It is well established that colorectal cancer develops from a series of precursor epithelial polyps, including tubular adenomas, villous/tubulovillous adenomas (VA/TVA), sessile serrated adenomas (SSA) and traditional...It is well established that colorectal cancer develops from a series of precursor epithelial polyps, including tubular adenomas, villous/tubulovillous adenomas (VA/TVA), sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA). Of these, TSAs are least common and account for only 5% of all serrated polyps. TSAs are characterised by the presence of a “pinecone-like” architecture, granular eosinophilic cytoplasm, luminal serrations, ectopic crypt foci (ECF) and elongated, pencillate nuclei. However, the distinct slit-like luminal serrations, reminiscent of small bowel mucosa, appear to be the most unique and reproducible feature to distinguish TSAs from other polyps. There is a contention that TSAs are not inherently dysplastic and that the majority do not show cytological atypia. Two types of dysplasia are associated with TSA. Serrated dysplasia is less well recognised and less commonly encountered than adenomatous dysplasia. In addition, it is now becoming increasingly evident that TSAs can be admixed with HP, SSA and VA/TVA. At a genetic level, polyps may switch phenotype as they accumulate genetic changes, evolving from a serrated pathway to a more conventional one, which could be the basis for a spectrum theory starting out with a TSA with serration and ECF evolving into a TSA with conventional dysplasia and, eventually, to a well-developed conventional adenoma. Nevertheless, there is an exigency for future studies to provide further illumination and bridge the gaps in our present understanding.展开更多
AIM To present a comprehensive review of the etiology, clinical features, macroscopic and pathological findings, and clinical significance of Gut-associated lymphoid tissue or "dome" carcinoma of the colon.M...AIM To present a comprehensive review of the etiology, clinical features, macroscopic and pathological findings, and clinical significance of Gut-associated lymphoid tissue or "dome" carcinoma of the colon.METHODS The English language medical literature on gut-or gastrointestinal-associated lymphoid tissue(GALT) or "dome" carcinoma of the colon was searched and appraised.RESULTS GALT/dome-type carcinomas of the colon are thought to arise from the M-cells of the lymphoglandular complex of the intestine. They are typically asymptomatic and have a characteristic endoscopic plaque-or "dome"-like appearance. Although the histology of GALT/dome-type carcinomas displays some variability, they are characterized by submucosal localization, a prominent lymphoid infiltrate with germinal center formation, tumor-infiltrating lymphocytes, absence of desmoplasia, and dilated glands lined by columnar epithelial cells with bland nuclear features and cytoplasmic eosinophilia. None of the patients reported in the literature with follow-up have developed metastatic disease or local recurrence.CONCLUSION Increased awareness amongst histopathologists of this variant of colorectal adenocarcinoma is likely to lead to the recognition of more cases.展开更多
Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution...Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.展开更多
文摘It is well established that colorectal cancer develops from a series of precursor epithelial polyps, including tubular adenomas, villous/tubulovillous adenomas (VA/TVA), sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA). Of these, TSAs are least common and account for only 5% of all serrated polyps. TSAs are characterised by the presence of a “pinecone-like” architecture, granular eosinophilic cytoplasm, luminal serrations, ectopic crypt foci (ECF) and elongated, pencillate nuclei. However, the distinct slit-like luminal serrations, reminiscent of small bowel mucosa, appear to be the most unique and reproducible feature to distinguish TSAs from other polyps. There is a contention that TSAs are not inherently dysplastic and that the majority do not show cytological atypia. Two types of dysplasia are associated with TSA. Serrated dysplasia is less well recognised and less commonly encountered than adenomatous dysplasia. In addition, it is now becoming increasingly evident that TSAs can be admixed with HP, SSA and VA/TVA. At a genetic level, polyps may switch phenotype as they accumulate genetic changes, evolving from a serrated pathway to a more conventional one, which could be the basis for a spectrum theory starting out with a TSA with serration and ECF evolving into a TSA with conventional dysplasia and, eventually, to a well-developed conventional adenoma. Nevertheless, there is an exigency for future studies to provide further illumination and bridge the gaps in our present understanding.
文摘AIM To present a comprehensive review of the etiology, clinical features, macroscopic and pathological findings, and clinical significance of Gut-associated lymphoid tissue or "dome" carcinoma of the colon.METHODS The English language medical literature on gut-or gastrointestinal-associated lymphoid tissue(GALT) or "dome" carcinoma of the colon was searched and appraised.RESULTS GALT/dome-type carcinomas of the colon are thought to arise from the M-cells of the lymphoglandular complex of the intestine. They are typically asymptomatic and have a characteristic endoscopic plaque-or "dome"-like appearance. Although the histology of GALT/dome-type carcinomas displays some variability, they are characterized by submucosal localization, a prominent lymphoid infiltrate with germinal center formation, tumor-infiltrating lymphocytes, absence of desmoplasia, and dilated glands lined by columnar epithelial cells with bland nuclear features and cytoplasmic eosinophilia. None of the patients reported in the literature with follow-up have developed metastatic disease or local recurrence.CONCLUSION Increased awareness amongst histopathologists of this variant of colorectal adenocarcinoma is likely to lead to the recognition of more cases.
基金the Edmond J Safra Philanthropic Foundation,the Krembil Foundation,and the Rossy FoundationThe funding bodies did not take part in design of the study,in collection,analysis,or interpretation of data,or in writing the manuscript.
文摘Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.
