RESUMO
OBJECTIVE: To analyze determinants of prognosis in patients with bronchial carcinoid tumors treated surgically and the potential concomitance of such tumors with second primary neoplasms. METHODS: This was a retrospective analysis of 51 bronchial carcinoid tumors treated surgically between 2007 and 2016. Disease-free survival (DFS) was calculated by the Kaplan-Meier method, and determinants of prognosis were evaluated. Primary neoplasms that were concomitant with the bronchial carcinoid tumors were identified by reviewing patient charts. RESULTS: The median age was 51.2 years, 58.8% of the patients were female, and 52.9% were asymptomatic. The most common histology was typical carcinoid (in 80.4%). Five-year DFS was 89.8%. Ki-67 expression was determined in 27 patients, and five-year DFS was better among the patients in whom Ki-67 expression was ≤ 5% than among those in whom it was > 5% (100% vs. 47.6%; p = 0.01). Concomitant primary neoplasms were observed in 14 (27.4%) of the 51 cases. Among the concomitant primary neoplasms that were malignant, the most common was lung adenocarcinoma, which was observed in 3 cases. Concomitant primary neoplasms were more common in patients who were asymptomatic and in those with small tumors. CONCLUSIONS: Surgical resection is the mainstay treatment of bronchopulmonary carcinoid tumors and confers a good prognosis. Bronchial carcinoid tumors are likely to be accompanied by second primary neoplasms.
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Neoplasias Brônquicas/cirurgia , Tumor Carcinoide/cirurgia , Segunda Neoplasia Primária/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/patologia , Tumor Carcinoide/patologia , Intervalo Livre de Doença , Feminino , Humanos , Antígeno Ki-67/análise , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Adulto JovemRESUMO
ID genes have an important function in the cell cycle, and ID proteins may help identify aggressive tumors, besides being considered promising therapeutic targets. However, their role in thyroid tumors is still poorly understood. We examined ID expression and their correlation with diagnostic and prognostic features aiming to find a clinical application in differentiated thyroid carcinoma (DTC) cases. mRNA levels of ID1, ID2, ID3, and ID4 genes were quantified and their expression was observed by immunohistochemistry in 194 thyroid samples including 68 goiters, 16 follicular adenomas, 75 classic papillary thyroid carcinomas, 18 follicular variants of papillary thyroid carcinoma, 5 follicular thyroid carcinomas, and 1 anaplastic thyroid cancer, besides 11 normal thyroid tissues. DTC patients were managed according to standard protocols and followed up for M = 28 ± 16 months. ID2, ID3, and ID4 mRNA levels were higher in benign (2.0 ± 1.9; 0.6 ± 0.6; and 0.7 ± 1.0 AU, respectively) than those in malignant nodules (0.30 ± 0.62; 0.3 ± 0.3; and 0.2 ± 0.3 AU, respectively, p < 0.0001 for all three genes) and were associated with no extra thyroid invasion or metastasis at diagnosis. ID3 nuclear protein expression was higher in benign than that in malignant cells (5.2 ± 0.9 vs 3.0 ± 1.8 AU; p < 0.0001). On the contrary, the cytoplasmic expression of ID3 was higher in malignant than that in benign lesions (5.7 ± 1.5 vs 4.0 ± 1.4 AU; p < 0.0001). Our data indicate that ID genes are involved in thyroid tumorigenesis and suggest these genes act impeding the evolution of more aggressive phenotypes. The different patterns of their tissue expression may help identify malignancy and characterize thyroid lesion aggressiveness.
