Epigenetic centromere specification directs aurora B accumulation but is insufficient to efficiently correct mitotic errors

Aurora B activity is inhibited when centromeric repeat sequences are absent, although kinetochores can still assemble

Refined Criteria for Separating Low-grade Dysplasia and Nondysplastic Barrett Esophagus Reduce Equivocal Diagnoses and Improve Prediction of Patient Outcome: A 10-Year Review

The indefinite for dysplasia (IFD) category in Barrett esophagus (BE) is used for biopsies that are neither unequivocally dysplastic nor negative for dysplasia (NFD). In 2012, we refined our criteria so that BE with maintained cell polarity and surface gastric-type mucin vacuoles is considered NFD even with mild to moderate nuclear enlargement. A total of 1549 cases from 1130 patients with BE biopsies were identified from 2007 to 2016. Follow-up on patients with IFD biopsies was obtained to learn if the new thresholds better defined risk of progression. The earlier cases (2007-2011) were less likely than later cases (2012-2016) to be NFD (84.0% vs. 90.4%) and more likely to be IFD (8.4% vs. 4.3%). The proportions of low-grade dysplasia (3.9% vs. 2.5%, high-grade dysplasia (1.4% vs. 1.3%), and intramucosal carcinoma (2.3% vs. 1.6%) were similar between the earlier and later cases, respectively. Later IFD cases were more frequently dysplastic (3/21, 14.3%) on the next biopsy than earlier cases (1/48, 2.1%). The rate of dysplasia on the next biopsy for NFD cases was not higher in the later cases (6/222, 2.7%) than the earlier cases (16/360, 4.4%). Improved diagnostic criteria reduced the proportion of IFD cases by nearly 50% from 2007 to 2016. This change coincided with a higher proportion of IFD cases having dysplasia on the next biopsy. NFD patients had no increase in dysplasia on the next biopsy providing evidence that dysplastic cases are not missed by the refined criteria

Perianal Paget's disease as spread from non-invasive colorectal adenomas

Paget's disease of the perianal skin is a rare form of extramammary Paget's disease, and may be a primary intraepithelial adnexal neoplasm or secondary due to spread from an underlying colorectal lesion, nearly always colorectal adenocarcinoma. Secondary perianal Paget's disease associated with non-invasive colorectal adenomas is exceedingly uncommon, with only a few reported cases. Herein, we present the clinical and pathological features of the largest series of secondary perianal Paget's disease arising in association with colorectal adenomas. There was gender parity and the median age was 72 years (range = 68-76 years). In all cases, perianal Paget's disease was associated with colorectal adenomas, including three (75%) conventional tubular adenomas and one (25%) tubulovillous adenoma with serrated foci. All adenomas had high-grade dysplasia and one had intramucosal adenocarcinoma (lamina propria invasion; Tis), but all lacked submucosal invasion. The intraepithelial Paget's cells showed a colorectal phenotype by immunohistochemistry in all cases. At follow-up, two patients had no evidence of disease at 6 and 87 months, one had residual perianal Paget's disease at 8 months and one developed invasive adenocarcinoma of the perianal tissue at 36 months. Similar to its mammary analogue, secondary perianal Paget's disease may arise in association with invasive and/or in-situ colorectal lesions. Although the latter is an uncommon presentation of a recognised rare disease, knowledge of this phenomenon is important to forestall overdiagnosis of invasion and potential overtreatment. The clinical course is variable, such that close follow-up is required

The quantitative architecture of centromeric chromatin.

The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ∼400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ∼4% of all centromeric nucleosomes, forms a ∼50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP-A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation.DOI: http://dx.doi.org/10.7554/eLife.02137.001

Aberrant p53 Expression in Gastric Biopsies and Resection Specimens Following Neoadjuvant Chemoradiation: A Diagnostic Pitfall

Gastric mucosal biopsies and resections from patients treated with neoadjuvant radiation and/or chemotherapy are frequently encountered. These samples may show histologic features related to therapy including inflammation, ulceration, and epithelial atypia. In some cases, epithelial atypia may be marked, prompting the use of adjunct p53 immunohistochemistry. We examined p53 expression by immunohistochemistry in gastric mucosa following therapy. We evaluated the histology and p53 immunohistochemical expression in gastric mucosa from 5 resections and mucosal biopsies, from 60 patients treated with radiation and/or chemotherapy for gastroesophageal carcinoma (n  =  33) or pancreatic carcinoma (n  =  27). We identified histomorphologic features of therapy-related epithelial changes in 50 of 60 cases (83%). Abnormal p53 expression was present at least focally in nearly half the cases (27 of 60 cases; 45%), all of which showed morphologic evidence of therapy-related epithelial changes Neuroendocrine cell micronests were present in 37 of 60 cases (62%). Next-generation sequencing (NGS) of foci with therapy-related epithelial changes showing abnormal p53 expression and carcinoma from the same patient was attempted and yielded results in 1 patient. Interestingly, differing alterations in the patient's adenocarcinoma and in a histologically benign esophageal submucosal gland with therapy-related epithelial changes and abnormal p53 expression were identified. Our results demonstrate that abnormal p53 expression is relatively common in gastric mucosal samples following radiation and/or chemotherapy and suggest that p53 expression should be avoided when distinguishing therapy related changes from dysplasia or carcinoma. Furthermore, our NGS results raise interesting biological questions, which may warrant further investigation

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract The Rodger C. Haggitt Memorial Lecture

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms

Cell polarity (the ‘four lines’) distinguishes gastric dysplasia from epithelial changes in reactive gastropathy

AIMS: Gastric dysplasia is a risk factor for synchronous and subsequent gastric carcinoma. Distinguishing gastric dysplasia from reactive changes is subject to interobserver disagreement and is a frequent reason for expert consultation. We previously used assessment of surface cell polarity (the ‘four lines’) as a key feature to decrease equivocal diagnoses in Barrett oesophagus. In the current study, we examined for the presence or absence of the four lines in gastric dysplasia and reactive gastropathy. MATERIALS AND METHODS: The study includes all (n = 91) in-house biopsies with at least gastric dysplasia from the surgical pathology archives of two academic institutions during a 5-year period from 2008 to 2012. A reactive gastropathy group (n = 60) was created for comparison. RESULTS: The dysplasia/neoplasia group was comprised of 14 biopsies of gastric foveolar-type dysplasia, 59 of intestinal-type dysplasia, 14 with dysplasia in fundic gland polyps, three pyloric gland adenomas and one oxyntic gland adenoma. Loss of surface cell polarity was seen in all 88 dysplasia cases with evaluable surface epithelium. All 57 reactive gastropathy cases with evaluable surface epithelium showed intact surface cell polarity except in focal areas directly adjacent to erosions in 17 cases, where the thin wisp of residual surface mucin could not be appreciated on haematoxylin and eosin. CONCLUSION: Surface cell polarity (the four lines) was lost in all gastric dysplasia biopsies with evaluable surface epithelium and maintained in all biopsies of reactive gastropathy. Caution should be taken in using this feature adjacent to erosions in reactive gastropathy

Tissue-location-specific transcription programs drive tumor dependencies in colon cancer

Abstract Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAF V600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAF V600E -driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development