Cristiane Furuse

Etiologic factors associated with oral squamous cell carcinoma in non-smokers and non-alcoholic drinkers: a brief approach

Oral squamous cell carcinoma (OSCC) is the fifth most common type of cancer in the world. The effect of some etiological factors is well established in the literature, such as consumption of tobacco and alcohol. However, approximately 15 to 20% of all oral cancer cases occur in patients without the traditional risk factors, reflecting in numerous cases of OSCC in non-smokers and non-alcoholic drinkers. Also, several studies have suggested a possible association between human papillomavirus and OSCC. Under these aspects, the purpose of this study is to address cases of oral cancer in non-smokers and non-drinkers focusing on the role of HPV, thus contributing to improve the diagnosis and monitoring of OSCC. A computer database search was performed using the Pubmed database. The search key words were: epidemiology, oral squamous cell carcinoma, risk factors and human papillomavirus. It is important to assess patients without the potential risk factors, since this knowledge may help identifying other features associated with the occurrence of oral cancer, enabling an appropriate clinical management and monitoring.

β-Catenin and E-Cadherin Expression in Salivary Gland Tumors

This study evaluated the expression of E-cadherin and β-catenin in salivary gland tumors. Twelve biopsy specimens from cases diagnosed as pleomorphic adenoma, 17 adenoid cystic carcinomas, 10 epithelial-myoepithelial carcinomas, and 4 polymorphous low-grade adenocarcinomas were immunohistochemically labeled for E-cadherin and β-catenin antibodies. Healthy salivary glands were used as controls. Membrane-associated E-cadherin and β-catenin expression was present in all the tumor types studied. E-cadherin and β-catenin showed a similar distribution; however, β-catenin labeling was weaker than that for E-cadherin. In the epithelial-myoepithelial carcinomas, myoepithelial cells exhibited diffuse nuclear staining, although occasional cells presented only focal labeling. Epithelial-myoepithelial carcinomas present changes in [.beta]-catenin expression but the other salivary tumors studied do not, which may reflect divergence in tumorigenesis of this extensive subset of salivary gland tumors.

Intravascular papillary endothelial hyperplasia: report of 2 cases and immunohistochemical study

Intravascular papillary endothelial hyperplasia (IPEH) is a benign, nonneoplastic, vascular lesion. The main significance of the lesion lies in the fact that it may be mistaken for angiosarcoma. Oral lesions are uncommon and the present paper reports 2 cases of oral IPEH, in different sites. Histologically, the tissue was characterized by papillary fronds lined by proliferating endothelium. Immunohistochemically (IHC), the lesion was positive for CD34, smooth muscle actin (SMA), type I and IV collagen, vimentin, and laminin, but it was negative for CD105. Local excision was the treatment of choice. No recurrence was observed during a 1-year and 6-month follow-up period, respectively. The clinical, histological, and immunohistochemical characteristics are discussed.

Glucose transporter protein 1 expression in mucoepidermoid carcinoma of salivary gland: correlation with grade of malignancy

Mucoepidermoid carcinoma (MEC), the most common primary salivary malignancy, shows great variability in clinical behaviour, thus demanding investigation to identify of prognostic markers. Since Warburg’s studies, unrestricted cell growth during tumorigenesis has been linked to altered metabolism, implying hypoxic stimulation of glycolysis and diminished contribution of mitochondrial oxidative phosphorylation to cellular ATP supply. Hypothesizing that the study of MEC metabolic status could lead to the discovery of prognostic markers, we investigated by immunohistochemistry the expression of glucose transporter 1 (Glut‐1), mitochondrial antigen and peroxiredoxin I (Prx I) in samples of MEC from different histological grades. Our results showed that mitochondrial antigen and Prx I were expressed in the majority of the MEC cases independent of the histological grade. In contrast Glut‐1 expression increased significantly as the tumours became more aggressive. These results suggested that oxidative phosphorylation may contribute to ATP supply in all stages of MEC progression, and that the relative contribution of glycolysis over mitochondria for cellular ATP supply increases during MEC progression, favouring growth under low oxygen concentration. In addition, the observed high Prx I protein levels could provide protection to tumour cells against reactive oxygen species generated as a consequence of mitochondrial function and hypoxia‐reoxygenation cycling. Altogether our findings suggest that upregulation of Glut‐1 and Prx I constitute successful adaptive strategies of MEC cells conferring a growth advantage over normal salivary gland cells in the unstable oxygenation tumour environment.

