Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.

Os tumores odontogênicos benignos compreendem um grupo de neoplasias originárias dos tecidos dentários. Pesquisas vêm buscando identificar moléculas envolvidas nos mecanismos moleculares que regulam a remodelação da matriz extracelular (MEC) e como isto influencia no comportamento localmente invasivo presente em alguns destes tumores. A Transição Epitélio-Mesenquimal (TEM conversão do fenótipo epitelial em mesenquimal) é bem caracterizada em diversos carcinomas, culminando em mestástase. MMPs são enzimas que degradam os componentes da MEC, geram moléculas bioativas, participam da TEM e o controle da remodelação da MEC dá-se pelo balanço entre elas, seus inibidores (TIMPs e RECK) e seu ativador (EMMPRIN). Assim, o objetivo deste trabalho foi delinear o perfil de expressão das MMPs (-2, -7, -9 e -14), seus inibidores (TIMPs -2, -3, -4 e RECK), seu ativador (EMMPRIN) e marcadores da TEM (Snail, Slug, N-caderina, Fibronectina, a-Actina de músculo liso e Vimentina) em Ameloblastomas (AB) e Tumores Odontogênicos Cístico Calcificantes (TOCC). Ainda, realizamos a comparação da expressão de cada molécula avaliada em cada compartimento celular (epitélio e estroma) e correlação entre as moléculas avaliadas no mesmo tumor. Utilizamos 19 casos de AB e 18 casos de TOCC (Serviço de Anatomia Patológica da FOUSP), localização das enzimas/proteínas por imunoistoquímica e analisadas nos compartimentos epitelial e estromal. Todas as proteínas/enzimas analisadas foram detectadas tanto nos AB quanto nos TOCC, sendo a maioria expressa em ambos os compartimentos. A N-caderina foi localizada apenas no epitélio dos AB e a Vimentina somente no estroma em ambos os tumores. Na comparação entre o epitélio x estroma dos ameloblastomas, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, EMMPRIN/CD147, Fibronectina, a-Actina de músculo liso, N-caderina, Vimentina, Snail e Slug. Na comparação entre o epitélio x estroma dos TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-9, RECK, EMMPRIN/CD147, Vimentina, N-caderina, Snail e Slug. Assim, entre o epitélio x estroma dos ameloblastomas e TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectina, Vimentina, a-Actina de músculo liso, N-caderina, Snail e Slug. Esta é a primeira vez que a EMMPRIN, RECK, TIMP-3, TIMP-4, Ncaderina, Snail e Slug são descritas em TOCC e TIMP-3, TIMP-4, Snail e Slug em ameloblastomas. Concluímos que estas proteínas/enzimas estão diferencialmente expressas tanto no epitélio quanto no estroma destes tumores e sugerimos que estes podem participar do comportamento localmente invasivo. / Odontogenic tumors comprise a group of benign neoplasms originating from dental tissues. Research looking for identify molecules involved in the molecular mechanisms that regulate extracellular matrix remodeling (ECM) and how this impacts on locally invasive behavior present in some of these tumors. Epithelial-Mesenchymal Transition (EMT - conversion of epithelial phenotype into mesenchymal phenotype) is well characterized in several carcinomas, leaving to metastasis. MMPs are enzymes that degrade ECM components, generate bioactive molecules, participating in the EMT and control ECM remodeling is given by the balance between them, their inhibitors (TIMPs and RECK) and its activator (EMMPRIN). The aim of this study was evaluate expression profile of MMPs (-2, -7, -9 and - 14), their inhibitors (TIMPs -2, -3, -4 and RECK), its activator (EMMPRIN) and EMT markers (Snail, Slug, N-cadherin, Fibronectin, -smooth muscle actin and Vimentin) in ameloblastomas (AB) and Calcifying Cystic Odontogenic Tumor (CCOT). We also compared the expression of each molecule assessed in each cellular compartment (epithelium and stroma) and correlation between molecules evaluated in the same tumor. We used 19 AB cases and 18 CCOT cases from files of Pathology Laboratory (FOUSP), localization of enzymes/proteins and analyzed by immunohistochemistry in epithelial and stromal compartments. All proteins/enzymes were detected in both AB and CCOT, mostly expressed in both compartments. N-cadherin was localized only in the epithelium of AB and Vimentin only in stromal in both tumors. Comparing \"epithelium vs stroma\" of AB, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, EMMPRIN/CD147, Fibronectin, -smooth muscle actin, N-cadherin, Vimentin, Snail and Slug. Comparing \"epithelium vs stroma\" of CCOT, we observed a statistically significant difference (p <0.05) for MMP-9, RECK, EMMPRIN/CD147, Vimentin, N-cadherin, Snail and Slug. Analizing epithelium vs stroma\" between AB and CCOT, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectin, Vimentin , -smooth muscle actin, N-cadherin, Snail and Slug. This is the first time that EMMPRIN, RECK, TIMP-3, TIMP-4, N-cadherin, Snail and Slug are described in CCOT and TIMP-3, TIMP-4, Snail and Slug in AB. We conclude that these proteins/enzymes are differentially expressed in both epithelium and stroma of these tumors and suggest that they may participate locally invasive behavior.