Assuntos
Adenocarcinoma Folicular/metabolismo , Adenoma/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Invasividade Neoplásica/patologia , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adenocarcinoma Folicular/patologia , Adenoma/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
ABSTRACT Objective: To analyze determinants of prognosis in patients with bronchial carcinoid tumors treated surgically and the potential concomitance of such tumors with second primary neoplasms. Methods: This was a retrospective analysis of 51 bronchial carcinoid tumors treated surgically between 2007 and 2016. Disease-free survival (DFS) was calculated by the Kaplan-Meier method, and determinants of prognosis were evaluated. Primary neoplasms that were concomitant with the bronchial carcinoid tumors were identified by reviewing patient charts. Results: The median age was 51.2 years, 58.8% of the patients were female, and 52.9% were asymptomatic. The most common histology was typical carcinoid (in 80.4%). Five-year DFS was 89.8%. Ki-67 expression was determined in 27 patients, and five-year DFS was better among the patients in whom Ki-67 expression was ≤ 5% than among those in whom it was > 5% (100% vs. 47.6%; p = 0.01). Concomitant primary neoplasms were observed in 14 (27.4%) of the 51 cases. Among the concomitant primary neoplasms that were malignant, the most common was lung adenocarcinoma, which was observed in 3 cases. Concomitant primary neoplasms were more common in patients who were asymptomatic and in those with small tumors. Conclusions: Surgical resection is the mainstay treatment of bronchopulmonary carcinoid tumors and confers a good prognosis. Bronchial carcinoid tumors are likely to be accompanied by second primary neoplasms.
RESUMO Objetivo: Analisar os determinantes do prognóstico em pacientes com tumores carcinoides brônquicos tratados cirurgicamente e possível segunda neoplasia primária concomitante. Métodos: Trata-se de uma análise retrospectiva de 51 tumores carcinoides brônquicos tratados cirurgicamente entre 2007 e 2016. A sobrevida livre de doença (SLD) foi calculada pelo método de Kaplan-Meier, e os determinantes do prognóstico foram avaliados. As neoplasias primárias concomitantes aos tumores carcinoides brônquicos foram identificadas por meio da análise dos prontuários dos pacientes. Resultados: A mediana de idade foi de 51,2 anos, 58,8% dos pacientes eram do sexo feminino e 52,9% eram assintomáticos. A classificação histológica mais comum foi carcinoide típico (em 80,4%). A SLD em cinco anos foi de 89,8%. A expressão de Ki-67 foi determinada em 27 pacientes, e a SLD em cinco anos foi melhor nos pacientes nos quais a expressão de Ki-67 foi ≤ 5% do que naqueles nos quais a expressão de Ki-67 foi > 5% (100% vs. 47,6%; p = 0,01). Neoplasias primárias concomitantes foram observadas em 14 (27,4%) dos 51 casos. Entre as neoplasias primárias malignas concomitantes, a mais comum foi o adenocarcinoma pulmonar, observado em 3 casos. Neoplasias primárias concomitantes foram mais comuns em pacientes assintomáticos e naqueles com tumores pequenos. Conclusões: A resseção cirúrgica é o principal tratamento de tumores carcinoides broncopulmonares e propicia um bom prognóstico. É provável que tumores carcinoides brônquicos se relacionem com segunda neoplasia primária.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Neoplasias Brônquicas/cirurgia , Tumor Carcinoide/cirurgia , Segunda Neoplasia Primária/cirurgia , Fatores de Tempo , Neoplasias Brônquicas/patologia , Tumor Carcinoide/patologia , Estudos Retrospectivos , Segunda Neoplasia Primária/patologia , Estatísticas não Paramétricas , Intervalo Livre de Doença , Antígeno Ki-67/análise , Tempo de InternaçãoRESUMO
The epidemiology of classical Hodgkin lymphoma varies significantly in populations with different socioeconomic conditions. Among other changes, improvement in such conditions leads to a reduction in the association with EBV infection and predominance of the nodular sclerosis subtype. This study provides an overview of the epidemiology of 817 cases of classical Hodgkin lymphoma diagnosed in five reference hospitals of the State of Sao Paulo, Brazil, over 54 years (1954-2008). The cases were distributed in 3 periods (1954-1979; 1980-1999; and 2000-2008). EBV-positive cases decreased from 87% to 46%. In children and adolescents (<15 years) and in young adults (15-45 years), EBV-positive cases decreased respectively from 96% to 64%, and from 85% to 32%. The percentage of male patients declined from 80% to 58%. In older patients (>45 years), the decrease in EBV infection was not significant. Nodular Sclerosis was the most common subtype in all periods. These results support the hypothesis that, in the Brazilian State of Sao Paulo, classical Hodgkin lymphoma has changed and now shows characteristics consistent with Pattern III observed in populations that experienced a similar socioeconomic transition.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
Cancer is rapidly growing to be one of the major health burdens in Brazil and Latin America. Access to tumor samples is one of the many barriers that need to be removed in order to promote clinical and translational research aimed at developing and improving cancer prevention and treatment in this region. Although there is a growing interest in establishing tumor collections in many hospitals and institutions, success is limited by the lack of knowledge of the complexities of this activity. This article reviews the regulatory, pathology, and molecular aspects that are relevant to the establishment of tumor banks in Brazil and Latin America. It also provides an overview of key players in the region (AU)
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Humanos , Brasil , Biologia Celular , Genes/genética , América LatinaRESUMO
Brazil and Latin America will face a cancer epidemic in the coming years. Efforts towards cancer prevention, early detection and treatment must be associated with active research that helps understanding the geographical variations of this disease. The creation of cancer-oriented biobanks should be part of this strategy. This article outlines the challenges of establishing a cancer-oriented biobank at the A. C. Camargo Center, a private, non-profit institution located in Sao Paulo, Brazil. We analyze important issues related to the day-to-day operations of the biobank within an institutional and national context, as well as the lessons learned over the years. It is hoped that the information contained in this paper will be useful for the development of other biobanks in Brazil and other countries in Latin America.
