal surgery, years since colorectal surgery, and stage were significantly associated with risk of progression to stage 4 disease. Five of 218 (2.3%) patients developed duodenal cancer at median age of 58 years (range: 51-65). The risk of developing duodenal cancer was 2.1% (95% CI: 0-5.2) at 15 years. CONCLUSIONS: Patients with advanced duodenal polyposis progress in the severity of disease (size and degree of dysplasia); however, the rate of progression to carcinoma is slow. Aggressive endoscopic and surgical intervention, especially in the presence of large polyps and high-grade dysplasia, appears to be effective in preventing cancer deaths in FAP.

Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression.

Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of ß-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

Inflammatory pseudotumours of the oesophagus--histological and immunohistochemical findings.

AIMS: Inflammatory oesophageal pseudotumours are rare lesions, thought to be reactive. Due to marked atypia of the stromal cells, these can be misdiagnosed as malignancies. The objective of this study was to characterize histological and immunohistochemical features of a series of inflammatory pseudotumours of the oesophagus. METHODS AND RESULTS: We present 12 cases of inflammatory oesophageal pseudotumours, occurring in seven females and five males, with a mean age of 57.3 years. Clinical presentations were variable; dysphagia, abdominal pain and weight loss and upper gastrointestinal bleed. In a majority of the cases, nodules or masses in the distal oesophagus were identified at endoscopy. Microscopically, the lamina propria in all 12 cases contained inflammation and granulation tissue. Ten of 12 cases showed mucosal ulceration and 11 of 12 cases had acutely inflamed epithelium. Markedly atypical pleomorphic stromal cells with prominent nucleoli were identified in all 12 cases. Immunohistochemistry showed uniform positivity for vimentin in 11 of 11 cases, and two of seven cases demonstrated weak focal positivity for smooth muscle actin. The cells were negative for all other markers. CONCLUSIONS: Reactive oesophageal lesions can show marked nuclear atypia in stromal fibroblasts/myofibroblasts, which are easily mistaken for malignancies. Pathologists must consider the diagnosis of an inflammatory pseudotumour if stromal atypia is present in an inflammatory background.

Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective.

Surveillance for neoplasia in colitis is the most challenging diagnostic colonoscopic procedure. The detection and treatment of colorectal dysplasia in inflammatory bowel disease remain problematic to the point that unsuspected colorectal cancers (CRCs) are still identified. Excellent bowel preparation and use of high-resolution colonoscopes with chromoendoscopy facilitate the detection and characterization of subtle neoplasia. This approach is superior to taking random biopsy specimens and should be the standard of care for surveillance but requires adequate training. Suspicious lesions should be assessed carefully and described using objective terminology. The terms dysplasia-associated lesions/masses and flat dysplasia are best avoided because they may be open to misinterpretation. Most suspicious lesions detected during surveillance can be removed endoscopically, precluding the need for surgery. Nevertheless, endotherapy in colitis can be difficult as a result of underlying inflammation and scarring. Lesions that are not endoscopically resectable need to be removed surgically, although the possibility that some lesions might be amenable to local resection (including lymphadenectomy) rather than subtotal colectomy may need to be re-evaluated. Despite surveillance programs, patients still present clinically with CRC. This may occur because lesions are missed (possibly because of the failure to use optimal techniques), lesions are not adequately removed, patients fail to return for colonoscopy, or CRCs arise rapidly in mucosa that is minimally dysplastic and the CRCs are not recognized as being potentially invasive even on biopsy. Future advances in, for example, stool DNA assays, use of confocal endomicroscopy, or use of endoscopic ultrasound, may help in the identification of high-risk patients and the assessment of dysplastic lesions.