A realização de um diagnóstico envolve várias etapas, dentre elas o exame radiográfico. Embora a experiência do profissional seja fundamental, é necessário que o mesmo se atualize constantemente, conhecendo as novas tecnologias e de que forma a era digital vem se incorporando nas mais diferentes áreas. Neste trabalho buscou-se avaliar se a tecnologia digital pode colaborar na elaboração de hipóteses diagnósticas de lesões ósseas. Para isso, foram selecionadas 24 radiografias panorâmicas nas quais existiam imagens de lesões do tipo ameloblastoma, tumor odontogênico queratocístico, mixoma e lesão central de células gigantes, atestadas por laudos anátomo-patológicos. As radiografias foram digitalizadas e entregues a 12 examinadores, sendo 3 profissionais para cada uma de 4 diferentes especialidades (radiologia, estomatologia, patologia e cirurgia buco-maxilo-facial). Os examinadores observaram as imagens em dois momentos diferentes. Primeiramente analisaram a radiografia convencional e depois a imagem digitalizada correspondente com intervalo mínimo de 30 dias. Quando do exame das imagens digitais, foi oferecida aos examinadores a opção de uso de ferramentas disponíveis no software, que pudessem auxiliá-lo no procedimento. As suas opiniões eram anotadas em formulários, cujos dados foram posteriormente tabulados e submetidos à análise estatística, por meio de equações de estimação generalizadas (EEG) e índice kappa. Os resultados possibilitaram concluir que houve equivalência na eficácia dos dois métodos avaliados, com boa concordância entre os diagnósticos dos especialistas, e que a probabilidade de acerto não depende da especialidade do observador e nem do tipo de lesão. O método digital foi o preferido para observação entre os avaliadores, sendo que a ferramenta brilho e contraste foi considerada como a melhor auxiliar na elaboração das hipóteses diagnósticas, não havendo uma padronização de valores para tal. Os resultados sugerem ainda que as ferramentas da análise digital favoreceram mais o diagnóstico de um determinado tipo de lesão em comparação aos outros. / The achievement of a diagnosis includes several steps, among them, the radiographic exam. Although the professional experience is fundamental, it is necessary that the professional has been updated constantly, learning new technologies and how the digital era has been incorporated to different areas of knowledge. This work aimed to assess if the digital technology might play a role in the elaboration of diagnostic hypothesis of bone lesions. For that, it was selected 24 panoramic radiographs in which it was possible to observe lesion images of ameloblastoma, keratinizing cystic odontogenic tumor, odontogenic myxoma and central giant cell lesion, with histophatological diagnosis. The radiographs were digitalized and delivered to 12 examiners, being 3 professionals for each one of the 4 specialties (radiology, stomatology, pathology and oral surgery). The examiners have observed the images in two different situations. First they analyzed the conventional radiography and then the corresponding digitalized images, after at least 30 days long. Joined to the digitalized images, it was provided to the examiners software facilities in order to support them in the procedures. Their opinions were filled in booking forms, whose information were tabulated and submitted to statistical analysis through generalized estimation equations (EEG) and kappa index. The outcome has indicated that there was an equivalent fficiency between the two selected methods of assessment. There was a good match of the diagnosis made by the examiners from each speciality, and the probability of a right judgment did not rely on the observer specialty nor on the type of lesion. The examiners have preferred the digital method, and the digital tools bright and contrast were considered the best support for the elaboration of diagnostic hypothesis. Moreover, it was not obtained standard values for bright or contrast. The outcome of this work also suggests that the use of digital analysis tools tends to be more effective for a specific type of lesion than others.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.

