published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

In situ follicular neoplasia (ISFN) is defined as a monoclonal proliferation of B cells with immunophenotypic and genetic features of follicular lymphoma (FL) but confined to germinal centers of lymph nodes or other organs. It may not be associated with underlying overt lymphoma. It can be associated with lymphoproliferative disorders other than FL. A fifty-seven-year-old caucasian male initially presented with atypical chest pain, which led to cardiology evaluation. Patient underwent a coronary CT angiogram, which revealed a calcium score of 0, however also incidentally revealed mediastinal lymphadenopathy. Patient had a bronchoscopy which revealed no endobronchial lesions bilaterally. Using endo-bronchial ultrasound, right carinal lymph node was visualized, and trans-bronchial fine needle aspiration was performed. Cytology was positive for necrotic lesion with atypical cells. Patient had a dedicated CT scan of chest which showed enlarged sub-carinal lymph node measuring 3.3 x 3.0 cm. PET/CT scan showed increased uptake in the sub-carinal lymph nodes, also increased uptake of mid para-esophageal lymph nodes. It also showed some low-grade lymphadenopathy in right lower paratracheal region as well as mesenteric lymphadenopathy with misty appearance. Small pulmonary nodules were also noted in right middle and lower lobes with no associated uptake. Patient was scheduled for a mediastinoscopy and lymph node dissection. Patient proceeded with mediastinoscopy and a total of 4 lymph node specimens were removed from level 4R and level 7. Pathology from one of the lymph nodes revealed necrotizing granulomatous inflammation with staining consistent with histoplasmosis. Interestingly, two other lymph nodes showed in situ follicular neoplasia. Immunohistochemical stains demonstrated rare secondary lymphoid follicles with unremarkable morphology, showing strong germinal center staining with BCL2. FISH analysis was normal indicating absence of t(14;18). Pathology showed morphologically unremarkable B-cell nodules, concentrated in the cortical area which were CD20 positive and BCL2-positive. Patient underwent subsequent treatment with anti-fungal agents for the Histoplasmosis and is currently under surveillance for in-situ follicular lymphoma. In-situ follicular neoplasia is considered a premalignant lesion and a precursor of follicular lymphoma. Incidence of ISFN is difficult to ascertain, as it is usually a subclinical diagnosis. Incidence of FL is 3.18 per 100,000 population in the United States and findings suggest that ISFN is likely more frequent than that. Also, similar to FL, ISFN is seen in middle-aged and older individuals, mean age being around the fifth decade of life.Incidentally found ISFN without prior or simultaneous lymphoma is associated with a very low rate of clinical progression. Because some cases of ISFN are associated with prior or concurrent lymphoma, screening studies including computed tomography (CT) scan and bone marrow biopsy should be conducted after the diagnosis of ISFN is made. In the absence of overt lymphoma, it has been recommended that patients with ISFN be observed without chemotherapy, based on the very low incidence of progression into overt FL. The clinical significance of ISFN is not fully understood, however studies have demonstrated that incidentally found ISFN without prior or simultaneous lymphoma is associated with a very low rate of clinical progression. (

Introdução: Os linfomas abrangem um grupo heterogêneo de neoplasias originadas no sistema linfático, diferentes quanto à sua histologia, prognóstico e epidemiologia, embora possa haver grande número de aspectos clínicos comuns. De acordo com sua morfologia, dividem-se dois grupos: os linfomas Hodgkin (LH) e os linfomas não-Hodgkin (LNH). Objetivo: Avaliar a tendência temporal da incidência de linfomas no período de 1997 a 2012, identificando a influência de fatores como o sexo, a idade, o período e a coorte e nascimento. Metodologia: Trata-se de um estudo ecológico. Foram obtidas, do Registro de Câncer de Base Populacional de São Paulo (RCBP-SP), informações sobre todos os casos novos de linfomas no Município de São Paulo, diagnosticados no período de 1997 a 2012. Informações sobre o número de habitantes do Município foram obtidas online através do site do Departamento de Informática do SUS. Para avaliar a tendência da incidência de linfomas no decorrer do período, segundo sexo e faixa etária, foram ajustados modelos lineares generalizados (MLG). Para avaliar a influência da idade, do período de diagnóstico e das coortes de nascimento