Thyroid epithelial tumours

The traditional classification of thyroid tumours is derived from follicular and ‘C’ cells and based on morphology and clinical features, but molecular studies have shown the involvement of distinct genes in each of these tumours. The high prevalence of papillary microcarcinoma in thyroid glands removed for other reasons underpinned the alteration of the TNM classification of thyroid tumors. Molecular studies showed that the high prevalence of BRAF mutations in papillary carcinomas, reaching ≤70% in some series, contrasts with lower levels of this mutation in cases of follicular variants. Follicular variants of papillary carcinoma share oncogene changes with follicular tumours, making the differential diagnosis of follicular lesions a challenge. Hyalinizing trabecular tumour has the same RET oncogene rearrangement encountered in many papillary carcinomas, raising the possibilty that it is a variant of papillary carcinoma. The ‘mixed medullary-follicular cell carcinoma’ is of uncertain histogenesis and merits separate classification.     

Gastric epithelial dysplasia

Gastric dysplasia is considered to be the penultimate stage of the gastric carcinogenesis sequence. Its clinical importance has been underscored since its association with gastric adenocarcinoma was established. High-grade dysplasia and to a lesser degree low-grade dysplasia are markers of increased cancer risk, although their natural histories are difficult to determine. There are many pitfalls in the diagnosis of gastric dysplasia. Its recognition and grading are subject to interobserver variability, particularly at the lower end of the histologic spectrum (negative v indefinite for dysplasia v low-grade dysplasia) when inflammation is present. Also, diagnostic criteria and grading schemes have evolved differently worldwide resulting in disagreement between pathologists. Against this background, the authors review contemporary issues related to gastric dysplasia, its definition, classification, grading, and natural history. We also discuss new classifications of gastric epithelial dysplasia designed to develop equivalence between grading schemes worldwide.     

Benign epithelial nephroblastoma

Summary The occurence of a malignant Wilms'tumor in the right kidney and of a benign epithelial nephroblastoma in the left kidney of a 5-year-old girl is reported. Both kidneys contained foci of persistent well differentiated blastema. In the left kidney a direct transformation of the primitive metanephric epithelium into a benign nephroblastoma is shown. This finding suggests an origin of epithelial nephroblastoma from persistent nephrogenic tissue and indicates that the former represents the benign counterpart of the malignant Wilms'tumor.Dedicated to Prof. Dr. Max Marcus on his 85th birthday     

Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity

The cellular origin, in vivo function and fate of donor bone marrow‐derived cells residing in the recipient intestinal epithelial cells, pericryptal myofibroblasts or endothelial cells remain obscure. Although ‘immunoprivileged’ mesenchymal stem cells (MSCs) are prime candidates for cell‐ and gene‐based therapy, their precise role in colitis remains largely undetermined. Using a dextran sulphate sodium (DSS) colitis with busulphan (BU)‐induced hypoplastic marrow model, we examined the therapeutic effects of MSC transplantation, focusing on the role of MSCs as both cell providers and immunomodulators. Donor‐derived MSCs were detected by eGFP immunofluorescence and fluorescence in situ hybridization for Y‐chromosome (Y‐FISH) analysis. Western blot analysis of apical‐most tight junction proteins was performed with antibodies against claudin‐2, ‐7, ‐8, ‐12, ‐13, ‐15 and ZO‐1. Cytokine and cell cycle profiles were analysed by semi‐quantitative RT‐PCR and flow cytometry. Susceptibility to DSS colitis was significantly increased by co‐existing BU‐induced bone marrow hypoplasia and this increase was significantly reduced by enhancing epithelial engraftment of MSCs, an effect depending on restoring epithelial barrier integrity rather than inhibiting host immune responses. We provide evidence that implicates MSCs in maintaining epithelial barrier function by reassembling apical‐most tight junction proteins, claudins. The therapeutic efficacy of extrinsic MSCs depends on enhancing epithelial engraftment in damaged crypts by busulphan conditioning. Such a role for the MSC‐derived intestinal cells in colitis therapy merits further examination and may offer a promising new treatment for inflammatory bowel disease (IBD). Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Malignant epithelial odontogenic tumors

