Appendicitis is the most commonly performed emergency abdominal surgery. The appendix can also be the site of a variety of neoplasms and unusual inflammatory conditions. A retrospective review was ...performed to determine the pathological diagnoses in appendicectomy specimens.
This study is a retrospective analysis of 2660 appendicectomies performed from 1997 to 2003. The reports were analyzed for the following parameters: age-related incidence of acute appendicitis, seasonal variation in presentation, perforation rate, rate of negative and incidental appendicectomy, and the incidence of other pathologies encountered.
Of the 2660 appendicectomy specimens, acute appendicitis was seen in 1718 patients (64.58%), with a peak in patients in their second decade (35.09% of cases of acute appendicitis). The perforation rate was 13.9% and was significantly higher in patients aged 70 years or more (P < 0.001). The negative appendicectomy rate was 28.8%, and was significantly higher in female patients (P < 0.001) and in the 11-30 year age group (P < 0.001). Other pathologies include carcinoid (0.52%), adenocarcinoma (0.39%), and mucinous cystadenoma (0.60%).
The high rate of negative appendicectomy among female patients and the increased incidence of perforation in elderly patients reinforce the validity of the judicious use of laparoscopy in these populations. There are still a number of unusual histologies found in appendicectomy specimens supporting the continued use of routine histology.
Summary TNM staging has made a major contribution to the clinical management of patients with cancer over the past 50 years, but are we sure it delivers what is needed to provide adequate advice in ...the 21st century, and are there ways in which the system can be improved? This article, by pathologists with a special interest in colorectal cancer, is intended to offer constructive criticism towards the TNM classification of colorectal cancer, make suggestions for improvement, and recommend the adoption of a robust evidence base for this system.
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co‐occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We ...investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal‐specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild‐type (WT) mice and mice with a predisposition to adenoma development (Apcfl/+). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life‐span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this ...interdependency in an in vivo setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted Brg1 in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using VillinCreERT2 and AhCreERT transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
To assess the interobserver agreement in the reporting of colorectal polyps among histopathologists participating in the Welsh Bowel Cancer Screening (BCS) programme.
Methods and results
Twelve ...benign polyps representative of BCS cases were identified from pathology files and reported by 28 BCS histopathologists using proforma sheets. The level of agreement between the participants and a gold standard was determined using kappa (κ) statistics. A moderate level of agreement was achieved in the reporting of polyp type κ = 0.45; 95% confidence interval (CI) 0.34–0.59 and adenomatous lesions were distinguished from non‐adenomatous lesions in 96% of cases. Substantial agreement was obtained in distinguishing low‐ and high‐grade dysplasias (κ = 0.67; 95% CI 0.50–0.86), but there was only fair agreement in reporting excision margin status (κ = 0.24; 95% CI 0.07–0.43) with frequent use of the ‘uncertain’ category. Significant issues included categorizing serrated lesions, recognizing focal high‐grade dysplasia and epithelial misplacement, and apparent overdiagnosis of villous change in adenomas.
Conclusions
Interobserver variability in some aspects of reporting colorectal polyps by BCS pathologists is suboptimal, with a potential impact upon patient management and the efficient running of the screening service. Approaches to addressing this are discussed.
Background & Aims Mutations in components of the Wnt signaling pathway, including β-catenin and AXIN1, are found in more than 50% of human hepatocellular carcinomas (HCCs). Disruption of Axin1 causes ...embryonic lethality in mice. We generated mice with conditional disruption of Axin1 to study its function specifically in adult liver. Methods Mice with a LoxP -flanked allele of Axin1 were generated by homologous recombination. Mice homozygous for the Axin1fl/fl allele were crossed with AhCre mice; in offspring, Axin1 was disrupted in liver following injection of β-naphthoflavone ( Axin1fl/fl / Cre mice). Liver tissues were collected and analyzed by quantitative real-time polymerase chain reaction and immunoprecipitation, histology, and immunoblot assays. Results Deletion of Axin1 from livers of adult mice resulted in an acute and persistent increase in hepatocyte cell volume, proliferation, and transcription of genes that induce the G2 /M transition in the cell cycle and cytokinesis. A subset of Wnt target genes was activated, including Axin2 , c-Myc , and cyclin D1 . However, loss of Axin1 did not increase nuclear levels of β-catenin or cause changes in liver zonation that have been associated with loss of the adenomatous polyposis coli (APC) or constitutive activation of β-catenin. After 1 year, 5 of 9 Axin1fl/fl/Cre mice developed liver tumors with histologic features of HCC. Conclusions Hepatocytes from adult mice with conditional disruption of Axin1 in liver have a transcriptional profile that differs from that associated with loss of APC or constitutive activation of β-catenin. It might be similar to a proliferation profile observed in a subset of human HCCs with mutations in AXIN1. Axin1fl/fl mice could be a useful model of AXIN1-associated tumorigenesis and HCC.
A wealth of evidence obtained using mouse models indicates that CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune ...responses. To date there is limited information about CD4(+) T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients.
Treg were identified and characterized as CD4(+)CD25(+)FOXP3(+) using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4(+) T cell responses, as observed by IFNgamma release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group.
Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.
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