A realização de um diagnóstico envolve várias etapas, dentre elas o exame radiográfico. Embora a experiência do profissional seja fundamental, é necessário que o mesmo se atualize constantemente, conhecendo as novas tecnologias e de que forma a era digital vem se incorporando nas mais diferentes áreas. Neste trabalho buscou-se avaliar se a tecnologia digital pode colaborar na elaboração de hipóteses diagnósticas de lesões ósseas. Para isso, foram selecionadas 24 radiografias panorâmicas nas quais existiam imagens de lesões do tipo ameloblastoma, tumor odontogênico queratocístico, mixoma e lesão central de células gigantes, atestadas por laudos anátomo-patológicos. As radiografias foram digitalizadas e entregues a 12 examinadores, sendo 3 profissionais para cada uma de 4 diferentes especialidades (radiologia, estomatologia, patologia e cirurgia buco-maxilo-facial). Os examinadores observaram as imagens em dois momentos diferentes. Primeiramente analisaram a radiografia convencional e depois a imagem digitalizada correspondente com intervalo mínimo de 30 dias. Quando do exame das imagens digitais, foi oferecida aos examinadores a opção de uso de ferramentas disponíveis no software, que pudessem auxiliá-lo no procedimento. As suas opiniões eram anotadas em formulários, cujos dados foram posteriormente tabulados e submetidos à análise estatística, por meio de equações de estimação generalizadas (EEG) e índice kappa. Os resultados possibilitaram concluir que houve equivalência na eficácia dos dois métodos avaliados, com boa concordância entre os diagnósticos dos especialistas, e que a probabilidade de acerto não depende da especialidade do observador e nem do tipo de lesão. O método digital foi o preferido para observação entre os avaliadores, sendo que a ferramenta brilho e contraste foi considerada como a melhor auxiliar na elaboração das hipóteses diagnósticas, não havendo uma padronização de valores para tal. Os resultados sugerem ainda que as ferramentas da análise digital favoreceram mais o diagnóstico de um determinado tipo de lesão em comparação aos outros. / The achievement of a diagnosis includes several steps, among them, the radiographic exam. Although the professional experience is fundamental, it is necessary that the professional has been updated constantly, learning new technologies and how the digital era has been incorporated to different areas of knowledge. This work aimed to assess if the digital technology might play a role in the elaboration of diagnostic hypothesis of bone lesions. For that, it was selected 24 panoramic radiographs in which it was possible to observe lesion images of ameloblastoma, keratinizing cystic odontogenic tumor, odontogenic myxoma and central giant cell lesion, with histophatological diagnosis. The radiographs were digitalized and delivered to 12 examiners, being 3 professionals for each one of the 4 specialties (radiology, stomatology, pathology and oral surgery). The examiners have observed the images in two different situations. First they analyzed the conventional radiography and then the corresponding digitalized images, after at least 30 days long. Joined to the digitalized images, it was provided to the examiners software facilities in order to support them in the procedures. Their opinions were filled in booking forms, whose information were tabulated and submitted to statistical analysis through generalized estimation equations (EEG) and kappa index. The outcome has indicated that there was an equivalent fficiency between the two selected methods of assessment. There was a good match of the diagnosis made by the examiners from each speciality, and the probability of a right judgment did not rely on the observer specialty nor on the type of lesion. The examiners have preferred the digital method, and the digital tools bright and contrast were considered the best support for the elaboration of diagnostic hypothesis. Moreover, it was not obtained standard values for bright or contrast. The outcome of this work also suggests that the use of digital analysis tools tends to be more effective for a specific type of lesion than others.