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Bancos de Espécimes Biológicos , Neoplasias/diagnóstico , Bancos de Espécimes Biológicos/ética , Bancos de Espécimes Biológicos/normas , Brasil , Humanos , Controle de QualidadeRESUMO
Whole-transcriptome evaluation by next-generation sequencing (NGS) has been widely applied in the investigation of diverse transcriptional scenarios. In many clinical situations, including needle biopsy samples or laser microdissected cells, limited amounts of RNA are usually available for the assessment of the whole transcriptome. Here, we describe an mRNA amplification protocol based on in vitro T7 transcription for transcriptome evaluation by NGS. Initially, we performed RNAseq from two human mammary epithelial cell lines and evaluated several aspects of the transcriptomes generated by linear amplification of Poly (A)(+) mRNA species, including transcript representation, variability and abundance. Our protocol showed to be efficient with respect to full-length transcript coverage and quantitative expression levels. We then evaluated the applicability of using this protocol in a more realistic research scenario, analyzing tumor tissue samples microdissected by laser capture. In order to increase the quantification power of the libraries only the 3' end of transcripts were sequenced. We found highly reproducible RNAseq data among amplified tumor samples, with a median Spearman's correlation of 80%, strongly suggesting that the amplification step and library protocol preparation lead to a consistent transcriptional profile. Altogether, we established a robust protocol for assessing the polyadenylated transcriptome derived from limited amounts of total RNA that is applicable to all NGS platforms.
Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias da Mama/genética , Linhagem Celular , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , RNA Mensageiro/genéticaRESUMO
Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) "clinical-pathological AD" (CP-AD)--subjects with neuropathological AD (Braak ≥ IV and CERAD = B or C) and clinical dementia (CDR ≥ 2, IQCODE>3.8); II) "pathological AD" (P-AD)--subjects with neuropathological AD (Braak ≥ IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) "normal aging" (N)--subjects without neuropathological AD (Braak ≤ II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.
Assuntos
Doença de Alzheimer/patologia , Apoptose , Dano ao DNA , Reparo do DNA , Neurônios/fisiologia , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Ciclo Celular , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Estresse Oxidativo , Análise Serial de Tecidos , TranscriptomaRESUMO
Chordomas are rare neoplasms arising from notochord remnants. Tyrosine kinase receptors (RTK) are altered in these lesions. We used a tissue microarray containing 58 chordomas to examine the expression of platelet-derived growth factor receptor (PDGFR)-α and PDGFR-ß, epidermal growth factor receptor (EGFR), c-Met, c-Kit, pAKT, mammalian target of rapamycin, and HER2 by immunohistochemistry and fluorescence in situ hybridization. Most tumors were positive for PDGFR-α (92%), PDGFR-ß (85%), c-Kit (77.4%), c-Met (96%), pAKT (82%), mammalian target of rapamycin (56%), HER2 (24%), and EGFR (26%) by immunohistochemistry. Amplifications or deletions could not be identified for HER2 or EGFR in the 13 cases available for fluorescence in situ hybridization analysis; however, chromosome 7 polysomy was detected in 29% of the cases. The only factor directly associated with a poorer survival rate was pAKT positivity (P = .042). The 5-year survival rate for patients with pAKT-negative chordomas was 100%, whereas it was 45% for patients with pAKT-positive chordomas. Our results confirm that RTKs are frequently altered in chordomas. Given the implications of pAKT positivity, RTK inhibitors might be efficacious, and drugs that inhibit AKT, alone or in combination with radiotherapy, could be an effective treatment for patients with refractory chordomas.
