Abstract Pancreatic cancer remains one of the deadliest malignancies, with dismal prognosis. Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia. Toll-like receptors (TLR) are receptors of the innate immunity responsible for initiating immune responses against invading pathogens. Their involvement in cancer progression is becoming evident. Hypoxia is a typical characteristic of pancreatic cancer and linked to poor prognosis. Typically, pancreatic cancer has an abundant desmoplastic stroma that contributes to the hypoxia and poor delivery of anti-tumor drugs to the cancer cells. Tenascin-C and fibronectin are proteins of the extracellular matrix. They are involved in normal organ development, but in recent years, their involvement in various cancers has become evident. This thesis examined the involvement of Toll-like receptors, hypoxia markers HIF-1alpha and Carbonic anhydrase 9 (CAIX) as well as stromal markers tenascin-C and fibronectin in pancreatic cancer. Furthermore, the prognostic effect of each protein was evaluated. The material consisted of whole section tissue samples of surgically treated patients with pancreatic ductal adenocarcinoma. The expression of the proteins was evaluated using immunohistochemical stainings. TLR, HIF-1alpha, CAIX, tenascin-C and fibronectin were all abundantly expressed in pancreatic cancer. High TLR9 associated with improved prognosis while weak HIF-1alpha indicated poor prognosis. In a subgroup analysis consisting of only T1 and T2 tumors, high tenascin-C associated with poor prognosis. There was no significant correlation between TLR and hypoxia marker expression. Based on these results, TLR2, TLR4 and TLR9 are expressed in pancreatic cancer, and high TLR9 associates with improved survival of the patients. Weak HIF-1alpha associated with poor prognosis, suggesting that other factors than hypoxia might be involved in the regulation of HIF-1alpha expression. Tenascin-C and fibronectin are not associated with patient prognosis in pancreatic cancer. / Tiivistelmä Haimasyövällä on kaikista syövistä yksi huonoimmista ennusteista. Haimasyöpä kehittyy tiehyidensisäisistä muutoksista, joita kutsutaan englanninkielisellä nimellä pancreatic intraepithelial neoplasia (PanIN). Tollin kaltaiset reseptorit (TLR) ovat luontaisen immuniteetin reseptoreja, ja niiden tehtävä on aloittaa elimistön puolustusvaste tunkeutuvia taudinaiheuttajia vastaan. Tollin kaltaisten reseptorien osuus on osoitettu eri syövissä. Hypoksia on tyypillistä haimasyövälle, ja se on yleensä yhteydessä huonontuneeseen ennusteen. Tyypillisesti haimasyövällä on voimakas sidekudosreaktio, joka osaltaan lisää kasvaimen hapenpuutetta ja vaikeuttaa sytostaattien kulkeutumista syöpäsoluihin. Tenaskiini ja fibronektiini ovat solunulkoisen tilan proteiineja, jotka osallistuvat normaaliin elimistön kehitykseen. Viime aikoina niillä on huomattu olevan osuutta myös erilaisten syöpien kehittymiseen. Tässä väitöskirjassa on tutkittu Tollin kaltaisten reseptorien, hypoksiamerkkiaineiden HIF-1alpha ja hiilihappoanhydraasi 9 (CAIX) sekä sidekudosmerkkiaineiden tenaskiini ja fibronektiini ilmentymistä haimasyövässä. Lisäksi tutkimuksessa selvitettiin näiden proteiinien osuutta haimasyövän ennusteeseen. Tutkimuksen materiaali koostuu haimasyöpäpotilaiden syöpäkudosnäytteistä. Näytteinä käytettiin kokoleikenäytteitä. Näytteille tehtiin immunohistokemialliset värjäykset, joista eri proteiinien ilmentymistä arvioitiin. Tollin kaltaiset reseptorit, HIF-1alpha, CAIX, tenaskiini ja fibronektiini ilmenivät kaikki haimasyövässä. Korkea TLR9 oli yhteydessä parantuneeseen ennusteeseen, kun taas heikko HIF-1alpha oli yhteydessä huonontuneeseen ennusteeseen. Huomioitaessa vain T1- ja T2-kasvaimet korkea tenaskiini oli yhteydessä huonontuneeseen ennusteeseen. Tollin kaltaisten reseptorien ja hypoksiamerkkiaineiden välillä ei ollut merkittävää yhteyttä. Tulosten perusteella haimasyövässä on runsaasti Tollin kaltaisia reseptoreita, ja korkea TLR9 on yhteydessä parantuneeseen ennusteeseen. Matala HIF-1alpha on yhteydessä huonoon ennusteeseen. Tenaskiinilla ja fibronektiinilla ei ole vaikutusta potilaiden ennusteeseen.

