1:  ESGE recommends cold snare polypectomy (CSP), to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of diminutive polyps (≤ 5 mm).Strong recommendation, high quality of evidence. 2:  ESGE recommends against the use of cold biopsy forceps excision because of its high rate of incomplete resection.Strong recommendation, moderate quality of evidence. 3:  ESGE recommends CSP, to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of small polyps (6-9 mm).Strong recommendation, high quality of evidence. 4:  ESGE recommends hot snare polypectomy for the removal of nonpedunculated adenomatous polyps of 10-19 mm in size.Strong recommendation, high quality of evidence. 5:  ESGE recommends conventional (diathermy-based) endoscopic mucosal resection (EMR) for large (≥ 20 mm) nonpedunculated adenomatous polyps (LNPCPs).Strong recommendation, high quality of evidence. 6:  ESGE suggests that underwater EMR can be considered an alternative to conventional hot EMR for the treatment of adenomatous LNPCPs.Weak recommendation, moderate quality of evidence. 7:  Endoscopic submucosal dissection (ESD) may also be suggested as an alternative for removal of LNPCPs of ≥ 20 mm in selected cases and in high-volume centers.Weak recommendation, low quality evidence. 8:  ESGE recommends that, after piecemeal EMR of LNPCPs by hot snare, the resection margins should be treated by thermal ablation using snare-tip soft coagulation to prevent adenoma recurrence.Strong recommendation, high quality of evidence. 9:  ESGE recommends (piecemeal) cold snare polypectomy or cold EMR for SSLs of all sizes without suspected dysplasia.Strong recommendation, moderate quality of evidence. 10:  ESGE recommends prophylactic endoscopic clip closure of the mucosal defect after EMR of LNPCPs in the right colon to reduce to reduce the risk of delayed bleeding.Strong recommendation, high quality of evidence. 11:  ESGE recommends that en bloc resection techniques, such as en bloc EMR, ESD, endoscopic intermuscular dissection, endoscopic full-thickness resection, or surgery should be the techniques of choice in cases with suspected superficial invasive carcinoma, which otherwise cannot be removed en bloc by standard polypectomy or EMR.Strong recommendation, moderate quality of evidence.

Supplementary Materials and Methods from Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations

Supplementary Table S2 from Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations

Gweon et al1Gweon T.-G. Lee K.-M. Lee S.-W. et al.Effect of prophylactic clip application for the prevention of postpolypectomy bleeding of large pedunculated colonic polyps: a randomized controlled trial.Gastrointest Endosc. 2021; 94: 148-154Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar are to be commended for conducting randomized trials on hemorrhage prevention from pedunculated colorectal polyps. Optimization of all outcomes in the management of malignant polyps requires testing new approaches with new outcomes and endpoints, including reducing adjuvant surgical therapy for malignant pedunculated polyps. Until then, there is a case for snare resection low on the stalk without preapplication of loops or clips, using currents associated with a low risk of immediate hemorrhage, and followed by clip closure of the transected stalk.

Colorectal cancer (CRC) is the third most common cancer in the United States, with approximately 135,430 new cases and 50,260 deaths every year.1,2 It has been widely recognized now that approximately 20%–30% of CRCs arise from serrated polyps through a serrated/methylated pathway that includes BRAF mutation and DNA methylation that is distinct from the traditional adenoma-carcinoma sequence.3–5 Sessile serrated polyps are flat/sessile and have similar color to the surrounding mucosa, making it difficult to differentiate between the normal colonic mucosa and the polyp itself.

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

BACKGROUND AND STUDY AIMS:The detection of advanced adenomas within organized screening programs using either immunochemical fecal occult blood test (FIT) or endoscopy has been associated with the prevention of colorectal cancer. The histological changes and pathogenetic mechanisms that lead to the detection of such lesions by either of these screening methods have not yet been addressed.PATIENTS AND METHODS:The histological specimens of 50 advanced adenomas detected by FIT were compared with those of 50 advanced adenomas detected by primary endoscopy screening that were matched for size and histology. The following variables were systematically recorded: 1) histopathological changes compatible with luminal bleeding induced by ischemia; 2) hypoxia in the adenomatous tissue, assessed through the expression of carbonic anhydrase IX; and 3) microvessel quantitative analysis, evaluated by CD31 and CD105 immunostains. All specimens were reviewed blindly by an expert gastrointestinal pathologist.RESULTS:Histopathological changes associated with ischemia-related luminal bleeding were significantly more frequent in FIT-positive than in endoscopy-detected advanced adenomas (78 % vs. 14 %; P < 0.001). Carbonic anhydrase IX expression was also significantly higher in FIT-detected advanced adenomas (immunohistochemical score: 12.0 vs. 4.1; P < 0.001). Conversely, no differences were found in microvessel density.CONCLUSIONS:The detection of advanced adenomas by FIT screening appears to be related to ischemia-associated luminal bleeding, which, in turn, may be due to periods of hypoxia. The absence of such changes in endoscopy-detected advanced adenomas would suggest that the two screening methods may be complementary for the detection of advanced neoplasia within organized screening programs.