Peroxiredoxin I, platelet-derived growth factor A, and platelet-derived growth factor receptor α are overexpressed in carcinoma ex pleomorphic adenoma: association with malignant transformation ☆

Carcinoma ex pleomorphic adenoma is a rare salivary gland malignancy. It constitutes an important model for the study of carcinogenesis, as it can display the tumor in different stages of progression, from benign pleomorphic adenoma to frankly invasive carcinoma. Growth signaling pathways undergo continuous activation in human tumors, commonly as a consequence of the overexpression of ligands and receptors such as platelet-derived growth factor and platelet-derived growth factor receptor. Hydrogen peroxide is produced after platelet-derived growth factor receptor activation, and it is essential for the sequential phosphorylation cascade that drives cell proliferation and migration. By their ability to degrade hydrogen peroxide, peroxiredoxins are involved in growth factor signaling regulation and in the oxidative stress response. To verify the potential association of peroxiredoxin I, platelet-derived growth factor-A, and platelet-derived growth factor receptor-alpha with carcinoma ex pleomorphic adenoma progression, we investigated the expression of these molecules in carcinoma ex pleomorphic adenoma showing different degrees of invasion. The peroxiredoxin I, platelet-derived growth factor-A, and platelet-derived growth factor receptor-alpha proteins were present in remnant pleomorphic adenoma to only a small extent, but, collectively, they were highly expressed as soon as the malignant phenotype was achieved and remained at elevated concentrations during progression to the advanced stages of carcinoma ex pleomorphic adenoma. In addition, their locations overlapped significantly, strengthening their connection to this growth-signaling pathway. Our results indicate that carcinoma ex pleomorphic adenoma cells acquire at least 2 significant advantages relative to their normal counterparts: resistance to oxidative stress-induced apoptosis, conferred by high peroxiredoxin I concentrations, and sustained growth, reflecting platelet-derived growth factor-A and platelet-derived growth factor receptor-alpha overexpression.

Angiogenesis in salivary carcinomas with and without myoepithelial differentiation

To investigate whether salivary carcinomas with and without myoepithelial differentiation could present differences regarding degree of angiogenesis, we compared tumor vascularization between adenoid cystic (31 cases) and epithelial-myoepithelial carcinomas (14) versus mucoepidermoid (37) carcinoma. The expression of peroxiredoxin I was also studied to verify the potential relationship between cellular metabolism and microvascular density. Microvascular density for CD34 and CD105 were significantly lower in carcinomas with myoepithelial differentiation. However, no correlation was found between degree of angiogenesis and amounts of myoepithelial cells. High-grade peroxiredoxin I expression was found in 73.7% of mucoepidermoid carcinomas, whereas 85.1% of carcinomas with myoepithelial differentiation presented low-grade expression. In conclusion, carcinomas with myoepithelial differentiation, regardless of the amounts of myoepithelial cells, are associated to a significantly lower vascular density. The reasons for this lower angiogenic activity remain to be determined but could be related to metabolic characteristics of the cancer cells.

Study of growth factors and receptors in carcinoma ex pleomorphic adenoma

Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant salivary gland tumor derived from a pre-existing pleomorphic adenoma. It is a good model to study the evolution of carcinogenesis, starting with in situ areas to frankly invasive carcinoma. Growth factors are associated with several biological and neoplastic processes by transmembrane receptors. In order to investigate, by immunohistochemistry, the expression of some growth factors and its receptors [EGF receptor, fibroblast growth factor, fibroblast growth factor receptor 1, fibroblast growth factor receptor 2, hepatocyte growth factor, c-Met, transforming growth factor (TGF) beta1, TGFbetaR-II and insulin-like growth factor receptor 1] in the progression of CXPA, we have used ten cases of CXPA in several degrees of invasion- intracapsular, minimally and frankly invasive carcinoma- with only epithelial component. Slides were qualitatively and semi-quantitatively evaluated according to the percentage of stained tumor cells from 0 to 3 (0 = less than 10%; 1 = 10-25%; 2 = 25-50%; 3 = more than 50% of cells). Malignant epithelial cells starting with in situ areas showed stronger expression than luminal cells of pleomorphic adenoma for all antibodies. Most of the intracapsular, minimally and frankly invasive CXPA presented score 3. However, score 2 was more evident in the frankly invasive one. In small nests of invasive carcinoma, negative cells were observed probably indicating that the proliferative process is replaced by the invasive mechanism. Altogether this data infers that these factors may contribute to cell proliferation during initial phases of the tumor.