Assuntos
Cordoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias da Coluna Vertebral/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Brasil/epidemiologia , Criança , Pré-Escolar , Cordoma/genética , Cordoma/mortalidade , Cordoma/patologia , Cromossomos Humanos Par 7 , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/patologia , Taxa de Sobrevida , Análise Serial de Tecidos , Adulto JovemRESUMO
This article discusses the importance of biobanking to health research advancement in developing countries by analyzing the impact of the establishment of a tumor bank at the A C Camargo Hospital, a cancer care and research center located in Sao Paulo, Brazil. For the past 13 years, the human biological samples provided by the tumor bank have been used by investigators to study various types of cancer. We analyze the impact of biobanking in the overall quality of research projects performed at our institution. We also summarize the main findings of these investigations focusing on breast, prostate, head-neck, and gastroesophageal tumors, as well as the lessons learned over these years. We conclude that biobanking should be part of the strategy employed by scientists and research institutions dedicated to the study of human diseases.
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The development of locoregional recurrence is the main reason for treatment failure in head and neck squamous cell carcinomas (HNSCC) and the remaining of tumor cells in surgical margins is associated with recurrence. Surgical margins are considered negative based on histologic assessment of the pathological specimen. However, this method lacks sensitivity in identifying cells that already started malignant transformation but have not yet developed a pathologic phenotype. We investigated the usefulness of assessing the expression of PTHLH, EPCAM, MMP9, LGALS1 and MET for the detection of molecular alterations in histologically negative surgical margins and determine the correlation of these tumor-related alterations with clinical and prognostic parameters. Differential gene expression was determined by quantitative RT-PCR analyses in normal mucosa, HNSCC and negative margin samples. Thirty-eight percent of the histologically negative surgical margins examined were margin-positive for overexpression of at least one of the genes evaluated. Moreover, MMP9 and PTHLH overexpression in the surgical margins was associated with the development of second primary tumors (p=0.002) and lower rates of local control (log rank test p=0.022; HR=4.186; p=0.035), respectively. These findings demonstrate that the overexpression of tumor-related genes in histologically negative surgical margins is a frequent event. The use of qRT-PCR may be an useful tool in detecting actually negative HNSCC surgical margins and the overexpression of specific genes in these margins could be helpful in the identification of patients with a higher risk of developing second primary tumors and local recurrences, thus aiding the surgeon in the delineation of the HNSCC resection extent and helping in the planning of adjuvant therapy.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , Neoplasia Residual/genética , Segunda Neoplasia Primária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Moléculas de Adesão Celular/metabolismo , Molécula de Adesão da Célula Epitelial , Seguimentos , Galectina 1/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estudos RetrospectivosRESUMO
O linfoma de Hodgkin clássico é uma neoplasia linfóide monoclonal caracterizada pela presença de raras células de Hodgkin e Reed-Sternberg em meio a um infiltrado inflamatório abundante constituído por linfócitos, eosinófilos, plasmócitos, macrófagos e neutrófilos. Aspectos específicos da patogênese desta neoplasia, particularmente as alterações que impedem a entrada das células neoplásicas em apoptose, não são ainda totalmente conhecidos... Material e métodos. Foram utilizadas 3 linhagens celulares negativas para o EBV (L428, L1236 e KM-H2) e uma linhagem positiva (L591), gentilmente cedidas pelo Prof. Dr. Harald Stein, e 10 amostras de tecido fresco congelado envolvidas por linfoma de Hodgkin clássico, fornecidas pelo Banco de Tumores do Hospital A C Camargo... Blocos de parafina contendo material conservado em formalina de 148 casos de LHC foram selecionados do arquivo do Departamento de Patologia do Centro de Tratamento e Pesquisa Hospital A C Camargo, São Paulo, Brasil, no período de 1970 a 2005... Resultados. Foi observada expressão diferencial de 756 genes, que após análise funcional se agruparam em diversos grupos relevantes, incluindo os grupos de genes relacionados à sinalização célula-célula, ao desenvolvimento do sistema imune, envolvidos na regulação da via de NFkB, e quimiotaxia... Conclusões. Os resultados do presente estudo sugerem a capacidade das CHRS de explorarem diversas vias de sinalização para alterar seu ciclo-celular e controle mitótico, assim como evadir ao sistema de imunovigilância do organismo...
