Programa de Pós-Graduação em Patologia Oral
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Doctoral Thesis Estudo imuno-histoquímico e in vitro de proteínas do sistema ativador de plasminogênio em carcinomas de células escamosas de língua oral(2020-02-14) Mafra, Rodrigo Porpino; Pinto, Leão Pereira; ; ; Barboza, Carlos Augusto Galvão; ; Nonaka, Cassiano Francisco Weege; ; Carvalho, Cyntia Helena Pereira de; ; Souza, Lelia Batista de;Squamous cell carcinoma (SCC) is the most frequent malignant neoplasm of the oral cavity and has an unfavorable prognosis. Thus, studies have sought to clarify the role of biomarkers in the biological behavior of oral SCC. Within this context, urokinase-type plasminogen activator (uPA) and its receptor (uPAR), as well as plasminogen activator inhibitor 1 (PAI-1), are particularly interesting. The present study analyzed, by means of immunohistochemistry, the expressions of uPA, uPAR and PAI-1 in oral tongue SCC (OTSCC) and their relationship with clinicopathological parameters. This experiment also evaluated the in vitro effects of recombinant human PAI-1 (rhPAI-1) on the OTSCC-derived cell line SCC-25. The immunoexpression of uPA, uPAR and PAI-1 was analyzed semiquantitatively in neoplastic cells of the invasion front of 60 OTSCC cases. Aiming to determine the association between immunohistochemical findings, clinicopathological variables and survival rates, the cases were classified as low expression (≤50% of positive cells) and high expression (>50% of positive cells). The following groups were analyzed in the in vitro experiment: G0 (control; cells cultured in the absence of rhPAI-1), G10 (cells treated with 10 nM rhPAI-1), and G20 (cells treated with 20 nM rhPAI-1). Differences between these groups were investigated using the following assays: cell viability (Alamar Blue), cell cycle (staining with propidium iodide, PI), apoptosis/necrosis (staining with Annexin V and PI), migratory activity (Wound healing), and cell invasion (Transwell). Immunohistochemical analysis revealed high expression of uPA in most OTSCC cases, but there were no significant associations with clinicopathological parameters. The high membrane expression of uPAR and PAI-1 was associated with local recurrence (p=0.019) and high tumor budding (p=0.046), respectively. Membrane expression of PAI-1 also presented a significant association with high-risk cases (p=0,043). Statistical analysis demonstrated no significant associations between the immunohistochemical variables (uPA, uPAR and PAI-1) and prognostic indicators of OTSCC (disease-specific and disease-free survival). In the in vitro experiment, 24 hours after administration of rhPAI-1, G10 and G20 exhibited greater cell viability compared to the control group (p=0.02), as well as increased progression to the S phase of the cell cycle (p=0.024). There were no significant differences in the percentages of apoptotic or necrotic cells between groups. In the groups cultured in the presence of rhPAI-1, migratory activity (p=0.039) and invasion potential (p=0.039) were found to be increased after 24 and 72 hours, respectively. The findings of this study suggest the involvement of uPA, uPAR and PAI-1 in the pathogenesis of OTSCC. Nevertheless, the expression of these biomarkers may not be related to survival of patients. The in vitro results suggest that PAI-1 exerts stimulatory effects on cell proliferation, migration and invasion and may therefore contribute to the biological aggressiveness of OTSCC.Doctoral Thesis Valor prognóstico dos polimorfismos funcionais nos genes da mmp-1, mmp-13 e IL-8 no carcinoma epidermóide oral e de orofaringe(UNIVERSIDADE FEDERAL RIO GRANDE DO NORTE, 2013-06-26) Matos, Felipe Rodrigues de; Freitas, Roseana de Almeida; ; http://lattes.cnpq.br/9512014003639405; ; http://lattes.cnpq.br/6755254213132873; Nonaka, Cassiano Francisco Weege; ; http://lattes.cnpq.br/0224522010734716; Silveira, Ericka Janine Dantas da; ; http://lattes.cnpq.br/2186658404241838; Santos, Jean Nunes dos; ; http://lattes.cnpq.br/0926138204356872; Souza, Lelia Batista de; ; http://lattes.cnpq.br/6671914892609743Master Thesis Análise imunohistoquímica do Gata-3 e Il-4 em carcinomas epidermóides de lábio inferior e língua oral(2019-02-28) Dantas, Afonso Nóbrega; Oliveira, Patricia Teixeira de; ; ; Costa, Edja Maria Melo de Brito; ; Queiroz, Lelia Maria Guedes;Squamous cell carcinoma (SCC) is the most common malignant neoplasm in the oral cavity, with the lower lip and oral tongue being the most frequent sites. Like all malignancies, SCC has etiology is multifactorial, with strong association with smoking, alcoholism and chronic exposure to solar radiation. At present many studies have turned attention to the role of the inflammatory