Peroxiredoxin I is overexpressed in oncocytic lesions of salivary glands

BACKGROUND Oncocytic lesions, particularly frequent in the salivary glands, are characterized by cells with an atypical accumulation of mitochondria. This accumulation has been recognized as a compensatory mechanism to intrinsic functional defects of these organelles, resulting in energy production impairment and increased generation of reactive oxygen species (ROS), including hydrogen peroxide (H(2)O(2)). Peroxiredoxin I (Prx I) is a H(2)O(2) scavenging protein and the expression of its yeast homolog was reported to be influenced by mitochondrial function. METHODS In this study, we evaluated Prx I expression in oncocytic lesions of salivary glands by immunohistochemistry. RESULTS Our results showed that Prx I is overexpressed in oncocytes regardless of the salivary gland lesion where they appear. CONCLUSIONS These results suggest that Prx I expression in oncocytes is related to its ability to decompose mitochondrial-derived H(2)O(2) and that it could provide to the cells a protective role in an environment that, by continuously producing potential DNA-damaging ROS, predisposes to genome instability and cellular transformation.

CD10 (Neutral Endopeptidase) Expression in Myoepithelial Cells of Salivary Neoplasms.

CD10 is a cell surface peptidase expressed in a wide variety of normal and neoplastic tissues, including breast myoepithelial cells. In salivary glands, expression of CD10 has only been used to identify neoplastic myoepithelial cells of pleomorphic adenomas and myoepithelial carcinomas. However, its accuracy in other salivary tumors with myoepithelial component has yet to be analyzed. We examined 72 salivary tumors with myoepithelial differentiation using immunohistochemical technique to detect CD10. In salivary glands, CD10 expression was not detected in myoepithelial cells. Only fibrocytes within the intralobular stroma were CD10 positive. In neoplastic myoepithelial cells, CD10 expression was found in 25.71% of benign and 32.43% of malignant neoplasms. When the different groups of tumors were compared, epithelial-myoepithelial carcinomas (EMEC) showed a stark contrast with the others (83.3% of cases with CD10 expression). Surprisingly, adenoid cystic carcinomas and basal cell adenomas were negative in 100% of the cases. Myoepitheliomas, pleomorphic adenomas, and myoepithelial carcinomas were positive in 27.7%, 30.0%, and 40% of the cases, respectively. In conclusion, salivary neoplastic myoepithelial cells gain CD10 expression in relation to their normal counterparts. However, the gain of this protein is not a sensitive marker for detecting myoepithelial cells in the majority of the tumors, except for EMEC. The high expression of CD10 by this carcinoma can be a valuable tool to separate EMEC from the tubular variant of adenoid cystic carcinomas in small incisional biopsies, where the precise diagnosis may be impossible.

Dentin Matrix Protein 1 (DMP1) Expression in Developing Human Teeth

Dentin matrix protein 1 (DMP1) is an acidic phosphoprotein that plays an important role in mineralized tissue formation by initiation of nucleation and modulation of mineral phase morphology. The purpose of the present study was to examine the immunoexpression of DMP1 in tooth germs of 7 human fetuses at different gestational ages (14, 16, 19, 20, 21, 23 and 24 weeks) comparing with completed tooth formation erupted teeth. The results showed the presence of DMP1 in the dental lamina, as well as in the cells of the external epithelium, stellate reticulum and stratum intermedium of the enamel organ. However, in the internal dental epithelium, cervical loop region and dental papilla some cells have not labeled for DMP1. In the crown stage, DMP1 was expressed in the ameloblast and odontoblast layer, as well as in the dentinal tubules of coronal dentin near the odontoblast area. Erupted teeth with complete tooth formation exhibited immunolabeling for DMP1 only in the dentinal tubules mainly close to the dental pulp. No staining was observed in the enamel, predentin or dental pulp matrix. DMP1 is present in all developing dental structures (dental lamina, enamel organ, dental papilla) presenting few immunoexpression variations, with no staining in mineralized enamel and dentin.