Background. Classical Hodgkin lymphoma is a monoclonal lymphoid neoplasm whose hallmark is the Reed-Sternberg cell and its variants, which are surrounded by an inflamatory background. Although extensively studied, many aspects of its pathogenesis, especially those involving the programmed cell death pathway, are still not understood. The role of Epstein-Barr virus (EBV), which is detected in approximately 50% of Hodgkin lymphomas, is also not well established. Although data on EBV association with clinical outcome of Hodgkin lymphoma patients are controversial, some studies suggest that the cases in which EBV is detected follow a different pathway leading to apoptosis blockage.This can stimulate the search for new treatments based on the presence or absence of EBV. Studies employing differential gene expression techniques can add new information to help solving these questions. Objective. This study analyzed the gene expression pattern of Hodgkin cell lines and tissues involved by classical Hodgkin lymphoma, comparing the differences related to the presence or absence of Epstein-Barr virus infection. Additionally, a Tissue Microarray containing cases of classical Hodgkin lymphoma was constructed to validate the protein expression of some of the genes observed in the analysis, comparing the results with Epstein-Barr status and clinical outcome of the patients. Materials and methods. Three EBV-negative Hodgkin cell lines (L428, L1236 e KM-H2), one EBV-positive Hodgkin cell line (L591), and 10 classical Hodgkin lymphoma frozen tissue samples were used in the gene expression analysis study. Following total RNA extraction, cRNA probes were hybridized in oligoarray glass slides. Data from the image acquisition were submitted to quality control pre-analysis prior to bioinformatic statistical analysis for gene clustering experiments and functional analysis. Paraffin-blocks from 148 retrospective cases of classical Hodgkin Lymphoma, diagnosed between 1970 and 2005, were retrieved from the archives of the Department of Pathology. Cases without enough formalin-fixed and paraffin-embedded tissue to run the immunohistochemical (IHC) reactions, relapse biopsies and HIVassociated HL were excluded. Histological diagnosis was revised, with the use of immunostains when necessary. A tissue microarray was built and immunostains performed with antibodies against Aurora-B, Caspase-1, Caveolin-1, CCL20, CDC2, MMP9 and LMP-1. Cases were also tested for EBV using "in situ" hybridization for "EBV early RNAs" (EBER-1). The reactions were analyzed and the results submitted to statistical analysis. Results. We observed that 756 genes are differentially expressed between EBV-positive and EBV-negative Hodgkin cell lines. These genes are functionally related to many relevant groups, such as cell-cell signaling, immune system development, NFkB regulation and chemotaxis. Some genes belonging to these groups were selected for immunoistochemical validation (Aurora-B, Caspase-1, Caveolin-1, CCL20, CDC2 and MMP9), whose protein expression was detected in 58,78%, 38,51%, 25,68%, 49,32%, 75,68% e 52,03% of the cases, respectively. CCL20 protein expression was specifically associated with EBV-infection (p<0,0001). Disease-specific survival rates of patients between 15 and 45 years who expressed Caspase-1 and MMP9 in neoplastic cells were significantly lower than those who did not express these markers. The expression of MMP9 by neoplastic cells was an independent prognostic factor is this group of patients. Conclusions. The results of this study suggest the ability of Hodgkin-ReedSternberg cells to explore different signaling pathways to control their cell-cycle and mitotic activity, as well as evade immunosurveillance, regulating different genes according to EBV infection status. CCL20 protein expression is associated with EBV infection in Hodgkin lymphoma cases. We also observed the expression of new proteins by Hodgkin-Reed-Sternberg cells, such as Caspase-1 and Caveolin-1. The expression of Caspase-1 and MMP9 by Hodgkin-Reed-Sternberg cells associates with a poor outcome in Hodgkin lymphoma patients between 15 and 45 years. MMP9 expression by neoplastic cells is an independent prognostic factor in this group of patients.
