Traditional serrated adenoma: An update

Although recognized 25 years ago, the traditional serrated adenoma (TSA) remains an ongoing source of diagnostic and biologic debate. Recent research has greatly improved our understanding of the morphological and molecular aspects of these polyps. In particular, the recognition of ectopic crypt foci (ECFs) in combination with typical cytology and slitlike serrations improves diagnostic reproducibility. Awareness that many TSAs, particularly BRAF-mutated TSAs, arise in precursor microvesicular hyperplastic polyps and sessile serrated adenomas can aid in making this diagnosis and should not be confused with a sessile serrated adenoma with dysplasia. At a molecular level, TSAs can be divided into 2 groups based on their BRAF or KRAS mutation status. The development of overt cytologic dysplasia is accompanied by TP53 mutation, Wnt pathway activation, and, in some cases, silencing of CDKN2A. Importantly, however, mismatch repair enzyme function is retained. Thus, the TSA is an important precursor of aggressive molecular subtypes of colorectal carcinoma

E-cadherin can limit the transforming properties of activating β-catenin mutations

Wnt pathway deregulation is a common characteristic of many cancers. But only Colorectal Cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve a Wnt deregulation and acquire a crypt-progenitor-cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with significantly higher expression of the β-catenin binding partner E-cadherin. This increased expression is associated with a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction of E-cadherin synergised with an activating mutation of β-catenin so there was now a rapid CPC phenotype within the colon and SI. Thus there is a threshold of β-catenin that is required to drive transformation and E-cadherin can act as a buffer to prevent β-catenin accumulation

A Study to investigate the role of p27 and Cyclin E immunoexpression as a prognostic factor in early breast carcinoma

<p>Abstract</p> <p>Background</p> <p>Cyclin E and p27 expression is easy to assess in human tissues by standard immunohistochemical techniques. Immunohistochemistry is cost effective, relatively easy to perform and will play more of a role in the future management of cancer. The aim of this study was to investigate the role of p27 and cyclin E immunoexpression as a prognostic factor in early breast carcinoma.</p> <p>Methods</p> <p>Cyclin E and p27 immunohistochemistry was performed on sixty six cases of breast carcinoma submitted over a five year period to the Division of Anatomical Pathology, Groote Schuur hospital; Whittaker and Associates; and PathCare. All tumours included in this study were less than 5 cm in diameter (pT1 and pT2 stage) and all the patients had wide local excisions performed. Follow up information was obtained from patient folders in the Department of Radiation Oncology.</p> <p>Results</p> <p>There was no significant association of cyclin E and p27 expression with distant metastasis free survival (MFS) for all invasive carcinomas in contrast to grade, lymph node spread and vascular invasion. However, there was a statistically significant direct association of cyclin E with distant metastases in all invasive carcinomas, in the subgroup of infiltrating duct carcinomas (IDC) and in the node negative group when cyclin E was stratified as negative and positive (low/high). In this study of early breast carcinoma, only 9/66 cases showed cyclin E expression. Of these, four patients had distant metastases, one patient had a local recurrence and four patients were alive at last follow-up. Furthermore, cyclin E expression was significantly associated with grade, lymph node spread, oestrogen receptor status and histological type. None of the lobular carcinomas showed cyclin E positivity and only one case of lobular carcinoma presented with distant metastases.</p> <p>59/66 cases were positive (low/high) for p27 while seven cases were negative, 22 cases showed low expression and 37 cases demonstrated high p27 expression.</p> <p>p27 was significantly associated with oestrogen receptor status only for all invasive carcinomas and in the IDC group. There was no statistical relationship between p27 and cyclin E, but 50 (76%) tumours with positive p27 expression were negative for cyclin E. There were similar results for the invasive ductal carcinoma subgroup.</p> <p>Conclusion</p> <p>This study shows that p27 and cyclin E are not good independent prognostic markers for early breast carcinoma in contrast to grade, lymph node spread and vascular invasion for all invasive carcinomas. However, cyclin E provides some prognostic value as there is a direct statistical association with the development of distant metastases. Many previous studies have correlated overexpression of cyclin E with an aggressive course. The inverse relationship between p27 and cyclin E expression which has been reported in the literature has been highlighted, but this was not statistically significant. Most cases showed positive p27 expression and negative Cyclin E expression. This may be due to the early stage of the disease.</p

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

Human immunodeficiency virus infection, Bcl-2, p53 protein, and Ki-67 analysis in ocular surface squamous neoplasia.