response in the development and tumor growth, mainly with respect to the cellular immune response. The aim of this study is to analyze the expression of GATA-3 and IL-4 in squamous cell carcinoma of the lower lip (SCCLL) and oral tongue (SCCOT). The selected cases were classified according to the WHO histological grading of malignancy and the immunohistochemical analysis of GATA-3 and IL-4 in 57 cases of SCCLL and SCCOT. The results showed statistical significance of GATA-3 in the stromal (p < 0.05) of these lesions and IL-4 in the parenchyma (p < 0.01), in the stroma (p < 0.01) and in the parenchyma and stroma together (p < 0.01). It also showed a positive correlation between the expression of GATA-3 in the parenchyma and IL-4 in the parenchyma (r = 0.438, p = 0.001), between GATA-3 in the parenchyma and IL-4 in the stroma (r = 0.378; p = 0.004), and between GATA-3 in the parenchyma and IL-4 in the parenchyma and stroma (r = 0.348; p = 0.008). Therefore, in all cases, the presence of the Th2 response was observed, implying the opening of new horizons in this area for new studies that may contribute to the understanding of this response in the growth and development of these lesions.Doctoral Thesis Análise do estresse oxidativo, reparo do DNA e alterações epigenéticas no líquen plano(2019-08-30) Gonzaga, Amanda Katarinny Goes; Medeiros, Ana Miryam Costa de; Silveira, Ericka Janine Dantas da; ; ; ; Souza, Lelia Batista de; ; Miguel, Márcia Cristina da Costa; ; Squarize, Cristiane Helena; ; Alves, Pollianna Muniz;Lichen planus (LP) is a mucocutaneous, inflammatory disease immunologically mediated by cytotoxic T lymphocytes (CD8+ CTL). While oral lichen planus (OLP) is considered a potentially malignant lesion, cutaneous lichen planus (CLP) is a typically self-limiting condition, suggesting that the pathogenesis of these lesions may be distinct. Thus, the aim of this study was, first, to evaluate the levels of oxidative stress markers in the saliva of patients with OLP and, subsequently, to analyze the expression profile of DNA repair proteins (XRCC1 and APE1) and H3K9 histone acetylation in the OLP and CLP. For the oxidative stress study, 34 individuals participated in the research, of which 22 were clinically and histopathologically diagnosed with OLP (reticular and erosive) and 12 were control cases. Non-stimulated sialometry was performed and, subsequently, oxidative stress (MPO, MDA) and antioxidant action (SOD, GSH) markers were determined. To perform the study on DNA repair and H3K9 histone acetylation, the total sample consisted of 89 cases of LP (66 OLP and 23 CLP). Analysis of APE1 and XRCC1 expression was performed by immunohistochemistry, whereas the analysis of H3K9 acetylation was performed by immunofluorescence. Five representative fields of the lesions were photographed and the analyzes were performed quantitatively. Statistical analysis was performed using SPSS and GraphPad Prism software. In the study related to oxidative stress, among the 22 patients diagnosed with OLP, most were female (n = 19; 86.4%) and reported to have entered menopause (63.2%). In the majority of cases, OLP lesions were in the active phase (77.3%), with a predominance of the reticular OLP (n = 15; 68.2%). Concerning to oxidative stress levels, no statistically significant differences were observed when comparing SOD, GSH, MPO and MDA values between case and control groups, as well as between erosive and reticular OLP (p > 0.05). Individuals with inactive OLP lesions presented higher SOD when compared to those with active lesions (p = 0.031). The study related to DNA repair and H3K9 histone acetylation showed that the immunoreactivity for APE1 and XRCC1 was significantly higher in CLP than in OLP (P = 0.003 and P = 0.034, respectively). There was a significant and moderate positive correlation between APE1 and XRCC1 in the OLP group (Rho=0.544; P<0.0001). Evaluation of H9K3 histone acetylation levels did not reveal significant results comparing OLP to CLP, neither comparing erosive to reticular OLP (P> 0.05). In conclusion, our findings revealed that oxidative stress markers in saliva of patients with OLP was similar to the control cases, which may be related to the high exposure of the oral cavity environment to several physical, chemical and microbiological stimuli, important generators of the oxidative stress. Furthermore, changes in the expression profile of the DNA repair proteins exerted greater influence in the cases of CLP than in the cases of OLP, in addition, H3K9 histone acetylation is an epigenetic event found in both lesions.Master Thesis Estudo da imunoexpressão do reg-gamma e da beta catenina em queilites actínicas e carcinomas de células escamosas de lábio inferior(2019-06-28) Parente, Patrícia