Assuntos
Humanos , Células de Reed-Sternberg , Doença de Hodgkin , Doença de Hodgkin/diagnóstico , Expressão Gênica , Patologia , Imuno-Histoquímica , ApoptoseRESUMO
A ocorrência de linfomas primários do trato genital feminino é rara. O diagnóstico normalmente não é possível pelo exame citológico, sendo necessária a biópsia do colo. Neste artigo, descrevemos duas pacientes encaminhadas ao nosso serviço por linfoma de colo uterino. Em uma delas, é claramente demonstrada a dificuldade diagnóstica que pode ocorrer nessa patologia. As duas pacientes foram tratadas com quimioterapia, apresentando evolução pós-operatória satisfatória. Não há um tratamento padrão para os linfomas de colo uterino. O tratamento local exclusivo é advogado por alguns estudos na literatura em estádio clínico IE, enquanto outros serviços optam pelo tratamento sistêmico em todos os estádios.
The occurrence of primary lymphomas of the female genital tract is rare. The diagnosis is usually not possible by the cytological examination; a tissue biopsy is necessary. The present paper reports two patients referred to our service with a diagnosis of cervical lymphoma. In one of them, the diagnostic difficulties are demonstrated. Both patients were submitted to chemotherapy with satisfactory post-operatory period. There is no standard treatment for uterine lymphomas. Exclusive local treatment is supported by some reports in the literature in clinical stage IE, while others prefer systemic treatment irrespective of clinical stage.
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Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Linfoma de Células B , Neoplasias do Colo do Útero , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapiaRESUMO
The occurrence of primary lymphomas of the female genital tract is rare. The diagnosis is usually not possible by the cytological examination; a tissue biopsy is necessary. The present paper reports two patients referred to our service with a diagnosis of cervical lymphoma. In one of them, the diagnostic difficulties are demonstrated. Both patients were submitted to chemotherapy with satisfactory post-operatory period. There is no standard treatment for uterine lymphomas. Exclusive local treatment is supported by some reports in the literature in clinical stage IE, while others prefer systemic treatment irrespective of clinical stage.
Assuntos
Linfoma de Células B , Neoplasias do Colo do Útero , Adulto , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapiaRESUMO
Introdução. O linfoma de Hodgkin (LH) é uma neoplasia caracterizada por uma minoria de elementos neoplásicos, chamados de células de Reed-Sternberg (CRS) e suas variantes, e uma mistura de células inflamatórias que infiltram a massa tumoral, incluindo linfócitos, eosinófilos, plasmócitos, histiócitos e fibroblastos. Estudos clínicos e biológicos nos últimos 20 anos demonstraram o LH é verdadeiramente um linfoma, constituído por duas entidades distintas: o LH forma predominância linfocitária nodular (LHPLN) e o LH Clássico (LHC). Além disso, forneceram evidências de que as CRS são derivadas de células B do centro germinativo que sofreram mutações defeituosas ("crippling" mutations) de seus genes de imunoglobulina, tornando-os não funcionais. Ao contrário de linfócitos normais, que entram em apoptose por não produzirem imunoglobulina ou por produzir imungolobulinas com baixa afinidade antigênica, as CRS, por mecanismos ainda não completamente elucidados, são capazes de escapar deste processo de morte celular programada. Diversos genes ligados à regulação da apoptose, como os genes da família bcl-2, fas, fasL, c-FLIP, NFkappaB, têm sido investigados no LH, alguns dos quais parecem ter influência na evolução clínica dos pacientes. O papel desempenhado pelo vírus de Epstein-Barr (EBV) no bloqueio da apoptose no LH também tem sido intensamente estudado. O óxido nítrico (ON) é uma molécula diatômica cuja participação na regulação de numerosos processos que governam a