OBJECTIVES: To determine the age and human immunodeficiency virus (HIV) status of patients with ocular surface squamous neoplasia (OSSN), and to analyze tumor proliferation, Bcl-2, and p53 oncoprotein expression in OSSN. METHODS: Only patients with histologically proved neoplasia were included in this study. The HIV status was obtained only with informed consent. Monoclonal antibodies to p53 and Bcl-2 protein were used after microwave antigen retrieval to enhance immunohistochemical staining of the sections. Proliferation was assessed by means of Ki-67 antigen expression. Positive staining in each specimen was expressed as a percentage and graded accordingly. RESULTS: Forty-one eyes in 40 black patients with a mean age of 37 years were found to have OSSN. Of the 41 lesions, 35 represented in situ or invasive carcinoma. The remaining 6 had mild or moderately dysplastic lesions. Seventeen patients agreed to an HIV test and, of these, 12 (70.6%) were HIV positive. All 12 were younger than 50 years, and 11 had either carcinoma in situ or invasive lesions. Twenty-two of 40 lesions expressed significant (greater than 50% of neoplastic cells) p53 positivity, while Bcl-2 expression was detected in 10. Ki-67 expression was low, even in the HIV-positive lesions. CONCLUSIONS: At our institution, OSSN occurs in young patients, many of whom are HIV positive. Expression of p53 is a common finding, whereas Bcl-2 immunoexpression occurs in the minority of cases. Ki-67 analysis showed that OSSN is a slow-growing tumor, even in the presence of HIV infection

Pancreatic endocrine neoplasia: familial syndromes

Inherited or familial neuroendocrine tumours of the pancreas are uncommon. The most frequently encountered syndromic form occurs in the setting of multiple endocrine neoplasia type 1 (MEN-1). Sixty per cent of patients with MEN-1 manifest pancreatic endocrine tumours (PETs). These tumours occur in younger patients and tend to be more aggressive than similar sporadic forms. The pancreas displays a range of morphological changes that can assist in making the diagnosis of MEN-1. Ductulo-insular complexes, islet dysplasia and multiple non-functioning microadenomas are typically encountered. If functional, the tumours tend to be gastrin producing. von Hippel-Lindau patients can also have PETs, although benign cysts and serous microcystic adenomas are commoner. Multiple tumours may be encountered and they are characterized by cells with lipid vacuoles. PETs may also be seen in patients with type 1 neurofibromatosis (NF-1) and they are usually somatostatin producing. PETs are less frequently encountered than duodenal tumours in the setting of NF-1. Very few cases of PET are seen in tuberous sclerosis. © 2009 Elsevier Ltd. All rights reserved

Reticular and microcystic schwannoma: a distinctive tumor of the gastrointestinal tract.

Reticular/microcystic schwannoma is a rare variant of schwannoma with a predilection for viscera, especially the gastrointestinal tract. Of the 9 cases reported thus far, 7 have occurred in female patients. The average age of presentation is 67 years. They are usually small, asymptomatic lesions ranging in size from 0.85 to 2.2 cm with a mean size of 1.35 cm. They usually occur in the stomach, small bowel, and proximal large intestine. It differs from usual schwannomas of the gastrointestinal tract by lacking the peripheral cuff of lymphocytes. The histologic appearance of slender bipolar spindle cells in a lace-like reticular pattern set within a myxoid stroma raises a wide differential diagnosis including gastrointestinal stromal tumor, perineurioma, and in more epithelioid examples, even carcinoma. Awareness of the entity and an immunohistochemical panel of markers will ensure that the correct diagnosis is made

Cyclin E and p27: Their putative role as prognostic markers

Abnormalities or derangements of the orderly proliferation and cycling of cells is the quintessential definition of a cancer or malignant cell. The complex nature of the interaction of several interdependent cell cycle proteins has and continues to be unravelled. Key functions have been ascribed to many of the proteins and the delicate balance that maintains cell normal cell cycling is now understood. Within the cell cycle, the GI proteins have come under intense scrutiny, especially the interaction between cyclin E and p27. Essentially, cyclin E drives the cell cycle forward towards mitosis, while p27 acts as a brake preventing cell cycle progression. The levels of these two proteins, independently and together, have been analysed in many studies in several tumour types. A pattern or trend has emerged: high cyclin E with low p27 is an adverse prognostic indicator in the majority of commonly encountered malignant tumours. Furthermore, in several instances, there is a stepwise increase of cyclin E and decrease of p27 that matches the progression from dysplastic, pre-invasive lesions to full-blown invasive malignant tumours. As a cautionary note, there are exceptions to this tenet as exemplified by bladder and oesophageal cancers, where the relationship between cyclin E and p27 is not straightforward. The body of evidence in the literature points to both cyclin E and p27 as being useful adjuncts to prognostication indices, but not unreservedly as independent portenders of outcome. © 2002 Elsevier Science Ltd