Os tumores odontogênicos benignos compreendem um grupo de neoplasias originárias dos tecidos dentários. Pesquisas vêm buscando identificar moléculas envolvidas nos mecanismos moleculares que regulam a remodelação da matriz extracelular (MEC) e como isto influencia no comportamento localmente invasivo presente em alguns destes tumores. A Transição Epitélio-Mesenquimal (TEM conversão do fenótipo epitelial em mesenquimal) é bem caracterizada em diversos carcinomas, culminando em mestástase. MMPs são enzimas que degradam os componentes da MEC, geram moléculas bioativas, participam da TEM e o controle da remodelação da MEC dá-se pelo balanço entre elas, seus inibidores (TIMPs e RECK) e seu ativador (EMMPRIN). Assim, o objetivo deste trabalho foi delinear o perfil de expressão das MMPs (-2, -7, -9 e -14), seus inibidores (TIMPs -2, -3, -4 e RECK), seu ativador (EMMPRIN) e marcadores da TEM (Snail, Slug, N-caderina, Fibronectina, a-Actina de músculo liso e Vimentina) em Ameloblastomas (AB) e Tumores Odontogênicos Cístico Calcificantes (TOCC). Ainda, realizamos a comparação da expressão de cada molécula avaliada em cada compartimento celular (epitélio e estroma) e correlação entre as moléculas avaliadas no mesmo tumor. Utilizamos 19 casos de AB e 18 casos de TOCC (Serviço de Anatomia Patológica da FOUSP), localização das enzimas/proteínas por imunoistoquímica e analisadas nos compartimentos epitelial e estromal. Todas as proteínas/enzimas analisadas foram detectadas tanto nos AB quanto nos TOCC, sendo a maioria expressa em ambos os compartimentos. A N-caderina foi localizada apenas no epitélio dos AB e a Vimentina somente no estroma em ambos os tumores. Na comparação entre o epitélio x estroma dos ameloblastomas, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, EMMPRIN/CD147, Fibronectina, a-Actina de músculo liso, N-caderina, Vimentina, Snail e Slug. Na comparação entre o epitélio x estroma dos TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-9, RECK, EMMPRIN/CD147, Vimentina, N-caderina, Snail e Slug. Assim, entre o epitélio x estroma dos ameloblastomas e TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectina, Vimentina, a-Actina de músculo liso, N-caderina, Snail e Slug. Esta é a primeira vez que a EMMPRIN, RECK, TIMP-3, TIMP-4, Ncaderina, Snail e Slug são descritas em TOCC e TIMP-3, TIMP-4, Snail e Slug em ameloblastomas. Concluímos que estas proteínas/enzimas estão diferencialmente expressas tanto no epitélio quanto no estroma destes tumores e sugerimos que estes podem participar do comportamento localmente invasivo. / Odontogenic tumors comprise a group of benign neoplasms originating from dental tissues. Research looking for identify molecules involved in the molecular mechanisms that regulate extracellular matrix remodeling (ECM) and how this impacts on locally invasive behavior present in some of these tumors. Epithelial-Mesenchymal Transition (EMT - conversion of epithelial phenotype into mesenchymal phenotype) is well characterized in several carcinomas, leaving to metastasis. MMPs are enzymes that degrade ECM components, generate bioactive molecules, participating in the EMT and control ECM remodeling is given by the balance between them, their inhibitors (TIMPs and RECK) and its activator (EMMPRIN). The aim of this study was evaluate expression profile of MMPs (-2, -7, -9 and - 14), their inhibitors (TIMPs -2, -3, -4 and RECK), its activator (EMMPRIN) and EMT markers (Snail, Slug, N-cadherin, Fibronectin, -smooth muscle actin and Vimentin) in ameloblastomas (AB) and Calcifying Cystic Odontogenic Tumor (CCOT). We also compared the expression of each molecule assessed in each cellular compartment (epithelium and stroma) and correlation