Prognostic Factors in Children and Adolescents with Lymphomas and Vertical Transmission of HIV in Rio de Janeiro, Brazil: A Multicentric Hospital-Based Survival Analysis Study.

Lymphomas related to HIV are generally aggressive and have a poor prognosis, despite the use of combined antiretroviral therapy (cART) and effective chemotherapy treatment. To determine survival and prognostic factors in children and adolescents living with HIV (CLWH) in Rio de Janeiro (RJ), Brazil, who developed lymphomas, we performed a retrospective and observational study of vertically infected CLWH aged from 0 to 20 incomplete years during1995 to 2018 at five reference centers for cancer and HIV/AIDS treatment. Of the 25 lymphomas, 19 were AIDS-defining malignancies (ADM) and 6 were non-AIDS-defining malignancies (NADM). The 5-year overall survival (OS) and 5-year event-free survival (EFS) probabilities were both 32.00% (95% CI = 13.72-50.23%), and the 5-year disease-free survival (DFS) probability was 53.30% (95% CI = 28.02-78.58%). In the multivariate Cox regression analysis, performance status 4 (PS 4) was considered a poor prognostic factor for OS (HR 4.85, 95% CI = 1.81-12.97, p = 0.002) and EFS (HR 4.95, 95% CI = 1.84-13.34, p = 0.002). For the DFS, higher CD4+ T-cell counts were considered a better prognostic factor (HR 0.86, 95% CI = 0.76-0.97, p = 0.017) in the multivariate Cox regression analysis. This study demonstrates, for the first time, survival and prognostic factors for CLWH who developed lymphomas in RJ, Brazil.

A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.

BACKGROUND: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the ANKRD26 and SRP72 variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution. CASE PRESENTATION: A 4-year-old girl showed repeated infections and severe neutropenia. Bone marrow presented hypocellularity with dysplastic features. The patient had a t(3;8)(p26;q21)c identified by G-banding and FISH analysis. The family nucleus investigation identified the paternal origin of the chromosomal translocation. The NGS study identified ANKRD26 and SRP72 variants of maternal origin. CGH-array analysis detected alterations in PRSS3P2 and KANSL genes. Immunohistochemistry showed abnormal p53 expression during the MDS evolution. CONCLUSION: This study shows for the first time, cytogenetic and genomic abnormalities inherited from the father and mother, respectively, and their clinical implications. It also shows the importance of investigating patients with constitutional cytogenetic alterations and/or germline variants to provide information to their family nucleus for genetic counseling and understanding of the pathogenesis of childhood MDS.

Incidence and Clinical Description of Lymphomas in Children and Adolescents with Vertical Transmission of HIV in Rio de Janeiro, Brazil, in Pre- and Post-Combined Antiretroviral Therapy Eras: A Multicentric Hospital-Based Survival Analysis Study.

The incidence of cancer in children living with HIV (CLWH) is high and lymphomas are the most common type of cancer in this population. The combined antiretroviral therapy (cART) changed the natural history of HIV infection. To determine the incidence and profile of these CLWH malignancies in Rio de Janeiro (RJ), Brazil, we conducted a retrospective and observational study of vertically infected CLWH, ranging from 0−20 incomplete years, from 1995 to 2018, at five reference centers. The study period was divided into three eras in accordance with the widespread use of cART in Brazil. 1306 patients were included. Of the 25 lymphomas found, 19 were AIDS-defining malignancies (ADM); 6 were non-AIDS-defining malignancies (NADM). The incidence rate (IR) of lymphoma developing was 1.70 per 1000 children-year (95% CI 1.09−2.50). ADM development IR decreased from 2.09−1.75−0.19 per 1000 children-year (p < 0.001) through cART eras. Cumulative Nelson−Aalen hazards of developing ADM over a 20-year period were 3.73% in the Early-cART era, 3.07% in the Mid-cART era, and 0.32% in the Late-cART era (p = 0.013). This study demonstrates the IR of lymphoma in CLWH in RJ, Brazil, as well as the benefit of cART in reducing ADM and death occurrence in the Post-cART era.

Mature T/NK-Cell lymphomas of the oral and maxillofacial region: A multi-institutional collaborative study.