na tendência da incidência dos linfomas, foi utilizado o modelo idade-período-coorte (IPC). Resultados e conclusões: Dos 18.037 casos analisados, 20,5% eram do tipo LH e 79,5% do tipo LNH. Entre os casos de LH, 52,6% eram homens e 70,0% tinham entre 20 e 39 anos. A taxa de incidência de LH padronizada por idade, por 100 mil habitantes, variou de 5,0 em 1997 para 4,0 em 2012, entretanto, não foi detectada nenhuma tendência significativa na incidência ao longo do tempo (p>0,05). O risco de desenvolver LH foi maior no sexo masculino do que no feminino apenas na faixa etária de 0 a 14 anos (p<0,001), nas demais, o risco foi semelhante para ambos os sexos (p>0,05). O risco de desenvolver LH segundo a faixa etária apresentou um padrão etário bimodal. No sexo feminino, os maiores riscos ocorreram nas faixas de 20 a 39 e de 65 anos e mais e, no masculino, nas faixas de 15 a 19 e de 65 anos e mais. O modelo IPC apontou uma influência da coorte de nascimento na incidência de LH em mulheres: para aquelas nascidas antes de 1960, quanto mais antiga a coorte, maior o risco de LH; para as nascidas após 1960, o risco relativo permaneceu estável. Entre os casos de LNH, 51,6% eram homens e 77,4% tinham mais de 40 anos. A taxa de incidência de LNH padronizada por idade, por 100 mil habitantes, passou de 22,6 em 1997 para 17,0 em 2012. Foi detectada uma tendência de decréscimo na incidência de LNH de 1,7% ao ano em todas as faixas etárias, em ambos os sexos (p<0,001). O risco de desenvolver LNH aumentou continuamente com o avançar da idade, em ambos os sexos. O modelo IPC não detectou efeitos de período. Para os homens, as coortes mais velhas apresentam maior risco e, as mais jovens, menor risco. Para as mulheres nascidas antes de 1960 o comportamento foi semelhante ao dos homens, para as nascidas após 1960, o risco relativo permaneceu estável. / Introduction: Lymphomas comprise a heterogeneous group of neoplasias originating in the lymphatic system, different in their histology, prognosis and epidemiology, although there may be a large number of common clinical aspects. According to their morphology, two groups are divided: Hodgkin\'s lymphomas (HL) and non-Hodgkin\'s lymphomas (NHL). Objective: To evaluate the temporal trend of the incidence of lymphomas in the period from 1997 to 2012, identifying the influence of factors such as sex, age, period and cohort and birth. Methodology: This is an ecological study. Information about all new cases of lymphomas in the city of São Paulo, diagnosed in the period from 1997 to 2012, were obtained from the São Paulo Population Based Cancer Registry. Information on the number of inhabitants of the Municipality were obtained online through the website of the SUS Department of Informatics. To evaluate the trend of lymphoma incidence during the period, according to sex and age group, generalized linear models (GLM) were adjusted. The age-period-cohort (APC) model was used to evaluate the influence of age, diagnosis period and birth cohorts on the trend of lymphoma incidence. Results and conclusions: Of the 18,037 cases analyzed, 20.5% were HL type and 79.5% NHL type. Among the cases of HL, 52.6% were men and 70.0% were between 20 and 39 years old. The age-standardized incidence rate of HL per 100,000 population ranged from 5.0 in 1997 to 4.0 in 2012, however, no significant trend in incidence over time was detected (p> 0.05). The risk of developing HL was greater in males than in females only in the age group 0 to 14 years (p <0.001), in the others, the risk was similar for both sexes (p> 0.05). The risk of developing HL according to the age group presented a bimodal age pattern. In females, the highest risks occurred in the 20-39 and 65-year-olds, and in the male, in the 15-19 and 65 years and older ranges. The APC model pointed to an influence of the birth cohort on the incidence of HL in women: for those born before 1960, the older the cohort, the higher the risk of HL; for those born after 1960, the relative risk remained stable. Among the cases of NHL, 51.6% were men and 77.4% were over 40 years old. The age-standardized incidence rate of NHL per 100,000 population increased from 22.6 in 1997 to 17.0 in 2012. A trend of a decrease in the incidence of NHL of 1.7% per year was observed in all ranges in both sexes (p <0.001). The risk of developing NHL increased steadily with advancing age in both sexes. The APC model did not detect period effects. For men, older cohorts are at higher risk, and younger cohorts are at lower risk. For women born before 1960 the behavior was similar to that of men, for those born after 1960, the relative risk remained stable.