between molecules evaluated in the same tumor. We used 19 AB cases and 18 CCOT cases from files of Pathology Laboratory (FOUSP), localization of enzymes/proteins and analyzed by immunohistochemistry in epithelial and stromal compartments. All proteins/enzymes were detected in both AB and CCOT, mostly expressed in both compartments. N-cadherin was localized only in the epithelium of AB and Vimentin only in stromal in both tumors. Comparing \"epithelium vs stroma\" of AB, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, EMMPRIN/CD147, Fibronectin, -smooth muscle actin, N-cadherin, Vimentin, Snail and Slug. Comparing \"epithelium vs stroma\" of CCOT, we observed a statistically significant difference (p <0.05) for MMP-9, RECK, EMMPRIN/CD147, Vimentin, N-cadherin, Snail and Slug. Analizing epithelium vs stroma\" between AB and CCOT, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectin, Vimentin , -smooth muscle actin, N-cadherin, Snail and Slug. This is the first time that EMMPRIN, RECK, TIMP-3, TIMP-4, N-cadherin, Snail and Slug are described in CCOT and TIMP-3, TIMP-4, Snail and Slug in AB. We conclude that these proteins/enzymes are differentially expressed in both epithelium and stroma of these tumors and suggest that they may participate locally invasive behavior.

Made available in DSpace on 2014-12-17T15:32:24Z (GMT). No. of bitstreams: 1 LuizERJ_DISSERT.pdf: 1737074 bytes, checksum: 8941b0b8844e6080e5a540ee05d65531 (MD5) Previous issue date: 2014-02-28 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Ameloblastomas and keratocystic odontogenic tumors (KOT) represent odontogenic lesions that, despite their benign nature, are distinguished by a distinct biological behavior, characterized by locally aggressive growth and recurrent episodes. The gnathic bone resorption caused by the growth of these lesions is a key to the expansion of the same, both being mediated by osteoclastic cells like enzymatic activity of various matrix metalloproteinases (MMPs) factor. The expression of stimulatory factors and inhibitors of bone resorption has been correlated with the development of these lesions, with emphasis to some MMPs such as collagenases and gelatinases and tissue inhibitors of metalloproteinases (TIMPs), among others. Based on the premise that stimulatory and inhibitory factors of osteolytic processes can be decisive for the growth rate of intraosseous odontogenic lesions, this experiment evaluated the immunoreactivity of MMP-9, -13 and TIMP-1 protein in the epithelium and mesenchyme of ameloblastoma and the KOT specimens, by a quantitative analysis of the immunoreactivity cells. Statistical analysis was performed using the Mann-Whitney and Wilcoxon tests with a significance level set at 5 %. Immunohistochemical expression of MMP-9, -13 and TIMP-1 was observed in 100% of cases both in the epithelium and in mesenchyme. The immunoreactivity in the epithelium of KOT and ameloblastomas revealed a predominance of score 3 for MMP-9 (p=0.382) and MMP-13 (p=0.069) and no statistically significance for TIMP-1, the latter being significantly higher immunoreactivity in ameloblastomas. In the mesenchyme, there was a higher score immunoreactivity of MMP-13 (p=0.031) in ameloblastomas in relation to KOT, whereas for MMP-9 and TIMP-1 no statistically significant difference (p=0.403 was observed, p=1.000). The calculation of the ratio of scores revealed expression of proteins in general, similarity of the lesions, a significant predominance of equal expression of TIMP-1 and MMP-9 was observed only in the epithelium of ameloblastoma. The marked immunostaining of MMP-9 , MMP-13 and TIMP-1 in epithelium and mesenchyme of the lesion indicate that these proteins involved