Malignant epithelial odontogenic tumors are very rare. They may arise from the epithelial components of the odontogenic apparatus. The rests of Malassez, the reduced enamel epithelium surrounding the crown of an impacted tooth, the rests of Serres in the gingiva, and the linings of odontogenic cysts represent the precursor cells for malignant transformation. Because metastatic carcinoma is the most common malignancy of the jaws, the diagnosis of a primary intraosseous carcinoma must always be made to the exclusion of metastatic disease. Odontogenic carcinomas include malignant (metastasizing) ameloblastoma, ameloblastic carcinoma, primary intraosseous squamous cell carcinoma, clear cell odontogenic carcinoma, and malignant epithelial ghost cell tumor. There are specific histopathologic features that support the diagnosis of a primary carcinoma of odontogenic epithelium which are presented in this article. Immunohistochemical (IHC) staining is important for distinguishing clear cell odontogenic carcinoma from metastatic renal cell tumors, yet IHC stains are not particularly helpful for other lesions in this group-all of which exhibit low molecular weight cytokeratin positivity. Aggressive growth and nodal and distant metastases occur with all of these entities.     

Mucin-positive epithelial mesothelioma.

Mucin-positive epithelial mesothelioma is a rare, frequently unrecognized entity that should not be misinterpreted as metastatic adenocarcinoma, as each is associated with differing treatment and prognosis. Presented herein is a case of an acidic and neutral mucin-positive papillary mesothelioma of the right pleura, with cytologic, histologic, histochemical, immunohistochemical, and ultrastructural evaluation.     

Lung epithelial stem cells

This review concentrates on recent evidence about lung stem cell origins and plasticity. The range of potential cells which can repopulate the injured lung, classically the basal and mucous secretory cells of the trachea, the Clara cells of the bronchiole, and the type II pneumocyte of the alveolus, has been extended to include the mucus-gland duct cells of the trachea and bronchus. Some evidence suggests that there are variant Clara cells that lack cytochrome P-450 and so are spared toxic activation of xenobiotics, and may aid bronchiolar repopulation after injury, such as with naphthalene. There may even be involvement of the neuroepithelial bodies or cells in this, though the evidence is not yet conclusive. The search for a resident pulmonary multipotent cell for repopulating any lung epithelium has not yet been successful. The picture remains similar to earlier conclusions, in that the local stem or precursor cell is the most likely to contribute to local needs in times of tissue damage. There remains a major challenge for lung cancer treatment, where high-dose chemo- or radio-therapy may be hoped to promote the seeding and repair of lung parenchyma by circulating bone marrow stem cells, as seen in liver models. Patient survival rates do not yet suggest that this occurs to any great extent, but this remains to be shown formally. The effects of prior fibrosis and tumour necrosis are probably confounding factors in this lack of rescue.     

Benign epithelial odontogenic tumors

Teeth are formed from a complex interaction of primitive ectoderm and ectomesenchymal tissues. Because humans develop 2 sets of teeth (deciduous and permanent), odontogenesis is a prolonged biologic process. Residues of odontogenic tissues are present in most humans- both during and after odontogenesis. These elements may be found in either bone or soft tissue of the jaws and may contribute to the formation of odontogenic tumors in these sites. Further, the mixture of epithelium and mesenchyme necessary for tooth formation allows for the development of tumors composed of either element or for mixed neoplasms. This article discusses 4 of the 5 benign odontogenic neoplasms that are of epithelial origin and offers an agreed on classification scheme, which includes important clinicopathological subtypes. Specifically discussed are ameloblastoma, calcifying epithelial odontogenic tumor (Pindborg tumor), adenomatoid odontogenic tumor, and squamous odontogenic tumor. A brief history of each tumor is given along with a discussion of demographic data, clinical findings, radiographic features, and gross features where useful. A thorough discussion is presented of diagnostic histopathology including histologic variants. Generally accepted modes of therapy and follow-up recommendations are discussed.     

Uncommon ovarian epithelial tumours

Epithelial ovarian tumours represent the most common type of ovarian tumour. Most of malignant cases represent high-grade serous, clear cell and endometrioid carcinomas; borderline serous and mucinous tumours of intestinal type are less common. This review focuses on the uncommon or rare epithelial tumours of the ovary which include borderline and malignant Brenner tumours, the recently-described mesonephric-like carcinoma of the ovary, and primary ovarian neuroendocrine tumours, with emphasis on helpful and diagnostic features.     