BACKGROUND: The diagnosis of oral and maxillofacial mature T/NK-cell neoplasms is challenging because of their rarity, morphological heterogeneity and complex immunophenotype with scarce available data describing their clinical and microscopic aspects. Therefore, in this study, we investigated a series of mature T/NK-cell neoplasms affecting this anatomical region and provided an updated literature review. METHODS: Cases diagnosed as mature T/NK-cell lymphomas affecting the oral and maxillofacial region were retrospectively retrieved from six pathology files and their diagnoses were confirmed using haematoxylin and eosin-stained slides, immunohistochemical reactions and in situ hybridization for Epstein-Barr virus (EBV) detection. Patients' clinical data were collected from their pathology forms. RESULTS: A total of 22 cases were included in this study. Eleven (50%) consisted of extranodal NK/T-cell lymphomas, nasal type; eight (36.4%) were peripheral T-cell lymphomas, NOS; two (9.1%) were adult T-cell leukaemia/lymphomas, and one (4.5%) was an ALK-positive anaplastic large cell lymphoma. Overall, males predominated, with a mean age of 55.7 years. The palate was the most affected site (50%), and tumours usually presented as destructive and painful ulcers. EBV was present in all cases of extranodal NK/T-cell lymphoma nasal type but was absent in the other subtypes. CONCLUSION: Among mature T/NK-cell lymphomas of the oral and maxillofacial region, extranodal NK/T-cell lymphoma, nasal type and peripheral T-cell lymphoma, NOS predominated. Older men were the most affected patients, and this heterogeneous group of neoplasms has a very aggressive clinical behaviour.

NADPH Oxidase 5 upregulation is associated with lymphoma aggressiveness.

OBJECTIVES: Lymphomas are a heterogeneous set of malignant neoplasias of lymphoid B and NK/T mature and immature cells at various stages of differentiation. Genetic and molecular biology tools are used to appropriately classify the type and prognosis of the lymphomas, which have implications in therapeutic effectiveness. Among them, the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase (NOX5) enzymes have been explored. This study analyzed the expression of NADPH oxidase 5 in lymphoma tissue according to the degree of tumor aggressiveness. METHODS: Slides from 64 patients with lymphoma who had paraffin-embedded tissue available were reviewed by two independent, experienced pathologists. They classified tumors according to the WHO classification (2017). NOX5 expression in tissues was assessed by immunohistochemical staining using a tissue microarray. The assay was interpreted using a scoring system of 0, 1, 2, and 3, for cytoplasmic staining of NOX5 corresponding to negative, weak, intermediate, and strong staining, respectively. We compared the expression of NOX5 in patients with aggressive versus non-aggressive lymphomas. RESULTS: NOX5 expression was positive in 100% (27/27) of aggressive lymphomas and in 19% (7/37) of non-aggressive ones. The seven patients with positive expression of NOX5 presented intermediate staining (2); strong staining (3) was observed only in tissues of aggressive lymphomas, and negative and weak staining (0 and 1) were observed only in non-aggressive lymphomas. CONCLUSIONS: Aggressive lymphomas overexpress NOX5 protein. The higher NOX5 expression in aggressive lymphomas can suggest an involvement of this enzyme on the acquisition of an aggressive phenotype in lymphoid neoplasia.

Anaplastic Large Cell Lymphoma with Oral Manifestation: A Series of Four Cases and Literature Review.

The aim of this study was to describe the clinicopathological and immunohistochemical features of four cases of anaplastic large cell lymphoma (ALCL) diagnosed through oral manifestations. Clinical data were collected from charts of a single oral pathology laboratory over a 5-year period (2014-2019) and all cases were evaluated by conventional hematoxylin and eosin staining and an extended immunohistochemical panel comprising CD45, CD20, CD3, CD4, CD7, CD30, CD99, CD138, cytokeratin AE1/AE3, EMA, ALK, MUM-1 and Ki-67. The study included 3 male (75%) and 1 female (25%) patients, with a median age of 44 years. The most common intraoral affected site was the alveolar ridge (50%). Clinically, all cases were characterized as an ulcerated bleeding mass. Microscopically, proliferation of anaplastic large lymphoid cells with medium to large-sized, abundant amphophilic to eosinophilic cytoplasm and eccentric nuclei were observed. All cases were positive for CD30, while two cases strongly express ALK. Two patients died of the disease. Careful correlation of clinical, morphological and immunohistochemical data are necessary to establish the diagnosis of oral manifestation of ALCL since its microscopical features may mimic other malignant tumors. Clinicians and pathologists should consider ALCL in the differential diagnosis when evaluating oral ulcerated swellings exhibiting large lymphoid cells in patients with lymphadenopathy.