A histopatologia é considerada um dos recursos diagnósticos mais importantes na prática médica e caracteriza-se pelo estudo das alterações estruturais e morfológicas das células e dos tecidos causadas por doenças. Atualmente, o principal método utilizado no diagnóstico histopatológico de imagens microscópicas, obtidas por meio de amostras em exames convencionais, é a avaliação visual do patologista, a qual se baseia na experiência do mesmo. O uso de técnicas de processamento computacional de imagens possibilita a identificação de elementos estruturais e a determinação de características inerentes, subsidiando o estudo da organização estrutural das células e de suas variações patológicas. A utilização de métodos computacionais no auxílio ao diagnóstico visa diminuir a subjetividade do processo de avaliação e classificação realizado pelo médico. Diferentes características dos tecidos podem ser mapeadas por meio de métricas específicas que poderão ser utilizadas em sistemas de reconhecimento de padrões. Dentro desta perspectiva, o objetivo geral deste trabalho inclui a proposta, a implementação e a avaliação de um método para a identificação e a análise de estruturas histológicas, a ser utilizado para a análise de lesões neoplásicas do colo do útero (NICs) a partir de amostras histopatológicas. Este trabalho foi desenvolvido em colaboração com uma equipe de patologistas, especialistas do domínio. As imagens microscópicas digitalizadas foram adquiridas a partir de lâminas previamente fixadas, contendo amostras de biópsias. Para segmentação dos núcleos celulares, foi implementado um pipeline de operadores morfológicos. Métodos de segmentação baseados em cor também foram testados e comparados à abordagem morfológica. Foi proposta e implementada uma abordagem baseada em camadas para representação do tecido, adotando-se a Triangulação de Delaunay (TD) como modelo de grafo de vizinhança. A TD apresenta algumas propriedades particulares que permitem a extração de métricas específicas. Foram utilizados algoritmos de agrupamento e morfologia de grafos, adotando-se critérios de semelhança e relações de adjacência entre os triângulos da rede, a fim de se obter a fronteira entre as camadas histológicas do tecido epitelial de forma automática. As seguintes métricas foram extraídas dos agrupamentos resultantes: grau médio, entropia e taxa de ocupação dos triângulos da rede. Finalmente, foi projetado um classificador estatístico levando-se em consideração os diferentes agrupamentos que poderiam ser obtidos a partir das imagens de treinamento. Valores de acurácia, sensitividade e especificidade foram utilizadas para avaliação dos resultados obtidos. Foi implementada validação cruzada em todos os experimentos realizados e foi utilizado um total de 116 imagens. Primeiro, foi avaliado a acurácia da metodologia proposta na determinação correta da presença de anomalia no tecido, para isto, todas as imagens que apresentavam NICs foram agrupadas em uma mesma classe. A maior taxa de acurácia obtida neste experimento foi de 88%. Em uma segunda etapa, foram realizadas avaliações entre as seguintes classes: Normal e NIC-I; NIC-I e NIC-II, e, NIC-II e NIC-III, obtendo-se taxas de acurácia máximas de 73%, 77% e 86%, respectivamente. Além disso, foi verificada também, a acurácia na discriminação entre os três tipos de NICs e regiões normais, obtendo-se acurácia de 64%. As taxas de ocupação relativas aos agrupamentos representativos das camadas basais e superficiais, foram os atributos que levaram às maiores taxas de acurácia. Os resultados obtidos permitem verificar a adequação do método proposto na representação e análise do processo de evolução das NICs no tecido epitelial do colo uterino. / Histopathology is considered one of the most important diagnostic tools in medical routine and is characterized by the study of structural and morphological changes of the cells in biological tissues caused by diseases. Currently, the visual assessment of the pathologist is the main method used in the histopathological diagnosis of microscopic images obtained from biopsy samples. This diagnosis is usually based on the experience of the pathologist. The use of computational techniques in the processing of these images allows the identification of structural elements and the determination of inherent characteristics, supporting the study of the structural organization of tissues and their pathological changes. Also, the use of computational methods to improve diagnosis aims to reduce the subjectivity of the evaluation made by the physician. Besides, different tissue characteristics can be mapped through specific metrics that can be used in pattern recognition systems. Within this perspective, the overall objective of this work includes the proposal, the implementation and the evaluation of a methodology for the identification and analysis of histological structures. This methodology includes the specification