in ECM remodeling required for tumor progression, however, specific differences in the expression of some of these proteins, are not sufficient to suggest differences in the biological behavior of ameloblastomas and KOTs / Os ameloblastomas e tumores odontog?nicos ceratoc?sticos (TOC) representam les?es odontog?nicas que, apesar de sua natureza benigna, se destacam por um comportamento biol?gico distinto, caracterizado pelo crescimento localmente agressivo e epis?dios recidivantes. A reabsor??o dos ossos gn?ticos provocada pelo crescimento dessas les?es constitui um fator determinante ? expans?o das mesmas, sendo mediada tanto por c?lulas osteocl?sticas como pela a??o enzim?tica de diversas metaloproteinases de matriz (MMPs). A express?o de fatores estimuladores e inibidores da reabsor??o ?ssea vem sendo correlacionada com o desenvolvimento destas les?es, merecendo destaque algumas MMPs como as colagenases e as gelatinases e os inibidores teciduais de metaloproteinases (TIMPs), dentre outros. Baseados na premissa de que fatores estimuladores e inibidores de processos osteol?ticos podem ser determinantes para o ritmo de crescimento de les?es odontog?nicas intra?sseas, o objetivo de estudo foi avaliar a imunoexpress?o das prote?nas MMP-9, -13 e TIMP-1 no epit?lio e mes?nquima de esp?cimes de ameloblastomas e TOC. A an?lise estat?stica foi realizada atrav?s dos testes de Mann-Whitney e Wilcoxon com n?vel de signific?ncia estabelecido em 5%. Atrav?s de uma an?lise quantitativa das c?lulas imunomarcadas, foi observada a express?o imuno-histoqu?mica das MMP-9, -13 e TIMP-1 em 100% dos casos, tanto no epit?lio quanto no mes?nquima tumoral. Mais de 76% das c?lulas epiteliais (escore 3) dos TOC e ameloblastomas apresentaram imunomarca??o para MMP-9 (p=0,382) e MMP-13 (p=0,069), sendo estatisticamente significativa para o TIMP-1 (p=0,003) nos ameloblastomas. No mes?nquima, observou-se maior escore de imunomarca??o da MMP-13 (p=0,031) nos ameloblastomas em rela??o aos TOC, enquanto para a MMP-9 e TIMP-1 n?o se observou diferen?a estatisticamente significativa (p=0,403; p=1,000). O c?lculo da raz?o entre os escores de express?o das prote?nas revelou, de uma maneira geral, similaridade entre as les?es, sendo observado predom?nio significante de igualdade de express?o do TIMP-1 e da MMP-9 apenas no epit?lio dos ameloblastomas. A imunoexpress?o marcante das MMP-9, MMP-13 e TIMP-1 no epit?lio e mes?nquima das les?es estudadas indica que estas prote?nas participam na remodela??o da MEC necess?ria ? progress?o tumoral, no entanto, as diferen?as pontuais observadas na express?o de algumas destas prote?nas, n?o s?o suficientes para sugerir diferen?as no comportamento biol?gico dos ameloblastomas e dos TOCs

Orientador: Fabio Ramoa Pires / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-12T19:21:56Z (GMT). No. of bitstreams: 1 Azevedo_RebecadeSouza_D.pdf: 3976330 bytes, checksum: c8e93167e95f91aad2f31f4a0a284024 (MD5) Previous issue date: 2009 / Resumo: O objetivo deste trabalho foi avaliar a freqüência relativa e os aspectos demográficos, clínicos, radiográficos e histopatológicos de uma série de tumores odontogênicos (TO) oriundos dos arquivos de 3 serviços de histopatologia bucal e 1 de histopatologia geral da cidade do Rio de Janeiro no período entre 1970 e 2008, após adequação de seu diagnóstico aos critérios da classificação elaborado pela Organização Mundial da Saúde (OMS) em 2005. Foram revisados 568 TO, representando 3,8% do total das amostras de biópsia da região oral e maxilofacial. A idade média dos pacientes foi de 32,4 anos, com variação entre 3 e 83 anos e maior distribuição na 2ª e 3ª décadas de vida. A relação homen-mulher foi de 1:1.2 e a maioria dos pacientes