Aim This study was performed to evaluate the concordance in pathological assessments of blood and lymphatic vessel invasion (BLI) in pT1 colorectal cancers and to assess the effect of diagnostic criterion on consistency in the assessment of BLI. Methods Forty consecutive patients undergoing surgical resection of pT1 colorectal cancers were entered into this study. H&E-stained, D2-40-stained and elastica-stained slides from the tumours were examined by 18 pathologists from seven countries. The 40 cases were divided into two cohorts with 20 cases each. In cohort 1, pathologists diagnosed BLI using criteria familiar to them; all Japanese pathologists used a criterion of BLI from the Japanese Society for Cancer of the Colon and Rectum (JSCCR). In cohort 2, all pathologists used the JSCCR diagnostic criterion. Results In cohort 1, diagnostic concordance was moderate in the US/Canadian and European pathologists. There were no differences in the consistency compared with results for Japanese pathologists, and no improvement in the diagnostic concordance was found for using the JSCCR criterion. However, in cohort 2, the JSCCR criterion decreased the consistency of BLI diagnosis in the US/Canadian and European pathologists. The level of decreased consistency in the assessment of BLI was different between the US/Canadian and European pathologists. Conclusions A uniform criterion strongly influences the diagnostic consistency of BLI but may not always improve the concordance. Further study is required to achieve an objective diagnosis of BLI in colorectal cancer. The varying effects of diagnostic criterion on the pathologists from Japan, the USA/Canada and Europe might reflect varied interpretations of the criterion. Internationally accepted criterion should be developed by participants from around the world.

Background Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors. Material and Methods A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria. Results A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome. Conclusion c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.

A crucial role for Aurora Kinase A (AURKA) gene has been demonstrated in the advanced steps of colorectal tumor progression. Little is known, however, about its role in the early phases of the adenoma-carcinoma sequence. Moreover, no data are currently available concerning AURKA involvement in the serrated tumorigenesis. Fluorescence in situ hybridization analysis and immunohistochemistry were used to assess gene copy number and protein expression in 40 colorectal adenomas, 20 cancerized adenomas, and 20 serrated polyps. An increased copy number was found either in adenomatous tissue or in early cancer in the vast majority of cancerized adenomas, but only in 5% of adenomas (P < .001). Protein expression strictly paralleled fluorescence in situ hybridization results. No changes in the gene copy number were observed in serrated polyps, regardless of their histotype and the presence of dysplasia, even if high percentages of immunostained cells were detected in all the subgroups. AURKA gene is associated with progressive colorectal adenomas but is uninvolved in the development of nonprogressive adenomas. The diploid status of the gene is maintained along the progression of serrated neoplasia. AURKA protein expression in serrated polyps is uncoupled from gene status and is likely to reflect apoptotic dysregulation.

Colorectal DiseaseVolume 17, Issue s1 p. 15-19 Original Article Serrated polyps M. Risio, Corresponding Author M. Risio Department of Pathology, Candiolo Cancer Institute, Candiolo-Torino, Italy Correspondence to: Mauro Risio, Department of Pathology, Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo-Torino, Italy. E-mail: mauro.risio@ircc.itSearch for more papers by this author M. Risio, Corresponding Author M. Risio Department of Pathology, Candiolo Cancer Institute, Candiolo-Torino, Italy Correspondence to: Mauro Risio, Department of Pathology, Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo-Torino, Italy. E-mail: mauro.risio@ircc.itSearch for more papers by this author First published: 16 December 2014 https://doi.org/10.1111/codi.12816Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume17, Issues1Special Issue: Colorectal Polyps: Recent Advances from Genetics to Management: 2nd Genoa Meeting 14 April 2014January 2015Pages 15-19 RelatedInformation