Davin Gomes; Pinto, Leão Pereira; ; ; Nonaka, Cassiano Francisco Weege; ; Freitas, Roseana de Almeida;Actinic cheilitis (QA) is a potentially malignant lesion that occurs mainly in men with light skin and a history of chronic sun exposure. Currently, it is not possible to predict which cases of QA will progress to Squamous Cell Carcinoma (SCC), so some biomolecular markers have been researched. Β-catenin is a multifunctional protein that is involved in cell-cell adhesion processes. The alteration of the cadherin-catenin complex has been demonstrated in SCC and correlated with tumor invasion, metastasis and worse prognosis of patients. REGγ is a proteasome activator that can promote the degradation of multiple proteins including p53 and MDM2. Studies show that REGγ is overexpressed in numerous cancers, suggesting that REGγ overexpression is involved in cancer progression. The aim of this study was to analyze the immunohistochemical expression of β-catenin and REGγ in cases of QA and lower lip squamous cell carcinoma (CCELI), comparing the immunohistochemical findings with the clinical and pathological data, in order to verify if there is any a correlation with tumor progression and whether they act synergistically in this process. Β-catenin and REGγ immunoexpression was analyzed semi-quantitatively in 30 cases of QA and 30 cases of CCELI according to the scores: 0 (no labeling); 1 (1-25% positive cells); 2 (26-50% positive cells); 3 (51-75% positive cells); 4 (> 75% positive cells). For statistical analysis, Mann-Whitney and Spearman tests were performed (p <0.05). Both QAs and CCELIs expressed the β-catenin protein, showing an increase in cytoplasmic and nuclear expression in cases of moderate and severe dysplasias. In CCELIs, membrane β-catenin immunoexpression was higher in cases of low grade malignancy. Both QAs and CCELIs expressed the REG-γ protein but no statistical significance between its expression and the degree of epithelial dysplasia was found, as well as between the immunoexpression of REG-γ and the clinicopathological parameters analyzed in the CCELIs. The results of the present study suggest that REG-γ overexpression and reduction in membrane expression of β-catenin may be important events in lip carcinogenesis. However, we believe that this protein is involved in the process of oral carcinogenesis. In this process, correlating the immunohistochemical expression of β-catenin with the expression of REG-γ, as we did not obtain statistically significant results, we suggest that β-catenin expression may not be directly influenced by the levels of REGγ expression.Master Thesis Análise da expressão imuno-histoquímica do t-bet e ifn-gama em carcinomas epidermoides de lábio inferior e língua oral(2019-06-07) Rodrigues, Rodrigo Rodrigues; Santos, Pedro Paulo de Andrade; ; ; Souza, Lelia Batista de; ; Alves, Pollianna Muniz;The treatment of oral squamous cell carcinomas (OSCC) has advanced in recent years and the understanding of molecular mechanisms has been fundamental. The study of markers such as T-bet, which is a specific cell transcription factor of the immune system, and IFN-γ, which is a cytokine participating in the innate immune response and specific immunity, are promising in the literature for better understanding of carcinoma behavior. In this research, 57 cases of OSCC were evaluated, 27 of them with lower lip and 30 with oral tongue of the Oral Pathology Service of the Federal University of Rio Grande do Norte, being classified according to the histological grading of malignancy of the World Health Organization (WHO) and subsequently subjected to immunohistochemistry and T-Bet was evaluated quantitatively and IFN-γ evaluated semi-quantitatively in both the parenchyma and stroma of the OSCC. We found that the LLSCC were classified mostly as well differentiated, while the moderately differentiated CEL were the most evidenced. Immunohistochemical analysis revealed strong cytoplasmic and nuclear labeling for T-Bet and IFN-γ in both the parenchyma and stroma of the OSCC. In this research, the immunohistochemical expression for T-Bet was higher in OTSCC compared to LLSCC showing a value of p = 0.001 when evaluating T-bet in the parenchyma separately and in the parenchyma and stroma. Already the percentage of immunoreactivity for IFN-γ was higher in LLSCC in relation to OTSCC with values of p = 0.049 and p = 0.040 when evaluated in stroma separately and parenchyma and stroma, respectively. The LLSCC showed a more efficient induction of Th1 response than the OTSCC, corroborating the distinct behavior of these lesions, with greater aggressiveness evident in the OTSCC.Master Thesis Expressão imuno-histoquímica de proteínas ING em desordens potencialmente malignas(2019-02-28) Gonçalo, Rani