carcinogênese, como o estímulo à profileração, ocorrência de mutações, bloqueio de apoptose, indução da angiogênese e ocorrência de metástases, tem sido intensamente estudada. O ON é produzido por uma família de enzimas denominadas sintases do óxido nítrico (NOS). Um aumento da expressão dos genes que codificam NOS e da produção de ON tem sido demonstrado em diversas neoplasias humanas, incluindo cânceres de mama, estômago, cólon, bexiga, próstata, pulmão e neoplasias hematopoiéticas. Objetivos. O objetivo deste estudo é analisar a expressão das sintases do óxido nítrico (NOS1, NOS2), da nitrotirosina (evidência indireta da produção de óxido nítrico) e de proteínas associadas a apoptose (bcl-2, bax, p53, fas e fasL) no LHC, para testar a hipótese de que a produção de NOS e ON pelas CRS está envolvida na regulação defeituosa da apoptose nesta neoplasia. Foi estudada ainda a possível correlação destas moléculas com a infecção pelo EBV observada no LHC. Finalmente, pesquisou-se a capacidade das células L&H do LHPLN de produzir NOS e ON. Material e métodos. Blocos de parafina contendo material conservado em formalina de 238 casos de LHC foram selecionados do arquivo do Departamento de Patologia do Centro de Tratamento e Pesquisa Hospital do Câncer A C Camargo, São Paulo, Brasil, no período de 1980 a 2000. Foram excluídos casos com material insuficiente para realização do estudo, biópsias de recidiva e casos HIV-positivos. Após revisão histopatológica e, quando necessário, imunoistoquímica, foram submetidos a estudo imunoistoquímico utilizando anticorpos para NOS1, NOS2, nitrotirosina, bcl-2, bax, p53, fas, fasL e LMP1. Foi realizada ainda hibridização in situ com sonda contra o transcrito EBER-1 do vírus de Epstein-Barr. As lâminas foram analisadas e os resultados submetidos à análise estatística. Foram selecionados ainda 7 casos de LHPLN, que, após confirmação diagnóstica, foram submetidos a estudo imunoistoquímico utilizando anticorpos para NOS1, NOS2 e nitrotirosina. Resultados. Dos 238 casos iniciais de LHC, 171 foram selecionados para análise. A expressão de NOS1 e de NOS2 foi observada em 42.1% e 55% dos casos, respectivamente. A expressão de nitrotirosina foi observada em 18.7% dos casos. As expressões de bcl-2, bax, p53, fas, fasL e LMP1 foram observadas, respectivamente, em 35.1%, 44.4%, 44.4%, 93,6%, 5.8% e 49.7% dos casos. O transcrito EBER-1 foi detectado em 46.8% dos casos. Foram observadas associações estatisticamente significativas entre fas e sexo masculino (p=0.032), EBV (LMP-1 e EBER) e sexo masculino (p<0.0001), EBV (LMP-1 e EBER) e subtipo histológico celularidade mista (p<0.0001), EBV e estadios avançados (LMP-1, p=0.0459; EBER, p=0.011), EBV (EBER) e sintomas B (p=0.0481), bax e p53 (p=0.036), bax e fasL (p=0.046), NOS1 e p53 (p=0.006), bax e NOS2 (p=0.022); e entre bcl-2 e NOS2 (p=0.034). Correlação inversa foi observada entre EBV (LMP-1) e NOS2 (p=0.018) , e entre EBV e bcl-2 (LMP-1, p=0.002; EBER, p=0.006). Observou-se ainda uma diminuição da sobrevida global associada à forte expressão de NOS2 (p=0.0098). A forte expressão de NOS2 pelas CRS também foi fator associado a um pior prognóstico em casos tratados com o esquema quimioterápico MOPP/ABVD (p=0.0003). Com relação ao LHPLN, observou-se expressão de NOS1 e NOS2 pelas células L&H em 42.9% e 71.4% dos casos, respectivamente. Não se observou a expressão de nitrotirosina. Conclusões. Os resultados do presente estudo demonstraram a capacidade das CRS de expressarem NOS e produzirem ON, assim como de expressarem genes produtores de proteínas reguladoras do ciclo celular. As correlações observadas entre NOS e as proteínas associadas a apoptose sugerem o envolvimento das NOS e do ON no controle deste processo. Observou-se ainda que a expressão de NOS2 está associada a uma menor sobrevida global nos casos de LHC. Com relação ao LHPLN, demonstrou-se que as células L&H são capazes de produzir NOS1 e NOS2. Não foi possível demonstrar, entretanto, a produção de nitrotirosina..
