Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a modern classification scheme for these lesions. Sessile serrated polyps with ...dysplasia represent the most clinically significant serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.
Aims
Immune check‐point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up‐regulation of cytotoxic T cells, which can ...lead to a lack of self‐tolerance and immune‐related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check‐point inhibitor therapy‐associated gastritis.
Methods and results
Gastric biopsies from patients on immune check‐point inhibitor therapy with clinical suspicion of drug‐associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow‐up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra‐epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug‐induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease‐associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab.
Conclusions
Awareness of the morphological spectrum of immune check‐point inhibitor therapy‐associated gastritis is important for the accurate diagnosis and prompt management of these patients.
Fibrin ring granulomas are an uncommon finding in liver biopsies although they have been described in liver injury secondary to several infectious and noninfectious entities, most notably Q fever. ...Immune checkpoint inhibitors are recent advances in cancer therapy, and stimulate the immune system to cause antitumoral effects but may also lead to adverse immune events such as hepatitis and colitis. We report 2 patients on combination ipilimumab/nivolumab who developed hepatitis and had fibrin ring granulomas in their liver biopsies.
Background & Aims Although the adenoma detection rate is used as a measure of colonoscopy quality, there are limited data on the quality of endoscopic resection of detected adenomas. We determined ...the rate of incompletely resected neoplastic polyps in clinical practice. Methods We performed a prospective study on 1427 patients who underwent colonoscopy at 2 medical centers and had at least 1 nonpedunculated polyp (5–20 mm). After polyp removal was considered complete macroscopically, biopsies were obtained from the resection margin. The main outcome was the percentage of incompletely resected neoplastic polyps (incomplete resection rate IRR) determined by the presence of neoplastic tissue in post-polypectomy biopsies. Associations between IRR and polyp size, morphology, histology, and endoscopist were assessed by regression analysis. Results Of 346 neoplastic polyps (269 patients; 84.0% men; mean age, 63.4 years) removed by 11 gastroenterologists, 10.1% were incompletely resected. IRR increased with polyp size and was significantly higher for large (10–20 mm) than small (5–9 mm) neoplastic polyps (17.3% vs 6.8%; relative risk = 2.1), and for sessile serrated adenomas/polyps than for conventional adenomas (31.0% vs 7.2%; relative risk = 3.7). The IRR for endoscopists with at least 20 polypectomies ranged from 6.5% to 22.7%; there was a 3.4-fold difference between the highest and lowest IRR after adjusting for size and sessile serrated histology. Conclusions Neoplastic polyps are often incompletely resected, and the rate of incomplete resection varies broadly among endoscopists. Incomplete resection might contribute to the development of colon cancers after colonoscopy (interval cancers). Efforts are needed to ensure complete resection, especially of larger lesions. ClinicalTrials.gov Number: NCT01224444.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 ...(BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.
Well-differentiated neuroendocrine tumors (WDNET) of the gastrointestinal tract, pancreas, and lung are histologically similar. Thus, predicting the site of origin of a metastasis is not possible on ...morphologic grounds. Prior immunohistochemical studies of WDNET have yielded conflicting results, and pancreatic and duodenal homeobox factor-1 (PDX-1) has not previously been evaluated in this context. We therefore analyzed the expression of CDX-2, PDX-1, TTF-1, and neuroendocrine secretory protein-55 (NESP-55), a recently described member of the chromogranin family, in primary and metastatic WDNET. In total, 64 gastrointestinal carcinoids (5 stomach; 5 duodenum; 31 ileum; 11 appendix; and 12 rectum); 39 pancreatic endocrine tumors (PET); and 20 pulmonary carcinoid tumors were studied. PET were positive for NESP-55 (16/39) and PDX-1 (11/39); 3/31 also showed heterogeneous positivity for CDX-2. Ileal carcinoids were exclusively positive for CDX-2 (30/31) and negative for all other markers. Appendiceal carcinoids were uniformly positive for CDX-2 (11/11). All rectal carcinoids were negative for CDX-2 and TTF-1; 2/12 were positive for PDX-1, and 1/12 for NESP-55. The gastric and duodenal carcinoids were only positive for PDX-1 (7/10). TTF-1 positivity was confined to pulmonary carcinoids (7/20); 1/20 was positive for NESP-55; and all were negative for CDX-2 and PDX-1. NESP-55 and PDX-1 positivity, in the presence of negative CDX-2 and TTF-1, was 97% specific for PET. The sensitivity and specificity of CDX-2 positivity for predicting an ileal primary, when PDX-1, NESP-55, and TTF-1 were negative, was 97% and 91%, respectively. TTF-1 positivity was confined to pulmonary carcinoids in our study but was present in only about a third of cases. A panel of these 4 markers may be useful in predicting the primary site of metastatic WDNET.
There has been much progress in our understanding of esophageal inflammatory disorders in the past few years. This is particularly true about esophageal eosinophilia and PPI responsiveness, ...lymphocytic esophagitis and motility disorders, and short-term risk of neoplasia in esophageal leukoplakia. The current review will summarize esophageal injury patterns that primarily occur due to non-reflux causes, with a focus on usual pitfalls in biopsy diagnosis and recent advances in our knowledge of the more common forms of esophagitis.
The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards ...identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques.
Summary
Ipilimumab is a novel immunomodulator demonstrating promising efficacy in treatment of melanoma and other cancers. The clinical benefit from ipilimumab can be hampered by the immure-related ...adverse events (irAEs) caused by dysregulation of host immune system. Ipilimumab associated hepatitis is also an important irAE, however, there have been limited descriptions of its clinicopathologic and imaging characteristics. We aim to describe the clinicopathologic and imaging characteristics of 6 patients who were diagnosed as ipilimumab associated hepatitis during the ipilimumab treatment for melanoma. The clinical features of these patients were as follows: (1) severe cases with systemic symptoms and highly increased level of liver function tests (LFTs), and (2) mild asymptomatic cases with mildly increased level of LFTs. In severe cases with ALT >1,000 IU/L, imaging findings were characterized by mild hepatomegaly, periportal edema, and periportal lymphadenopathy, while mild cases showed normal imaging findings. This spectrum of imaging findings in our series was similar to that of common causes of acute hepatitis. Among 3 cases with pathologic specimen, two cases showed severe panlobular hepatitis with prominent perivenular infiltrate with endothelialitis, suggestive of predominant injury to hepatocytes, while the other case showed mild portal mononuclear infiltrate around proliferated bile ductules, suggestive of predominant injury to bile ducts. In summary, ipilimumab associated hepatitis may demonstrate variable imaging findings according to its clinical severity, and histologically may manifest either as a predominant injury to hepatocytes (acute hepatitis pattern) or as a predominant injury to bile ducts (biliary pattern).
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