of a method for the analysis of cervical intraepithelial neoplasias (CINs) from histopathological samples. This work was developed in collaboration with a team of pathologists. Microscopic images were acquired from blades previously stained, containing samples of biopsy examinations. For the segmentation of cell nuclei, a pipeline of morphological operators were implemented. Segmentation techniques based on color were also tested and compared to the morphological approach. For the representation of the tissue architecture an approach based on the tissue layers was proposed and implemented adopting the Delaunay Triangulation (DT) as neighborhood graph. The DT has some special properties that allow the extraction of specific metrics. Clustering algorithms and graph morphology were used in order to automatically obtain the boundary between the histological layers of the epithelial tissue. For this purpose, similarity criteria and adjacency relations between the triangles of the network were explored. The following metrics were extracted from the resulting clusters: mean degree, entropy and the occupation rate of the clusters. Finally, a statistical classifier was designed taking into account the different combinations of clusters that could be obtained from the training process. Values of accuracy, sensitivity and specificity were used to evaluate the results. All the experiments were taken in a cross-validation process (5-fold) and a total of 116 images were used. First, it was evaluated the accuracy in determining the correct presence of abnormalities in the tissue. For this, all images presenting CINs were grouped in the same class. The highest accuracy rate obtained for this evaluation was 88%. In a second step, the discrimination between the following classes were analyzed: Normal/CIN 1; CIN 1/CIN 2, and, CIN 2/CIN 3, which represents the histological grading of the CINs. In a similar way, the highest accuracy rates obtained were 73%, 77% and 86%, respectively. In addition, it was also calculated the accuracy rate in discriminating between the four classes analyzed in this work: the three types of CINs and the normal region. In this last case, it was obtained a rate of 64%.The occupation rate for the basal and superficial layers were the attributes that led to the highest accuracy rates. The results obtained shows the adequacy of the proposed method in the representation and classification of the CINs evolution in the cervical epithelial tissue.

ABSTRACT The morphological premalignant changes in prostate epithelium such as high grade prostatic intraepithelial neoplasia (HGPIN) precede invasive prostate cancer (PC) by several decades. The overall aim of this project was to identify patterns of gene expression in HGPIN and early PC which increase our understanding of the early biology of PC and identify genes and pathways that correlate with an aggressive phenotype. A comprehensive tissue cohort of premalignant prostate lesions was collected in a tissue microarray (TMA) platform that was utilised for high-throughput validation of target genes. Using this unique resource, the expression of the tumour suppressor gene PTEN was assessed using immunohistochemistry in an initial candidate gene approach based on mouse models implicating PTEN in carcinogenesis. No significant difference in expression of PTEN was detected in premalignant and benign epithelium. A transcript profiling approach was undertaken by integrating laser capture microdissection, linear RNA amplification and oligonucleotide microarrays to perform a screen of matched patient samples of normal, HGPIN and PC cells. The expression patterns of two genes encoding secreted proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine (MIC-1) were validated using immunohistochemistry on TMAs representing the progression model of early PC. Increased expression of these proteins in PC was confirmed to occur early in the disease process and altered expression of NPY and MIC-1 was associated with worse clinical outcome. Further analysis of global gene expression patterns using a structured network knowledge base identified a notable aberration in the expression of extracellular matrix and extracellular matrix associated proteins in HGPIN and provided novel evidence for the role of this class of molecules in the development of PC. In summary, contrary to current dogma based on work in animal models, altered PTEN expression is unlikely to represent an important event in the development of malignancy in the human prostate. In contrast, the expression patterns and prognostic value of NPY and MIC-1 in HGPIN support their further evaluation as biomarkers for the development and progression of PC. The aberrant expression of genes and networks of genes detected in HGPIN will assist in further identification of biological pathways which may be targeted in therapeutic strategies against the development and progression of PC.