The last 30 years have witnessed a significant increase in the diagnosis of early-stage rectal cancer and the development of new strategies to reduce the treatment-related morbidity. Currently, there is no consensus on the definition of early rectal cancer (ERC), and the best management of ERC has not been yet defined. The European Association for Endoscopic Surgery in collaboration with the European Society of Coloproctology developed this consensus conference to provide recommendations on ERC diagnosis, staging and treatment based on the available evidence. A multidisciplinary group of experts selected on their clinical and scientific expertise was invited to critically review the literature and to formulate evidence-based recommendations by the Delphi method. Recommendations were discussed at the plenary session of the 14th World Congress of Endoscopic Surgery, Paris, 26 June 2014, and then posted on the EAES website for open discussion. Tumour biopsy has a low accuracy. Digital rectal examination plays a key role in the pre-operative work-up. Magnification chromoendoscopy, endoscopic ultrasound and magnetic resonance imaging are complementary staging modalities. Endoscopic submucosal dissection and transanal endoscopic microsurgery are the two established approaches for local excision (LE) of selected ERC. The role of all organ-sparing approaches including neoadjuvant therapies followed by LE should be formally assessed by randomized controlled trials. Rectal resection and total mesorectal excision is indicated in the presence of unfavourable features at the pathological evaluation of the LE specimen. The laparoscopic approach has better short-term outcomes and similar oncologic results when compared with open surgery. The management of ERC should always be based on a multidisciplinary approach, aiming to increase the rate of organ-preserving procedures without jeopardizing survival.

AimsThe tumour budding ability to predict cancer progression is felt to be worthy of investigation with regard to its biological properties. This study was aimed at evaluating the role of hypoxia and microvascularization in the morphogenesis of tumour budding in colorectal carcinoma.Methods and resultsThe immunohistochemical expression of hypoxia‐inducible factor‐1α (HIF‐1α) and carbonic anhydrase IX in cancer cells and CD105 in carcinoma‐induced microvascularization were assessed in 479 colorectal cancers. Furthermore, MET proto‐oncogene, receptor tyrosine kinase (MET) gene amplification was searched using fluorescence in‐situ hybridization (FISH). Carbonic anhydrase IX and HIF‐1α overall scores differed significantly in low‐ compared to high‐grade tumour budding cancers (P < 0.001), both in pT1 and in pT2–4 tumours. Intratumour analysis of budding foci showed a striking absence of carbonic anhydrase IX immunostain in detaching cells with respect to the surrounding microsectors. The mean microvessel density values were significantly higher in the low‐ compared to the high‐grade tumour budding groups (P < 0.001). A similar copy number of MET gene was detected in the two groups.ConclusionsOur study shows that tumour budding is associated with hypoxia induced by hypovascularization at the advancing front of colorectal cancer and that budding cells express a HIF‐1α‐mediated hypoxic tumour phenotype. MET gene amplification is not related to tumour budding morphogenesis.

The observed variability in the prevalence estimates of serrated lesions may be partly attributed to lack of agreement in the classification criteria adopted by pathologists from different countries/ regions. Several studies have indeed shown that the reproducibility of the pathological diagnosis of serrated lesions is poor.

Material and methods: Prospective analysis of 1,000 outpatient screening colonoscopies performed between March and October 2013 in asymptomatic Italian patients, aged 50 to 75 years.Standard non -HD Olympus videoendoscopes were employed.Rectal retrovision was systematically done.Validated quality indicators were used as outcome measures.Results: Mean age of the population was 63.3±10.5 years, there were 457 males (45.7%).Cecal intubation was successful in 96.0% of the patients.In the remnant cases, caecum was not reached due to a poor bowel cleansing (19), stricture (8) or intolerance (13).Adequate (good to excellent) bowel cleansing was recorded in 85.4% of patients, while it was rated as sufficient and poor in 12.3% and 2.3% of cases, respectively.The majority of procedures were performed under conscious sedation (62.5%), whereas deep sedation with propofol was used in only 1.1% of patients.Calculated mean withdrawal time was 9.1 minutes (SD 3.6) (range 6-14).Overall, CRC was detected in 38 pts (3.8%), while a total of 477 patients were diagnosed with at least one precancerous lesion (polyp detection rate 47.7%).The adenoma detection rate (ADR) was 34.6% (38% in males vs. 26.6% in females).The advanced adenoma detection rate was 16.0%.The size of the main precancerous lesion detected per patient was <5 mm in 88 cases, between 5-9 mm in 181 and >10 mm in 208.Shape of the overall 855 precancerous lesions was polypoid in 719 and non polypoid in 128 (including 19 laterally spreading tumours): Lesions were prevalent in the left colon (58.1%), while proximally located lesions accounted for 39.9% of the total and 9% were in rectum.Conclusions: A structured colonoscopy screening program can be carried out with high-quality standards and results in high detection rate of precancerous lesions.