Benign epithelial odontogenic tumors

The group of benign epithelial odontogenic tumors consists of the four member types of the ameloblastoma family (solid/multicystic, extraosseous/peripheral, desmoplastic, unicystic), squamous odontogenic tumors, calcifying odontogenic tumors, adenomatoid odontogenic tumors, and keratocystic odontogenic tumors, the former "keratocysts" that were recently reclassified by the World Health Organization and are now regarded as tumors. The latter are by far the most frequent tumors in this group, followed by solid/multicystic ameloblastoma. Although the etiology of these lesions is still unknown, a close relationship to normal tooth development is obvious, which is partially imitated by some tumors. Despite some similarities to each other, at least in part, the biological behavior of these lesions is quite different, as are treatment modalities. The diagnosis is essentially based on localization (intraosseous vs. extraosseous/peripheral) and histology, whereupon the correlation of histological findings with radiographic morphology may be of additional diagnostic value. Because of the range of variation, immunohistochemical investigations are not helpful in diagnosing a particular case.     

Fascin与上皮组织肿瘤

Fasc in基因属于fasc ins家族,其蛋白质编码产物是一种结构独特、进化保守的肌动蛋白(actin)交联蛋白,位于细胞膜皱褶、微棘及应力纤维,在各种转化细胞中促使细胞膜突起并增加细胞运动性。近年来的研究发现,fasc in在许多上皮来源的肿瘤组织细胞中表达上调,在肿瘤的进展中起重要作用。本文综述了fasc in的研究现状及其在上皮组织肿瘤中的研究进展。     

Rat glomerular epithelial cells in culture. Parietal or visceral epithelial origin?

Isolated glomeruli from rats were explanted under standard culture conditions and outgrowths were studied by light and electron microscopy in order to identify the cells. Rat glomerular samples contained 20 to 30% structurally well-preserved encapsulated glomeruli which had a large rate of attachment to the substrate and very constantly gave rise to cellular outgrowth. In order to label cells from which outgrowth originated the glomerular incorporation of [3H]thymidine was studied in the preattachment phase. By light and electron microscope autoradiograph it was demonstrated that label was located only over visceral and parietal epithelial cells during the first 3 days of culture. Incorporation of [3H]thymidine was seen in mesangial cells after 5 days, i.e., after the glomeruli had attached to the culture vessels and the initial outgrowth had appeared. Consequently the first cells to grow out were of epithelial origin. Glomeruli were then incubated with [3H]thymidine for the first 2 1/2 days of culture in order to label the epithelial cells, then were allowed to attach to the substrate and induce cell outgrowth. By light microscope autoradiography performed with the outgrowths in situ two types of cells with labeled nuclei were seen: (a) a small, polyhedral ciliated cell which grew in colonies where the cells were joined by junctional complexes (type I), and (b) a second very large, often multinucleated cell (type II). Based on the structural resemblance with their counterparts in situ and on comparisons with positively identified visceral epithelial cells in outgrowths from other species it is suggested that type I cells are derived from the parietal epithelium of Bowman's capsule and type II cells from the visceral epithelium. Type I cells proliferated for approximately two weeks around the glomerular explant and then reached steady state while type II cells showed only very limited proliferative capacity. Furthermore, rapidly proliferating cells of supposed mesangial origin (type III cells) grew out later from isolated rat glomeruli. Thus, the present results suggest that outgrowths from rat glomeruli contain three types of cells which can be identified on basis of structure and growth characteristics as visceral and parietal epithelial cells and mesangial cells, while endothelial cells do not proliferate.     

Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies

The nose is an attractive source of airway epithelial cells, particularly in populations in which bronchoscopy may not be possible. However, substituting nasal cells for bronchial epithelial cells in the study of airway inflammation depends upon comparability of responses, and evidence for this is lacking. Our objective was to determine whether nasal epithelial cell inflammatory mediator release and receptor expression reflect those of bronchial epithelial cells. Paired cultures of undifferentiated nasal and bronchial epithelial cells were obtained from brushings from 35 subjects, including 5 children. Cells were subject to morphologic and immunocytochemical assessment. Mediator release from resting and cytokine-stimulated cell monolayers was determined, as was cell surface receptor expression. Nasal and bronchial cells had identical epithelial morphology and uniform expression of cytokeratin 19. There were no differences in constitutive expression of CD44, intercellular adhesion molecule-1, alphavbeta3, and alphavbeta5. Despite significantly higher constitutive release of IL-8, IL-6, RANTES (regulated on activation, normal T cell expressed and secreted), and matrix metalloproteinase (MMP)-9 from nasal compared with bronchial cells, the increments in release of all studied mediators in response to stimulation with IL-1beta and TNF-alpha were similar, and there were significant positive correlations between nasal and bronchial cell secretion of IL-6, RANTES, vascular endothelial growth factor, monocyte chemoattractant protein-1, MMP-9, and tissue inhibitor of metalloproteinase-1. Despite differences in absolute mediator levels, the responses of nasal and bronchial epithelial cells to cytokine stimulation were similar, expression of relevant surface receptors was comparable, and there were significant correlations between nasal and bronchial cell mediator release. Therefore, nasal epithelial cultures constitute an accessible surrogate for studying lower airway inflammation.     