Aukšto laipsnio prostatos intraepitelinė neoplazija (ALPIN, angl. – HGPIN – high grade prostatic intraepithelial neoplasia ) priskiriama prie priešvėžinių būklių ( arba prostatos vėžio prekursorių) ir susijusi su padidėjusia kartu esamo vėžio diagnozavimo rizika arba vėlesne jos progresija iki vėžio. Manoma, kad pacientai, kuriems nustatyta ALPIN prostatos biopsinėje medžiagoje, yra tinkami kandidatai chemoprevencijai. Šio darbo tikslas buvo nustatyti 5-alfa reduktazės inhibitoriaus dutasterido reikšmę prostatos vėžio prevencijai esant didelei šios ligos rizikai. Darbo uždaviniai : 1. Nustatyti prostatos vėžio dažnį esant didelei šios ligos rizikai (biopsinėje medžiagoje nustatyta aukšto laipsnio prostatos intraepitelinė neoplazija). 2. Įvertinti pakartotinių biopsijų reikšmę prostatos vėžio diagnozavimo dažniui. 3. Įvertinti tiriamojo vaisto reikšmę prostatos vėžio prevencijai (ar sumažina prostatos vėžio diagozavimo dažnį) esant didelei šios ligos rizikai. 4. Palyginti diagnozuoto prostatos vėžio diferenciacijos skirtumus tiriamosiose grupėse. / A high grade prostatic intraepithelial neoplasia (HPIN) is traditionally ascribed to pre-cancerous conditions or prostate cancer (PC) precursors, and associated with an increased risk of concomitant cancer or its later progression to malignant disease. After evaluation of the data indicating HPIN as a pre–cancerous condition, it is thought that the patients having HPIN in the prostate biopsy material are suitable candidates for chemoprevention.The aim of the study was to find out the significance of dutasteride, a 5–alpha reductase inhibitor, for the prevention of development of prostate cancer in case of a high risk for the disease. Objectives of the study: 1. To determine the rate of prostate cancer in case of a high risk for the disease (when a high grade prostatic intraepithelial neoplasia is found in biopsy material). 2. To find out the significance of repeat biopsies for the detection rate of prostate cancer. 3. To find out the significance of the investigatory medication for the prevention of development of prostate cancer in case of a high risk for the disease. 4. To compare the differences in the differentiation of diagnosed prostate cancer between the study groups.

ABSTRACT The morphological premalignant changes in prostate epithelium such as high grade prostatic intraepithelial neoplasia (HGPIN) precede invasive prostate cancer (PC) by several decades. The overall aim of this project was to identify patterns of gene expression in HGPIN and early PC which increase our understanding of the early biology of PC and identify genes and pathways that correlate with an aggressive phenotype. A comprehensive tissue cohort of premalignant prostate lesions was collected in a tissue microarray (TMA) platform that was utilised for high-throughput validation of target genes. Using this unique resource, the expression of the tumour suppressor gene PTEN was assessed using immunohistochemistry in an initial candidate gene approach based on mouse models implicating PTEN in carcinogenesis. No significant difference in expression of PTEN was detected in premalignant and benign epithelium. A transcript profiling approach was undertaken by integrating laser capture microdissection, linear RNA amplification and oligonucleotide microarrays to perform a screen of matched patient samples of normal, HGPIN and PC cells. The expression patterns of two genes encoding secreted proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine (MIC-1) were validated using immunohistochemistry on TMAs representing the progression model of early PC. Increased expression of these proteins in PC was confirmed to occur early in the disease process and altered expression of NPY and MIC-1 was associated with worse clinical outcome. Further analysis of global gene expression patterns using a structured network knowledge base identified a notable aberration in the expression of extracellular matrix and extracellular matrix associated proteins in HGPIN and provided novel evidence for the role of this class of molecules in the development of PC. In summary, contrary to current dogma based on work in animal models, altered PTEN expression is unlikely to represent an important event in the development of malignancy in the human prostate. In contrast, the expression patterns and prognostic value of NPY and MIC-1 in HGPIN support their further evaluation as biomarkers for the development and progression of PC. The aberrant expression of genes and networks of genes detected in HGPIN will assist in further identification of biological pathways which may be targeted in therapeutic strategies against the development and progression of PC.