Iani Costa; Queiroz, Lelia Maria Guedes; ; ; Costa, Antonio de Lisboa Lopes; ; Barbosa, Natalia Guimarães;Potentially malignant disorders (PMD) are lesions that can affect the oral cavity and present a potential for malignant transformation. Molecular biomarkers have been studied to help predict the risk of malignant transformation of these lesions. Among them, the ING (inhibitor of growth) proteins (1-5) are highlighted. The objective of this study is to evaluate the expression of ING-1 and ING-2 proteins in lesions diagnosed as hyperkeratosis and ED (mild, moderate and severe), and to correlate the expression pattern observed with the degree of epithelial dysplasia. This is a cross-sectional, retrospective, semi-quantitative and comparative study. The sample consisted of 60 specimens of hyperkeratosis and epithelial dysplasia (ED), which were morphologically evaluated and reclassified according to the binary classification system of ED proposed by Kujan et al. (2006). The immunoexpression for ING-1 and ING-2 in the studied lesions was evaluated semi-quantitatively from the assignment of scores ranging from 0 to 4, according to the percentage of epithelial cells positive for those markers. For the statistical analysis, the Mann-Whitney and Spearman tests (p ≤ 0.05) were performed. Of the 60 cases analyzed, 37 (61.7%) presented as low-risk lesions and 23 (38.3%) as highrisk lesions. For both ING-1 and ING-2, 93.3% of the dysplastic lesions studied presented cytoplasmic and nuclear marking on epithelial cells, with predominance of positivity in the basal and suprabasal layers. Regarding the immunohistochemical marking scores, there was a predominance of cases with high expression (score 4) for both markers. However, when comparing these scores (nuclear, cytoplasmic and general) with the histological gradation of ED, for both ING-1 and ING-2, no statistically significant difference was observed. Thus, the results of the present study suggest that immunoexpression of ING-1 and ING-2 is not related to the degree of oral ED. However, the high expression observed in these lesions suggests that these proteins would be involved in the oral carcinogenesis process.Master Thesis Expressão imuno-histoquímica das proteínas NF-kB e VEGF165 no líquen plano oral(2019-02-28) Silva, Nelmara Sousa e; Costa, Antonio de Lisboa Lopes; ; ; Medeiros, Ana Miryam Costa de; ; Moura, Jamile Marinho Bezerra de Oliveira;The oral Lichen Planus (LPO) is a relatively common chronic inflammatory disease whose etiopathogenesis is still not fully understood. Clinically the LPO is classified into six well identified standards: plate, Bullous, reticular, papular and atrophic erosive. The objective of this research was to compare the expression of nuclear factor Kappa (NF-κB) and vascular endothelial growth factor (VEGF165) in the LPO. This research consisted of a retrospective cross-sectional study of quantitative character and comparative immunohistochemical expression of expression of NF-κB and descriptive of VEGF165 in specimens of oral Lichen Planus Reticularis (30 cases) and erosion (10 cases) and 15 cases of inflammatory fibrous hyperplasia (control). Then analysis Immunohistochemistry to investigate differences in the expression of NF-κB (number of cores positive) in relation to the number of cells with nuclei in particular regions of the specimen negative, being used the methodology adapted from Rich et al. (2018). In the statistical analysis we used the tests (non-parametric test of Kruskal-Wallis one-way ANOVA with Bonferroni corrections and, with a significance level of 5% (p < 0.05). It was observed that for every case of LPO present in this study, there were marking the VEGF165, both in epithelial tissue as in inflammatory infiltrate cells and blood vessels. In the case of HFI, this markup had lower intensity when compared to that of LPO. For the NF-κB no statistically significant difference was found in the epithelial lining against inflammatory fibrous hyperplasia (control), already in the connective tissue (superficial and deep inflammatory infiltrate) expression in this protein was lower than in the case of LPO about inflammatory fibrous hyperplasia. It can be concluded that the inflammatory response in the LPO would be in a supporting role in pathogenesis, and it would not be the isolated factor responsible for the development and perpetuation of the LPO, and may be crucial to presence of epigenetic changes in the immune system to trigger the disease.Master Thesis Estudo imunoistoquímico das proteínas CD34 e α-SMA em cistos radiculares e cistos radiculares residuais(2019-02-28) Freitas, Camila Tatyanne Santos de; Galvão, Hebel Cavalcanti; ; ; Santos, Pedro Paulo de Andrade; ; Nunez, Manuel