NADPH Oxidase 5 upregulation is associated with lymphoma aggressiveness

SUMMARY OBJECTIVES Lymphomas are a heterogeneous set of malignant neoplasias of lymphoid B and NK/T mature and immature cells at various stages of differentiation. Genetic and molecular biology tools are used to appropriately classify the type and prognosis of the lymphomas, which have implications in therapeutic effectiveness. Among them, the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase (NOX5) enzymes have been explored. This study analyzed the expression of NADPH oxidase 5 in lymphoma tissue according to the degree of tumor aggressiveness. METHODS Slides from 64 patients with lymphoma who had paraffin-embedded tissue available were reviewed by two independent, experienced pathologists. They classified tumors according to the WHO classification (2017). NOX5 expression in tissues was assessed by immunohistochemical staining using a tissue microarray. The assay was interpreted using a scoring system of 0, 1, 2, and 3, for cytoplasmic staining of NOX5 corresponding to negative, weak, intermediate, and strong staining, respectively. We compared the expression of NOX5 in patients with aggressive versus non-aggressive lymphomas. RESULTS NOX5 expression was positive in 100% (27/27) of aggressive lymphomas and in 19% (7/37) of non-aggressive ones. The seven patients with positive expression of NOX5 presented intermediate staining (2); strong staining (3) was observed only in tissues of aggressive lymphomas, and negative and weak staining (0 and 1) were observed only in non-aggressive lymphomas. CONCLUSIONS Aggressive lymphomas overexpress NOX5 protein. The higher NOX5 expression in aggressive lymphomas can suggest an involvement of this enzyme on the acquisition of an aggressive phenotype in lymphoid neoplasia.

RESUMO OBJETIVOS Os linfomas são um grupo heterogêneo de neoplasias malignas de células linfoides B e NK/T maduras e imaturas em vários estágios de diferenciação. Ferramentas de biologia molecular e genética são usadas para classificar adequadamente o tipo e o prognóstico dos linfomas, os quais têm implicações na eficácia terapêutica. Entre eles, as enzimas nicotinamida adenina dinucleótido fosfato oxidase (NADPH) oxidase (NOX5) foram exploradas. Este estudo analisou a expressão da NADPH oxidase 5 em linfomas de acordo com o grau de agressividade tumoral. MÉTODOS As lâminas de 64 pacientes com linfoma, que tinham tecido embebido em parafina disponível, foram revisadas por dois patologistas experientes independentemente. Eles utilizaram a classificação da OMS (2017). A expressão de NOX5 nos tecidos foi avaliada por coloração imuno-histoquímica utilizando microarray de tecido. O ensaio foi interpretado com um sistema de pontuação de 0, 1, 2 e 3, para coloração citoplasmática de NOX5 correspondente à coloração negativa, fraca, intermediária e forte, respectivamente. Comparamos a expressão de NOX5 em pacientes com linfomas agressivos versus não agressivos. RESULTADOS A expressão de NOX5 foi positiva em 100% (27/27) dos linfomas agressivos e em 19% (7/37) dos linfomas não agressivos. Os sete pacientes com expressão positiva de NOX5 apresentaram coloração intermediária (2); coloração forte (3) foi observada apenas em tecidos de linfomas agressivos, e negativos e fracos (0 e 1) observados apenas em linfomas não agressivos. CONCLUSÕES Linfomas agressivos superexpressam a proteína NOX5. A expressão aumentada de NOX5 em linfomas agressivos pode sugerir um envolvimento dessa enzima na aquisição de um fenótipo agressivo na neoplasia linfoide.

DUOX1 Silencing in Mammary Cell Alters the Response to Genotoxic Stress.

DUOX1 is an H2O2-generating enzyme related to a wide range of biological features, such as hormone synthesis, host defense, cellular proliferation, and fertilization. DUOX1 is frequently downregulated in lung and liver cancers, suggesting a tumor suppressor role for this enzyme. Here, we show that DUOX1 expression is decreased in breast cancer cell lines and also in breast cancers when compared to the nontumor counterpart. In order to address the role of DUOX1 in breast cells, we stably knocked down the expression of DUOX1 in nontumor mammary cells (MCF12A) with shRNA. This led to higher cell proliferation rates and decreased migration and adhesion properties, which are typical features for transformed cells. After genotoxic stress induced by doxorubicin, DUOX1-silenced cells showed reduced IL-6 and IL-8 secretion and increased apoptosis levels. Furthermore, the cell proliferation rate was higher in DUOX1-silenced cells after doxorubicin medication in comparison to control cells. In conclusion, we demonstrate here that DUOX1 is silenced in breast cancer, which seems to be involved in breast carcinogenesis.