ABSTRACT The morphological premalignant changes in prostate epithelium such as high grade prostatic intraepithelial neoplasia (HGPIN) precede invasive prostate cancer (PC) by several decades. The overall aim of this project was to identify patterns of gene expression in HGPIN and early PC which increase our understanding of the early biology of PC and identify genes and pathways that correlate with an aggressive phenotype. A comprehensive tissue cohort of premalignant prostate lesions was collected in a tissue microarray (TMA) platform that was utilised for high-throughput validation of target genes. Using this unique resource, the expression of the tumour suppressor gene PTEN was assessed using immunohistochemistry in an initial candidate gene approach based on mouse models implicating PTEN in carcinogenesis. No significant difference in expression of PTEN was detected in premalignant and benign epithelium. A transcript profiling approach was undertaken by integrating laser capture microdissection, linear RNA amplification and oligonucleotide microarrays to perform a screen of matched patient samples of normal, HGPIN and PC cells. The expression patterns of two genes encoding secreted proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine (MIC-1) were validated using immunohistochemistry on TMAs representing the progression model of early PC. Increased expression of these proteins in PC was confirmed to occur early in the disease process and altered expression of NPY and MIC-1 was associated with worse clinical outcome. Further analysis of global gene expression patterns using a structured network knowledge base identified a notable aberration in the expression of extracellular matrix and extracellular matrix associated proteins in HGPIN and provided novel evidence for the role of this class of molecules in the development of PC. In summary, contrary to current dogma based on work in animal models, altered PTEN expression is unlikely to represent an important event in the development of malignancy in the human prostate. In contrast, the expression patterns and prognostic value of NPY and MIC-1 in HGPIN support their further evaluation as biomarkers for the development and progression of PC. The aberrant expression of genes and networks of genes detected in HGPIN will assist in further identification of biological pathways which may be targeted in therapeutic strategies against the development and progression of PC.

Foi realizada uma análise quantitativa sistemática da literatura para verificar a acurácia do biomarcador ProEx C em pacientes com ASC-US, ASCH e SIL. Metodologia: A pesquisa foi realizada no MEDLINE (PubMed e OVID), EMBASE, LILACS, IBECS, BIOSIS, Web of Science, SCOPUS, desde 1966 até Novembro de 2011. Esta revisão esteve centrada em estudos que cumpriram as três condições para a seleção do estudo, que incluem teste de Papanicolaou, teste de triagem ProEx C e histopatologia como o teste de referência. Resultados: Cinco estudos, incluindo 713 mulheres, foram analisados. Das biopsias positivas, 83% (355/429) foram positivas para ProEx C, enquanto 14% (41/284) das biópsias negativas foram positivas para ProEx C. A sensibilidade combinada foi de 83% (95% IC, 79-87) e especificidade foi de 85% (95% IC, 80-89) usando o soaftware Meta-Disc. Para lesão cervical vs biópsia positiva ou negativa, a área sob a curva (AUC) foi de 0,90 com valor do ponto Q * de 0,84. Conclusão: nossos dados concordam com a hipótese de que ProEx C representa um evento precoce na carcinogênese cervical e que poderiam estar associados com a iniciação e progressão de lesões cervicais e, se expressados nos exames estudados podem revelar maior acurácia diagnóstica destes exames. / Undertook a quantitative systematic review of the literature to ascertain the accuracy of the biomarker ProEx C in patients with ASC-US, ASC-H and SIL. Methods: A comprehensive search of the MEDLINE (PubMed and OVID interface), EMBASE, LILACS, IBECS, BIOSIS, Web of Science, SCOPUS, index from 1966 to November 2011. This review focused on studies that fulfill the three mandatory conditions for study selection that include Pap Test, triage testing ProEx C and histopathology like the reference test. Results: Five studies, including 713 women, were analyzed. 83% (355/429) of positive biopsy were positive for ProEx C activity, while 14% (41/284) of the negative biopsy were positive for ProEx C activity. Pooled sensitivity was 83% (95% IC, 79 to 87) and specificity was 85% (95% IC, 80-89) using software Meta-Disc. For cervical lesion vs positive or negative biopsy, the area under the curve (AUC) was 0.90 with Q* point value of 0.84. Conclusion: our data agree with the hypothesis that ProEx C represents an early event in cervical carcinogenesis that could be associated with the initiation and progression of cervical lesions and is expressed in the studied tests may reveal greater diagnostic accuracy of these tests.