Background. Hodgkin' s lymphoma (HL) is a neoplasm composed by a minority of neoplastic cells, named Hodgkin and Reed-Stemberg (H-RS) cells, set in an inflammatory background consisting of lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells and fibroblasts. Clinicai and biological studies over the past 20 years have concluded that HL is indeed a lymphoma, divided into 2 distinct entities: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classical Hodgkin lymphoma (CHL ). Furthermore, they gave evidence that H-RS cells are derived from germinai center B cells with rearranged immunoglobulin genes bearing crippling mutations. Unlike normal B lymphocytes, which suffer apoptosis when failing to produce immunoglobulins, or producing low-antigenic affinity immunoglobulins, H-RS cells, by tnechanisms not fully understood, are capable of escaping apoptotic cell death. Many apoptotic regulators, such as bcl-2 family members, fas, fasL, c-FLIP, and NFkappaB, have been investigated in HL, some of which appearing to influence the clinicai outcome o f HL patients. The role o f EBV in the resistance to apoptotic cell death o f H-RS cells has also been under study. Nitric oxide (NO) is a diatomic molecule involved in multiple steps of carcinogenesis, such as DNA mutations, proliferation, blockage of apoptosis and angiogenic stimulation. NO is produced by a family of enzymes known as the nitric oxide synthases (NOS). NOS gene overexpression and NO production have been observed in many human tumors from various sites such as the breast, stomach, colon, bladder, prostate, lung and the haematopoietic system. Objective. The purpose o f this study was to analyze the role o f NOS (NOS 1, NOS2) and apoptosis-associated proteins expression in HL, to test the hypothesis that NOS and NO production by H-RS cells are involved in the deffective apoptotic program of this neoplasm. We also investigated the role of EBV expression in HL on NOS expression and NO production. Finally, we investigated if L&H cells of NLPHL could produce NOS and NO. Material and methods. 238 retrospective cases of HL, diagnosed between 1980 and 2000, were retrieved from the archives o f the Departamento de Patologia do Centro de Pesquisa do Hospital do Câncer A C Camargo. Cases without enough formalin-fixed and paraffin-embedded tis sue to run the immunohistochemical (IH C) reactions, relapse biopsies and HIVassociated HL were excluded. Histological diagnosis was revised, with the use of immunostains when necessary. Immunostains with antibodies against NOS 1, NOS2, nitrotyrosine, bcl-2, bax, p53, fas, fasL and LMP1 were performed. Cases were also tested for EBV presence using in situ hybridization for EBV early RNAs (EBER). We also selected 7 cases diagnosed as NLPHL, which were tested for NOS 1, NOS2 and nitrotyrosine expression. Results. A total o f 171 cases from the original 23 8 cases collected were available for analysis. NOS 1 and NOS 2 expression were detected in 42.1% and 55% of the cases, respectively. Nitrotyrosine expression was observed in 18.7% ofthe cases. Bcl-2, bax, p53, fas, fasL and LMP1 expression were observed in 35.1 %, 44.4%, 44.4%, 93,6%, 5.8% e 49.7o/o of the cases, respectively. The EBER-1 transcript was detected in 46.8% of the cases. Significant associations were established between fas and male gender (p=0.032), EBV (LMP-1 e EBER) and male gender (p<0.0001), EBV (LMP-1 e EBER) and mixed cellularity subtype (p<0.0001), EBV and late stages ofthe disease (LMP-1, p=0.0459; EBER, p=0.011 ), EBV (EBER) and B symptons (p=0.0481), bax and p53 (p=0.036), bax and fasL (p=0.046), NOS1 and p53 (p=0.006), bax and NOS2 (p=0.022); and between bcl-2 e NOS2 (p=0.034). An inverse correlation was observed between EBV (LMP-1) and NOS2 (p=0.018), and between EBV and bcl-2 (LMP-1, p=0.002; EBER, p=0.006). Strong NOS2 expression was associated with a shorter overall survival (p=0.0098). It also predicted a poor prognosis in those cases treated with MOPP/ ABVD (p=0.0003). Regarding NLPHL, NOS1 and NOS2 expression by L&H cells was detected in 42.9% and 71.4% ofthe cases, respectively. Nitrotyrosine expression was not detected. Conclusions. We conclude that H-RS cells are capable of expressing NOS and producing NO. They are also capable of producing many apoptosisassociated proteins. The correlations observed between NOS and apoptosisassociated proteins suggest that NOS and NO are involved in the defective apoptotic program of HL. Strong NOS2 expression is associated with a poor outcome in HL. We also conclude that L&H cells ofNLPHL express NOSI and NOS2. Nitrotyrosine expression, however, could not be established.