tinha cor de pele branca (57,9%). Do total, 559 tumores localizavam-se no interior dos ossos gnáticos, 393 na mandíbula (70,3%) e 147 na maxila (26,3%), especialmente na região posterior e anterior, respectivamente. A distribuição dos 568 TO encontrados indicou 191 tumores odontogênicos queratocísticos, 174 ameloblastomas, 76 odontomas, 31 tumores odontogênicos císticos calcificantes, 26 mixomas/fibromixomas odontogênico, 13 cementoblastomas, 11 fibromas odontogênicos, 10 tumores odontogênicos adenomatóides, 7 fibro-odontomas ameloblásticos, 6 tumores odontogênicos epiteliais calcificantes, 4 fibromas ameloblásticos, 3 tumores odontogênicos escamosos, 3 tumores dentinogênicos de células fantasmas, e 6 carcinomas odontogênico, incluindo 3 carcinomas espinocelulares intraósseos primários, 2 carcinomas ameloblásticos e 1 carcinoma odontogênico de células claras. Foram ainda encontrados 7 tumores odontogênicos não-classificáveis. Os TO são lesões incomuns nesta população brasileira, em que as lesões malignas são extremamente raras. O paciente é mais freqüentemente do gênero feminino, de cor de pele branca entre 10 e 29 anos de idade, e as lesões envolvem principalmente a região posterior da mandíbula como uma imagem radiolúcida unilocular de limites precisos. A freqüência relativa e a distribuição das informações demográficas, clínicas, radiográficas e histopatológicas dos subtipos histológicos mostraram semelhanças com a encontrada na literatura revisada de diferentes países, excluindo-se o tumor odontogênico queratocístico. / Abstract: The aim of this study was to evaluate the relative frequency and demographical, clinical, radiological and pathological features of a series of odontogenic tumors (OT) from the files of 3 oral histopathology services and 1 general histopathology service from the city of Rio de Janeiro in the period from 1970 to 2008, after reviewing their final diagnosis according to the diagnostic criteria elaborated by the World Health Organization in 2005. A total of 568 OT was reviewed, representing 3,8% of all oral and maxillofacial biopsy samples. Mean age of the patients was 32.4 years-old, ranging from 3 to 83 years, with most cases in the 2nd and 3rd decades of life. The male-female ratio was 1:1.2 and most patients were Caucasians (57.9%). From the total, 559 OT were centrally located on maxillary bones, being 393 in the mandible (70.3%) and 147 in the maxilla (26.3%), especially in the posterior and anterior regions, respectively. Distribution of the 568 OT revealed 191 keratocystic odontogenic tumors, 174 ameloblastomas, 76 odontomas, 31 calcifying cystic odontogenic tumors, 26 odontogenic myxomas/fibromyxomas, 13 cementoblastomas, 11 odontogenic fibromas, 10 adenomatoid odontogenic tumors, 7 ameloblastic fibro-dontomas, 6 calcifying epithelial odontogenic tumors, 4 ameloblastic fibromas, 3 squamous odontogenic tumors, 3 dentinogenic ghost cell tumors and 6 odontogenic carcinomas, including 3 cases of primary intraosseous squamous cell carcinomas, 2 ameloblastic carcinomas and 1 clear cell odontogenic carcinoma. Also, 7 OT were considered non-classifiable. OT are uncommon lesions in this Brazilian population, and malignant lesions are extremely rare. The patient is more commonly female, Caucasian, between 10 and 29 years-old, and the lesions occur in the posterior mandible as a well-defined unilocular radiolucency. The relative frequency and distribution of the demographical, clinical, radiological and pathological information obtained from each histological subtype showed similarities to the revised literature from different countries, excluding the keratocystic odontogenic tumor. / Doutorado / Patologia / Doutor em Estomatopatologia