Introdução: Os linfomas abrangem um grupo heterogêneo de neoplasias originadas no sistema linfático, diferentes quanto à sua histologia, prognóstico e epidemiologia, embora possa haver grande número de aspectos clínicos comuns. De acordo com sua morfologia, dividem-se dois grupos: os linfomas Hodgkin (LH) e os linfomas não-Hodgkin (LNH). Objetivo: Avaliar a tendência temporal da incidência de linfomas no período de 1997 a 2012, identificando a influência de fatores como o sexo, a idade, o período e a coorte e nascimento. Metodologia: Trata-se de um estudo ecológico. Foram obtidas, do Registro de Câncer de Base Populacional de São Paulo (RCBP-SP), informações sobre todos os casos novos de linfomas no Município de São Paulo, diagnosticados no período de 1997 a 2012. Informações sobre o número de habitantes do Município foram obtidas online através do site do Departamento de Informática do SUS. Para avaliar a tendência da incidência de linfomas no decorrer do período, segundo sexo e faixa etária, foram ajustados modelos lineares generalizados (MLG). Para avaliar a influência da idade, do período de diagnóstico e das coortes de nascimento na tendência da incidência dos linfomas, foi utilizado o modelo idade-período-coorte (IPC). Resultados e conclusões: Dos 18.037 casos analisados, 20,5% eram do tipo LH e 79,5% do tipo LNH. Entre os casos de LH, 52,6% eram homens e 70,0% tinham entre 20 e 39 anos. A taxa de incidência de LH padronizada por idade, por 100 mil habitantes, variou de 5,0 em 1997 para 4,0 em 2012, entretanto, não foi detectada nenhuma tendência significativa na incidência ao longo do tempo (p>0,05). O risco de desenvolver LH foi maior no sexo masculino do que no feminino apenas na faixa etária de 0 a 14 anos (p<0,001), nas demais, o risco foi semelhante para ambos os sexos (p>0,05). O risco de desenvolver LH segundo a faixa etária apresentou um padrão etário bimodal. No sexo feminino, os maiores riscos ocorreram nas faixas de 20 a 39 e de 65 anos e mais e, no masculino, nas faixas de 15 a 19 e de 65 anos e mais. O modelo IPC apontou uma influência da coorte de nascimento na incidência de LH em mulheres: para aquelas nascidas antes de 1960, quanto mais antiga a coorte, maior o risco de LH; para as nascidas após 1960, o risco relativo permaneceu estável. Entre os casos de LNH, 51,6% eram homens e 77,4% tinham mais de 40 anos. A taxa de incidência de LNH padronizada por idade, por 100 mil habitantes, passou de 22,6 em 1997 para 17,0 em 2012. Foi detectada uma tendência de decréscimo na incidência de LNH de 1,7% ao ano em todas as faixas etárias, em ambos os sexos (p<0,001). O risco de desenvolver LNH aumentou continuamente com o avançar da idade, em ambos os sexos. O modelo IPC não detectou efeitos de período. Para os homens, as coortes mais velhas apresentam maior risco e, as mais jovens, menor risco. Para as mulheres nascidas antes de 1960 o comportamento foi semelhante ao dos homens, para as nascidas após 1960, o risco relativo permaneceu estável. / Introduction: Lymphomas comprise a heterogeneous group of neoplasias originating in the lymphatic system, different in their histology, prognosis and epidemiology, although there may be a large number of common clinical aspects. According to their morphology, two groups are divided: Hodgkin\'s lymphomas (HL) and non-Hodgkin\'s lymphomas (NHL). Objective: To evaluate the temporal trend of the incidence of lymphomas in the period from 1997 to 2012, identifying the influence of factors such as sex, age, period and