Made available in DSpace on 2015-07-22T20:50:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-03-26. Added 1 bitstream(s) on 2015-08-11T03:25:45Z : No. of bitstreams: 1 Publico-10807.pdf: 786945 bytes, checksum: a640250d88b5bd045dc6f2f53834bd45 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Objetivos: Estudar a expressao imuno-histoquimica de topoisomerase IIƒ¿ e de caspase-3 ativada, marcadores de proliferacao e de apoptose, respectivamente, a deteccao de DNA HPV e a evolucao da lesao cervical em mulheres portadoras de lesao intra-epitelial escamosa de baixo grau (LBG). Metodos: Foram avaliadas 40 mulheres portadoras de LBG e 32 sem neoplasia cervical, diagnosticadas por exame cito-colpo-histopatologico, quanto a imunoexpressao de topoisomerase IIƒ¿ e de caspase-3 ativada e quanto a deteccao de DNA HPV por PCR consensual (GP5+/GP6+) em material de esfregaco cervico-vaginal. Os achados foram relacionados as variaveis clinicas das pacientes e a evolucao clinica das lesoes cervicais em 12 meses. As pacientes assinaram termo de consentimento livre e esclarecido. Resultados: A media percentual de celulas imunomarcadas por topoisomerase foi de 11,71% e 4,13%, no grupo com LBG e controle, respectivamente, com diferenca estatisticamente significante. Observou-se que houve expressao de caspase-3 em 17 (42,5%) e em 5 (15,63%) pacientes com e sem LBG, respectivamente, com diferenca estatisticamente significante. Foi detectado HPV DNA em 65% das pacientes com LBG e em 59,4% das pacientes sem lesao cervical, sem relacao com a expressao de topoisomerase IIƒ¿ ou caspase-3. Na presenca de DNA-HPV, a expressao de topoisomerase IIƒ¿ no grupo com LBG foi significativamente maior do que em fragmentos sem lesao. Nao foi observada diferenca quanto a evolucao da lesao cervical em 12 meses de acordo com a imunoexpressao de topoisomerase IIƒ¿. Com relacao a caspase-3 ativada, a maioria das pacientes com imuno-histoquimica negativa teve regressao da lesao cervical. Conclusoes: A imunoexpressao de topoisomerase IIƒ¿ e de caspase-3 ativada podem ser considerados marcadores de proliferacao e de apoptose em lesao cervical de baixo grau, sem relacao com a presenca de DNA-HPV. / Purpose: To evaluate the correlation between the expression of topoisomerase II alpha, active caspase-3 and infection with human papillomavirus in low-grade cervical intraepithelial lesion and in the normal cervix, and whether they might influence susceptibility to, or evolution of, cervical lesion. Patients and methods: Forty cervical biopsies patients with low-grade cervical intraepithelial lesion and thirty-two with normal cervix were stained by immunohistochemistry for topoisomerase IIá and active caspase-3 and were investigated for the presence of HPV on exfoliated cells by general primer GP5+/6+ PCR amplification of DNA. These findings were correlated with clinicopathological features of the patients including their clinical outcome after twelve months. Subjects provided written informed consent. Results: Low-grade CIN patients as a group had a significantly higher expression of topoisomerase II alpha compared to controls, without correlation to disease outcome at 12 months. Caspase-3 was expressed in 42.5% of CIN patients and in 15.63% without disease, and most of women without caspase-3 receded cervical lesion. HPV DNA testing was positive in 65% of the patients with cervical lesion, and in 59.4% of the control group and was not associated to the expression of topoisomerase IIá or active caspase-3. In the presence of a positive HPV DNA testing, women with cervical lesion had a significantly higher expression of topoisomerase II alpha compared to controls. Conclusion: Topoisomerase II alpha and active caspase-3 might be useful diagnostic and prognostic markers in low-grade cervical lesions, delaying a better follow-up. / CNPq: 134106/2005-9 / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2011-11-09T14:45:46Z (GMT). No. of bitstreams: 2 license.txt: 1648 bytes, checksum: e095249ac7cacefbfe39684dfe45e706 (MD5) 000232.pdf: 784982 bytes, checksum: 4f41fbc5c9c9b8e2a3af0a8aa222d83e (MD5) Previous issue date: 2008 / Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil / A