Bronchial carcinoid tumors: second primary neoplasms and outcomes of surgical treatment / Tumores carcinoides brônquicos: segunda neoplasia primária e desfechos do tratamento cirúrgico

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.

Tumor banking for health research in Brazil and Latin America: time to leave the cradle

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)

Inflammatory pseudotumor-like follicular dendritic cell tumor: an underdiagnosed neoplasia

Follicular dendritic cell (FDC) tumor is an uncommon neoplasm. It generally presents as a slow-growing, painless mass, without systemic symptoms. Histological features usually include low grade spindle cell proliferation. This tumor occurs primarily in lymph nodes, especially cervical and axillary, however, involvement of extranodal sites such as the tonsils, spleen, liver, and gastrointestinal tract has been reported. Inflammatory pseudotumor-like follicular dendritic cell tumor (IPT-like FDCT) is a rare, distinctive histological subtype of this low-grade malignant neoplasm, with consistent Epstein-Barr virus (EBV) association. The differential diagnosis with other fibro-inflammatory tumor proliferations, as inflammatory pseudotumor (IPT) and inflammatory myofibroblastic tumor (IMT), may be challenging. In the present article, two cases of IPT-like FDCT of the spleen are presented, with a broad overview of the literature: one 77-year-old male and one 70-year-old female. A large immunohistochemical panel should be used for diagnosis, as no single specific and totally sensitive markers are available, including markers for CD21, CD23, CD35, CNA42, and clusterin. Individual cases may express one or more of these markers, so that all of them should be investigated. In situ hybridization for EBV is constantly positive. Immunostaining for ALK should be negative, as it is present in roughly half of the cases of IMT. This panel should be used in combination of clinical, laboratory, and topographic evidences. Importantly, inclusion of this lesion as a possible option in clinical and pathological investigation represents the basis for a correct diagnosis (AU)

Biobanking for health research in Brazil: present challenges and future directions / Bancos de materiales biológicos para la investigación en salud en el Brasil: retos actuales y perspectivas futuras

This article outlines and discusses Brazil's new regulations on the use of human biological materials for research, specifically, Resolution CNS 441/11, enacted by the National Health Council of Brazil in May 2011, and the National Guidelines for Biorepositories and Biobanks (Ordinance No. 2201) published by the Ministry of Health in September 2011. The authors examine the differences between sample collections for single studies and large-scale collections for multiple studies (e.g., the National Tumor Bank at the Brazilian National Cancer Institute and the A. C. Camargo Hospital Biobank). Also discussed are the ethical and operational implications, i.e.,informed consent process, strategies for sample collection, custodianship, access to samples, and rules for disposal. Insights gained may be useful for developing national biobanking regulations in other countries in Latin America.

En este artículo se describen y se analizan los nuevos reglamentos del Brasil -para el uso de materiales biológicos humanos para la investigación; específicamente, la Resolución CNS 441/11, sancionada por el Consejo Nacional de Salud del Brasil en mayo del 2011, y las Directrices Nacionales para Repositorios Biológicos y Bancos de Materiales Biológicos (Ordenanza Nº. 2201), publicadas por el Ministerio de Salud en septiembre del 2011. Los autores examinan las diferencias entre la recolección de muestras para un estudio único y la recolección en gran escala para múltiples estudios (por ejemplo, el Banco Nacional de Tumores del Instituto Nacional del Cáncer del Brasil y el Banco de Materiales Biológicos del Hospital A. C. Camargo). También se analizan las implicaciones éticas y operativas, como el proceso de consentimiento informado, las estrategias de obtención de las muestras, su custodia, el acceso a las muestras y las reglas para desecharlas. Estos conocimientos pueden ser útiles para establecer reglamentos nacionales para los bancos de materiales biológicos en otros países de América Latina.

Análise do perfil de expressão gênica em amostras de linfoma de Hodgkin clássico: estudo da patogênese com ênfase no papel da infecção pelo vírus de Epstein-Barr / Gene expression analysis in classical Hodgkin lymphoma: a pathogenetic study emphasizing the role of Epstein-Barr virus infection

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.

Linfoma do colo uterino: relato de dois casos e revisão da literatura / Lymphoma of the uterine cervix: report of two cases and review of the literature

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.

Expressão imuno - histoquímica de c - erb - B2 e p53 em carcinomas gástricos / Imunohistochemical expression of c - erb - B2 and p53 in gastric carcinomas

INTRODUÇAO: Em nosso meio, os carcinomas gástricos ainda são neoplasias bastante freqüentes e responsáveis por altas taxas de mortalidade. Recentemente, têm-se demonstrado a expressão de p53 e a amplificacão do gene c-erb-B2 nos carcinomas gástricos. A relevância e o significado biológico destas alteracões ainda não foram totalmente estabelecidos. OBJETIVO: Estudar as expressões imuno-histoquímicas de p53 e c-erb-B2 em 482 casos de carcinomas gástricos. MATERIAL E MÉTODOS: Foram construídos três blocos de tissue microarray (TMA) utilizando-se duplicatas de 482 casos de carcinomas gástricos. Os cortes foram corados por hematoxilina e eosina (HE), tendo sido feita pesquisa para p53 e c-erb-B2. Foram considerados positivos para p53 os casos com marcacão nuclear em mais de 10 por cento das células tumorais. Para o c-erb-B2 foram considerados positivos os casos com marcacão de membrana completa em mais de 10 por cento das células tumorais. RESULTADOS: A expressão de p53 e c-erb-B2 foi observada em 30 por cento e 12 por cento dos casos, respectivamente. Em relacão aos tipos histológicos observou-se correlacão entre os carcinomas do tipo intestinal e a expressão de c-erb-B2 (p < 0,001). A expressão de p53 foi mais freqüente nos carcinomas com mais de 5cm de diâmetro (p = 0,036). Não foram observadas alteracões nas curvas de sobrevida dos pacientes em relacão às expressões desses marcadores. CONCLUSAO: Em nosso meio, carcinomas gástricos do tipo intestinal são mais freqüentemente positivos para c-erb-B2 nos tipos intestinais do que nos difusos. A expressão de p53 está associada ao tamanho tumoral. A técnica do TMA é válida e eficiente para o estudo de marcadores imuno-histoquímicos, com forte correlacão com os cortes tradicionais de representacão do tumor.