Antonio Gordon;Introduction: Radicular cysts are inflammatory lesions resulting from infectious processes of pulp necrosis. Myofibroblasts (MFs) and angiogenesis are important factors in the development and progression of cystic lesions, so that MFs secrete growth factors and proteases, as well as angiogenesis stimulates matrix deposition and cell migration, affecting the growth of periapicopathies. Objective: This study aims to evaluate the immunohistochemical expression of CD34 and α-SMA in radicular cysts (CRs) and residual radicular cysts (CRRs), in order to contribute a better understanding of expansion and progression of periapical lesions. Materials and Methods: Clinical, morphological and immunohistochemical analyzes were performed on 30 CRs and 30 CRRs. The present study constitutes a descriptive, quantitative and comparative analysis of CD34 and α-SMA positive immunohistochemical expression in the specimens. Expression of α-SMA was evaluated in the fibrous capsule, at 100x magnification 10 fields of higher immunolabeling were selected below epithelial lining, thereafter at 400X magnification, the positive cells were quantified and at the end were calculated the averages of positive cells per field. However, angiogenic index was performed by counting microvessels immunolabelled by anti-CD34 antibody in 10 (200x) fields. Statistical analysis was performed using the Mann-Whitney, Pearson's Chi-square test and Spearman's correlation, with significance level set (p <0.05). Results: The results showed that there were statistically significant differences regarding α-SMA and α-SMAxCD34, however with respect to the CD34 immunostaining, there were no statistical differences between the lesions. Conclusion: Myofibroblasts and angiogenic index among studied lesions presented a significant correlation. Thus, they are believed contribute to the repair of the periapicopathies.Doctoral Thesis Sobrevida e fatores prognóstico do Carcinoma Epidermóide de Boca e Orofaríngeo: análise de 1776 casos(2018-12-20) Queiroz, Salomão Israel Monteiro Lourenço; Gurgel, Bruno César de Vasconcelos; ; ; Silveira, Ericka Janine Dantas da; ; Lima, Kenio Costa de; ; Lira, Cláudia Cazal; ; Santos, Edilmar de Moura;The most common type of cancer in the head and neck region is the squamous cell carcinoma (SCC), which is more frequent in the mouth (SCCM) and oropharyngeal (SCCO), with a presentation of more than 90% in these regions, representing 6% of all carcinomas. Epidemiological evaluation of this population-based pathology is still scarce and this neoplasm is a public health problem in Brazil and in the world. Faced with these facts, this study aims to describe and analyze survival, highlighting the main factors associated with its prognosis. For this, a retrospective prognostic study was carried out in databases and medical records, where all the cases diagnosed with SCCM and SCCO of the North League Riograndense Against Cancer of the last 11 years were selected. Survival were calculated with Kaplan-Meier and comparison of functions with Log-Rank. The risks calculated in univariate Cox models and predictive models in the multivariate analysis of Cox. For SCCM's Disease Free Survival (DFS) the poor prognostic factors, the histopathological gradation system of malignancy (HGSM) of the World Health Organization (WHO) in little differentiated, location in the retromolar region, not having conjugal companion, advanced staging and more complex treatments. These characteristics were repeated in the Global Survival (GS) for SCCM, with the exception of the current marital status. In the GS of the SCCO, localization in basis of language and alcohol consumption obtained the worst prognoses. Already for DFS of SCCO, the HGSM in little differentiated, smoking and having no marital partner, obtained the worst prognoses. The HGSM appears to be an effective prognostic factor for SCCM. Not having a partner can compromise DFS (SCCM and SCCO), with repercussion on patient's quality of life, adherence and maintenance of treatment. Wellestablished risk factors, such as alcohol and smoking, seem to be important prognostic factors in SCCO, but should be approached with caution, especially when the type, time, and quantity used are not checked. Even with the improvement in the SCCM's and SCCO's survival through advances in treatment, she is still worrisome, as the difficulty of diagnosis increases (Lip> Oral> Oropharynx). Both SCCM and SCCO were considered median, reaffirming already well established prognostic factors, such as clinical staging and localization, others still controversial, such as HGSM, smoking and drinking habits, gained strength as independent prognostic factors and an unexpected coadjutant, the current marital status.