classificação citológica cérvico-vaginal mais atualizada, e que tem sido empregada em quase todo o mundo, é a do Sistema Bethesda. Sua última atualização, em 2001, subdividiu a categoria de células escamosas atípicas de significado indeterminado (Atypical Squamous Cells of Undetermined Significance – ASCUS) em ASC-US (de significado indeterminado) e ASC-H (quando não se pode excluir lesão intra-epitelial de alto grau), na qual espera-se maior probabilidade de se encontrar lesão precursora do câncer do colo. No Brasil, esta subdivisão foi adotada oficialmente pelo SUS (Sistema Único de Saúde) em junho de 2006, fazendo parte da Nomenclatura Brasileira para Laudos Citopatológicos. Esta pesquisa tem por objetivo medir a prevalência de lesão intra-epitelial escamosa de alto grau e câncer cervical em pacientes encaminhadas do SUS com citologia ASC-H, e comparar o risco desta lesão nas subcategorias de células escamosas atípicas (Atypical Squamous Cells - ASC) através do cálculo da Razão de Prevalências. Sua metodologia é baseada em casos com citologias ASCUS do SITEC (Sistema Integrado de Tecnologia em Citopatologia) recebidos no IFF (Instituto Fernandes Figueira) no período de agosto de 1998 a setembro de 2007, que foram revisados de acordo com o Sistema Bethesda 2001 até que se chegasse a um diagnóstico de consenso. Os casos ASC-H e ASC-US resultantes desta revisão, bem como os casos novos recebidos a partir de 2004, foram incluídos e analisados em relação ao desfecho. Para esta análise, incluíram-se os casos com diagnóstico histológico. Nos casos sem histologia, a colposcopia e a citologia foram consideradas como padrão-ouro. A prevalência da lesão de alto grau na citologia ASC-H foi de 19,29% (IC 95% 9,05 – 29,55%) e a possibilidade de doença de alto grau foi maior entre as pacientes com citologia ASC-H comparado às pacientes com citologia ASC-US (RP = 10,42 ICvii 95% 2,39 – 45,47) p = 0,0000764. Encontrou-se lesão de alto grau com maior freqüência nas pacientes abaixo dos 50 anos (RP = 2,67 IC 95% 0,38 – 18,83) porém sem significância estatística (p = 0,2786998). Não foram encontrados casos de câncer do colo do útero. A prevalência de lesão de alto grau em pacientes com citologia ASC-H foi significativa e a divisão em subcategorias do diagnóstico ASC se mostrou com boa capacidade para discriminar a presença de lesões de alto grau. / The Bethesda System is the most recent cervical and vaginal citopathology classification used almost worldwide. The Bethesda System’s last revision (2001) subdivided the category of Atypical Squamous Cells of Undetermined Significance (ASCUS) in ASC-US (of undetermined significance) and ASC-H (cannot exclude highgrade intraepithelial lesion), the last one carrying greater probability of finding precursors lesions of cervical cancer. This subdivision was adopted oficially by Brasilian Public Health System (SUS) in June 2006, becoming part of the Brasilian Nomenclature for Citopathological Reports. The aim of the study was measure the prevalence of High-grade Squamous Intraepithelial Lesion (HSIL) and cervical cancer, in patients whit citology of ASC-H and compare the risk of HSIL in the subcategories of ASC-H and ASC-US by Prevalence Ratio. The metodology was based in cases with citology ASCUS from SITEC (Integrated System of Tecnology in Citopatology) received in IFF (Fernandes Figueira Institute) from August 1998 to September 2007. The cytologies were reviwed by Bethesda System 2001 until a consensus diagnostic. The resultant cases of ASC-H and ASC-US from this review and the new cases recived from 2004, were included and analysed in relation to final diagnostic. This analysis included histology (gold standard) and those cases without histology, citology and colposcopy were the gold standard. We found 19,29% (CI 95% 9,05 – 29,55%) of prevalence of HSIL in ASC-H citology and the possibility of HSIL was greater in ASC-H cytology than in ASC-US (PR= 10,42, CI 95% 2,39 – 45,47%). We did not find cervical cancer. The prevalence of high-grade intraepithelial lesion in patients with ASC-H citology was significant and the subdivision of ASC (Atypical Squamous Cells) was good in discriminating the presence of HSIL.