Sensory epithelial cells acquire features of prosensory cells via epithelial to mesenchymal transition

Epithelial to mesenchymal transition (EMT) plays a critical role during normal development and in adult tissue repair. It is known that immortalized epithelial cells can undergo an EMT and become cancer stem cells, and that epithelial cells from mouse pancreatic islet and avian inner ear can acquire mesenchymal traits in vitro via EMT. However, it is unclear whether epithelial cells from mammalian sensory system can undergo an EMT and obtain features of stem/progenitor cells. In this study, we used mouse utricle sensory epithelial cells (MUCs) as a mammalian cell model to address this issue. When cultured on 2-dimensional substrates, dissociated MUCs gradually lost their columnar shape and started to expand on the substrate with downregulation of expression of epithelial junction markers and upregulation of genes and proteins that are widely shown in mesenchymal cells. Moreover, MUCs expressed genes and proteins that are usually presented in prosensory epithelial cells and stem cells. These MUCs showed potential to differentiate into epithelial cells via a reverse EMT when they were forced to suspend in culture medium. Our findings reveal that sensory epithelial cells from mammalian tissue can undergo an EMT to become cells expressing features of stem cells that can be induced to become epithelial cells via a reverse EMT. The outcomes of this study may provide a novel approach to generate epithelial progenitors for use in cell replacement therapy to treat a number of human diseases, such as hearing loss and vision loss.     

Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF

Inappropriate repair after injury to the epithelium generates persistent activation, which may contribute to airway remodeling. In the present study we hypothesized that IL-13 is a normal mediator of airway epithelial repair. Mechanical injury of confluent airway epithelial cell (AEC) monolayers induced expression and release of IL-13 in a time-dependent manner coordinate with repair. Neutralizing of IL-13 secreted from injured epithelial cells by shIL-13Ralpha2.FC significantly reduced epithelial repair. Moreover, exogenous IL-13 enhanced epithelial repair and induced epidermal growth factor receptor (EGFR) phosphorylation. We examined secretion of two EGFR ligands, epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), after mechanical injury. Our data showed a sequential release of the EGF and HB-EGF by AEC after injury. Interestingly, we found that IL-13 induces HB-EGF, but not EGF, synthesis and release from AEC. IL-13-induced EGFR phosphorylation and the IL-13-reparative effect on AEC are mediated via HB-EGF. Finally, we demonstrated that inhibition of EGFR tyrosine kinase activity by tyrphostin AG1478 increases IL-13 release after injury, suggesting negative feedback between EGFR and IL-13 during repair. Our data, for the first time, showed that IL-13 plays an important role in epithelial repair, and that its effect is mediated through the autocrine release of HB-EGF and activation of EGFR. Dysregulation of EGFR phosphorylation may contribute to a persistent repair phenotype and chronically increased IL-13 release, and in turn result in airway remodeling.     

Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation

Summary: There are accumulating data to show that thymic epithelium expresses a remarkable array of molecules previously considered to be tissue‐specific antigens, such as parathyroid hormone, thyroglobulin, insulin, and C‐reactive protein. From an immunological perspective, this property of thymic epithelium would provide an ideal mechanism to effect central tolerance of epithelial‐restricted antigens. However, from a mechanistic perspective, this phenomenon remains mysterious. Two explanations have been proposed. One invokes promiscuous gene expression by medullary thymic epithelial cells that would allow transient derepression of selected gene expression. The other proposes that the expression of tissue‐restricted genes by thymic epithelium reflects alternate pathways of epithelial development by small numbers of cells to form a mosaic of different epithelial types within the thymus. Here we show thymic expression of lung‐associated gene products by an organized epithelial ‘organoid’ with ultrastructural features of respiratory epithelium and present data suggesting that the thymus also contains structures that ultrastructurally and phenotypically resemble solitary thyroid follicles. Based on these data, it is proposed that some thymic epithelial progenitor cells resemble pharyngeal endoderm in terms of their developmental potential and that alternative differentiation fates taken by these cells serve to maintain the spectrum of epithelial ‘self’ in the thymus.