This study shows that HCCs in patients with features of MS as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver. In addition, some of them arise through malignant transformation of a preexisting liver cell adenoma.
Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.
4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.
Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.
Camptocormia, also referred to as bent spine syndrome (BSS) is defined as an abnormal flexion of the trunk, appearing in standing position, increasing during walking and abating in supine position. BSS was initially considered, especially in wartime, as a psychogenic disorder. It is now recognized that in addition to psychiatric syndromes, many cases of reducible BSS have a somatic origin related to a number of musculo-skeletal or neurological disorders. The majority of BSS of muscular origin is related to a primary idiopathic axial myopathy of late onset, appearing progressively in elderly patients. Diagnosis of axial myopathy first described by Laroche et al. is based upon CT/MRI examination demonstrating massive fatty infiltration of paravertebral muscles. The non-specific histological aspect includes an extensive endomysial fibrosis and fat tissue with irregular degenerated fibers. Weakness of the paravertebral muscles can be secondary to a wide variety of diseases generating diffuse pathologic changes in the muscular tissue. BSS can be the predominant and sometimes revealing symptom of a more generalized muscular disorder. Causes of secondary BSS are numerous. They must be carefully assessed and ruled out before considering the diagnosis of primary axial myopathy. The principal etiologies include on the one hand inflammatory myopathies, muscular dystrophies of late onset, myotonic myopathies, endocrine and metabolic myopathies, and on the other hand neurological disorders, principally Parkinson's disease. Camptocormia in Parkinsonism is caused by axial dystonia, which is the hallmark of Parkinson's disease. There is no specific pharmacologic treatment for primary axial myopathy. General activity, walking with a cane, physiotherapy, and exercises should be encouraged. Treatment of secondary forms of BSS is dependent upon the variety of the disorder generating the muscular pathology. Pharmacologic and general management of camptocormia in Parkinson's disease merge with that of Parkinsonism. Levodopa treatment, usually active on tumor rigidity and akinesia, has poor or negative effect on BSS.
Histopathological features of cutaneous meningeal heterotopias are various and sometimes misleading. Fibrous lesions should not be misdiagnosed as aplasia cutis. Podoplanin-positive pseudovascular spaces represent the main pitfall and should not be diagnosed as lymphangioma. Correct diagnosis is confirmed by EMA and NSE coexpression within the lesion.
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