Made available in DSpace on 2014-08-26T17:31:46Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 69587.pdf: 2997505 bytes, checksum: dc74916c69c19057bfb89c77256c2717 (MD5) / Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil / Introdução: O câncer do colo do útero é a 3ª neoplasia mais frequente no Brasil e tem alto potencial de prevenção e de cura. Não conhecemos a frequência de doença invasiva em mulheres com diagnóstico citopatológico de lesão de alto grau não podendo excluir microinvasão (HSIL-micro). Objetivo: Estimar o risco, por meio da razão de prevalências (RP), de lesão pré-invasiva e de lesão invasiva em mulheres com exame citopatológico de HSIL-micro em comparação àquelas com lesão de alto grau (HSIL), bem como sua relação com os achados colposcópicos. Metodologia: Estudo de corte transversal em que mulheres com HSIL-micro encaminhadas para duas unidades de referência foram identificadas na base de dados do laboratório que centralizava esses exames no município do Rio de Janeiro, no período de junho de 2006 a junho de 2012. Para cada mulher com HSIL-micro foram identificadas quatro mulheres com diagnóstico de HSIL recebidas em datas mais próximas de cada uma com HSIL-micro e que preenchessem os critérios de inclusão. Os dados foram obtidos a partir de revisão dos prontuários. Resultados: Foram incluídas 47 pacientes com laudo de HSIL-micro e 188 pacientes com laudo de HSIL. Controlando para idade, mulheres com HSIL-micro apresentaram RP de lesões pré-invasivas e invasivas 1,25 (IC95% 1,10-1,42) vezes maior do que as com HSIL. Para lesão invasiva, a RP foi 3,67 (IC95% 2,30-5,85) vezes maior nas mulheres com HSIL-micro. Não encontramos associação significativa entre a presença de lesões e achados colposcópicos ou possibilidade de visão da Junção escamo-colunar. / Introduction: Cervical cancer is the 3rd most common cancer in Brazil and has a high potential for prevention and cure. We do not know the prevalence of invasive and pre–invasive disease in women with cytological diagnosis of high-grade lesion-can not exclude microinvasion (HSIL-micro). Objective: To estimate the prevalence ratio(PR)of pre-invasive and invasive lesions in women with HSIL-micro Pap smearcompared to those with high-grade lesion (HSIL), as well as their relationship with colposcopic findings. Methods: Cross-sectional study in which women with HSIL-micro and HSIL routed to two reference units were identified in the cytology lab database, from June 2006 to June 2012. For each woman with HSIL-micro, four women with a diagnosis of HSIL who fulfilled the inclusion criteria were identified. Data were obtained from review of medical records. Results: We included 47 patients with report of HSIL -micro and 188 patients with report of HSIL. Controlling for age, women with HSIL-micro presented a PR of pre-invasive and invasive lesions of 1.25 (95% CI 1.10 to 1.42) times greater than those with HSIL. For invasive lesion only, the PR was 3.67 (95%CI 2.30 to 5.85) times greater in women with HSIL micro. We did not find a significant association between the presence of lesions and colposcopic findings or possibility of vision of the squamocolumnar junction .