cohort and birth. Methodology: This is an ecological study. Information about all new cases of lymphomas in the city of São Paulo, diagnosed in the period from 1997 to 2012, were obtained from the São Paulo Population Based Cancer Registry. Information on the number of inhabitants of the Municipality were obtained online through the website of the SUS Department of Informatics. To evaluate the trend of lymphoma incidence during the period, according to sex and age group, generalized linear models (GLM) were adjusted. The age-period-cohort (APC) model was used to evaluate the influence of age, diagnosis period and birth cohorts on the trend of lymphoma incidence. Results and conclusions: Of the 18,037 cases analyzed, 20.5% were HL type and 79.5% NHL type. Among the cases of HL, 52.6% were men and 70.0% were between 20 and 39 years old. The age-standardized incidence rate of HL per 100,000 population ranged from 5.0 in 1997 to 4.0 in 2012, however, no significant trend in incidence over time was detected (p> 0.05). The risk of developing HL was greater in males than in females only in the age group 0 to 14 years (p <0.001), in the others, the risk was similar for both sexes (p> 0.05). The risk of developing HL according to the age group presented a bimodal age pattern. In females, the highest risks occurred in the 20-39 and 65-year-olds, and in the male, in the 15-19 and 65 years and older ranges. The APC model pointed to an influence of the birth cohort on the incidence of HL in women: for those born before 1960, the older the cohort, the higher the risk of HL; for those born after 1960, the relative risk remained stable. Among the cases of NHL, 51.6% were men and 77.4% were over 40 years old. The age-standardized incidence rate of NHL per 100,000 population increased from 22.6 in 1997 to 17.0 in 2012. A trend of a decrease in the incidence of NHL of 1.7% per year was observed in all ranges in both sexes (p <0.001). The risk of developing NHL increased steadily with advancing age in both sexes. The APC model did not detect period effects. For men, older cohorts are at higher risk, and younger cohorts are at lower risk. For women born before 1960 the behavior was similar to that of men, for those born after 1960, the relative risk remained stable.

BACKGROUND:Marek's Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2 / MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the non-neoplastic cells (CD30lo) form the majority of population. MD is a unique natural in-vivo model of human CD30hi lymphomas with both natural CD30hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30lo expressing phenotype to CD30hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling / we compare the global gene expression of CD30lo and CD30hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-kappaB) family and CD30 / we also identify a novel Meq protein interactome.RESULTS:Our results show that a) CD30lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes / b) multiple transformation mechanisms exist and are potentially controlled by Meq / c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-kappaB, and, in turn, increases Meq transcription / d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis.CONCLUSIONS:In the context of the MD lymphoma microenvironment (and potentially in other CD30hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-kappaB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

abstract / Medicine / Doctoral / Doctor of Philosophy

No description available.

Orientador: Maria Aparecida Custódio Domingues / Banca: Flavio de Oliveira Lima / Banca: Gilson Luchese Delgado / Resumo: O Sarcoma Histiocítico (SH) é uma neoplasia maligna caracterizada pela proliferação de células grandes que possuem aspecto morfológico e imunofenotípico semelhantes ao histiócito maduro tecidual. É uma neoplasia rara, perfazendo menos que 1% dos Linfomas Não-Hodgkin. Tal raridade pode ser explicada pela dificuldade de sua caracterização diagnóstica e morfológica, confundindo-se com outras neoplasias malignas pleomórficas. Os objetivos do presente estudo são: avaliar alterações no padrão de ganhos e perdas genômicas pela técnica de Hibridação Genômica Comparativa (CGH-array), avaliação do perfil de MicroRNA (miRNA), apontar os principais critérios morfológicos e marcadores imunoistoquímicos (IMH) que venham a definir esta entidade e identificar quais entidades que erroneamente podem levar a subdiagnostico.Para tanto, foram revisados 7.600 laudos anatomopatológicos e, destes, foram selecionados 47 casos possíveis de SH, com apresentação nodal. Somando-se a estes, quatro casos sabidamente com diagnóstico de SH foram incluídos na análise. Foram avaliados 12 critérios morfológicos e 05 marcadores IMH. Dos 47 casos, foram localizados 07 SH, cujo diagnóstico inicial foi de neoplasia indiferenciada metastática (carcinoma indiferenciado) ou melanoma metastático. Os marcadores IMH que se mostraram mais eficientes para complementação diagnóstica foram CD163 e CD68. A avaliação do perfil de 377 miRNAs demonstrou clusterização de 51 miRNA, quando comparado ao controle, sendo 44 hipoexpresssos e 07 hiperexpressos, sendo os mais relevantes: miR-10b-5p, miR-455-5p e miR-19 (hiperexpressos); miR-486-5p, miR-92a, miR-15b-5p (hiporegulados). Tais miRNA estão envolvidos nas vias da apoptose, crescimento e proliferação celular. Os principais genes envolvidos na patogenia e candidatos a validação com futuros estudos são: ERBB2, TGFB1,TNF(ativados) e TP53 e PD98059 (inibidos).Tais genes podem corresponder a futuros... / Abstract: Histiocytic sarcoma (HS) is a malignant neoplasm characterized by the proliferation of large cells that have morphological and immunophenotypic features similar to mature tissue histiocytes. It is a rare neoplasm, accounting for less than 1% of non-Hodgkin lymphomas. This rarity is partly explained by the difficulties in its diagnostic and morphological characterization, since it is confused with other pleomorphic malignant neoplasms. The objectives of this study were to evaluate changes in genomic gains and losses using the comparative genomic hybridization technique (CGH-array), microRNA profile (miRNA) evaluation, determine the principal morphological criteria and immunohistochemical markers (IMH) that could define this entity, and identify entities that can mistakenly lead to underdiagnosis. To achieve this, 7,600 pathology reports were reviewed and, of these, 47 possible cases of HS with nodal presentation were selected. Four cases with an established diagnosis of HS were also included in the analysis. Twelve morphological criteria and 5 IMH markers were evaluated. Among the 47 cases, 7 cases of HS were identified that had initially been diagnosed as undifferentiated metastatic neoplasm (undifferentiated carcinoma) or metastatic melanoma. The IMH markers that were most efficient for complementary diagnosis were CD163 and CD68. Evaluation of the profiles of 377 miRNAs showed clustering of 51 miRNA compared with the control; 44 were hypoexpressed and 7 were hyperexpressed and the most relevant were: miR-486-5p, miR-92a, miR-15b-5p (hyporegulated); and miR-10b-5p, miR-455-5p and miR-19 (hyperexpressed). These miRNA are involved in apoptosis, cell growth and proliferation pathways. The main genes involved in pathogenesis and candidates for validation in future studies are: ERBB2, TGFB1, TNF (activated); and TP53 and PD98059 (inhibited). These genes may represent future therapeutic targets. The CGH-array proved to be unfeasible in ... / Mestre

Thesis--M. Med. Sc., University of Hong Kong, 1986. / Photocopy from typescript.