Clinicopathological and Immunohistochemical Study of Head and Neck Langerhans Cell Histiocytosis from Latin America.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic proliferation with variable clinical behavior caused by the accumulation of CD1a+/CD207+ histiocytes, associated with a variable number of eosinophils, lymphocytes, plasma cells and multinucleated giant cells, most commonly observed in male children. LCH is uncommon in the head and neck region, occurring as ulcerated and reddened plaques or nodules that cause destruction of adjacent soft tissues and bone. The exact etiology of LCH is still unknown and controversial, with possible etiologic role of viruses, including Epstein-Barr virus (EBV). The aim of this study was to describe the clinicopathologic and immunohistochemical features of patients with LCH of the head and neck region. Clinical data from 19 patients with LCH were obtained from the archives of the Federal University of Rio de Janeiro and the Clinical Head and Neck Center of Guatemala. All cases were submitted to morphological, immunohistochemical analysis with CD1a, CD207, CD3, CD20, CD68, S-100 and Ki-67 and in situ hybridization for EBV. Ten cases were female and 9 male, with mean age of 11.5 years. Fourteen cases were located in the oral cavity, three cases in lymph nodes, and two cases in the scalp. In regard to the oral lesions, 13 cases were intra-osseous with six cases in anterior mandible, five cases in posterior mandible, and two cases in posterior maxilla while one case was located exclusively in the gingiva. The inflammatory pattern showed variation in the number of plasma cells, eosinophils and lymphocytes, while tumor cells were positive for CD1a, S-100 and CD68 in all cases, and positive for CD207 in 18 cases. In situ hybridization for EBV were negative in all cases.

Malacoplaquia pulmonar associada à imunodeficiência por HTLV-1 e HIV / Pulmonary malakoplakia associated with immunodeficiency by HTLV-1 and HIV

Malakoplakia is a rare chronic inflammatory disease often confused with neoplasia. In this paper we report two cases of pulmonary Malakoplakia, both with typical clinical diagnosis of tuberculosis and lung cancer. A patient with human T-lymphotropic virus type I (HTLV-1) and diagnosis of adult T-cell leukemia/lymphoma, and another patient with human immunodeficiency virus (HIV), which was treated for tuberculosis, but, after pulmonary lobectomy, was evidenced Rodococosis equi, progressed to death...

Malacoplaquia é uma rara doença inflamatória crônica muitas vezes confundida com neoplasia. Neste artigo, relatam-se dois casos de malacoplaquia pulmonar, ambos com quadro clínico sugestivo de tuberculose e neoplasia pulmonar. Uma paciente com vírus T-linfotrópico humano tipo I (HTLV-1) e diagnóstico de leucemia/linfoma de células T do adulto, e um paciente com vírus da imunodeficiência humana (HIV), tratado para tuberculose, mas após lobectomia pulmonar foi evidenciado Rodococose equi, evoluindo para óbito...

Uveíte anterior como manifestação da Doença de Kikuchi e Fujimoto / Anterior Uveitis as an ocular manifestation of Kikuchi and Fujimoto's Disease

Apresentação de um caso de febre de origem obscura numa paciente feminina de 35 anos, com queda do estado geral, adenomegalia cervical posterior, monilíase oral, parotidite e irite.Após o parecer oftalmológico, o tratamento foi iniciado e posteriormente com o resultado do exame histopatológico de um linfonodo, diagnosticou-se a Doença de Kikuchi e Fujimoto. Sugerimos que a uveíte anterior seja reconhecida como mais um sinal de suspeita desta doença. São comentados os achados oculares, os aspectos histopatológicos e o tratamento da Doença de Kikuchi e Fujimoto.

Report of a case on Kikuchi and Fujimoto's Disease in a young lady who developed a long standing spiking fever, weight loss, cervical adenomegalia, oral moniliasis, parotiditis and iritis.The histopathological findings, course and treatment as well as the importance of a multidisciplinar approach are commented.

The prognostic value of the expression of Bcl-2, p53 and LMP-1 in patients with Hodgkin's lymphoma.

This study was undertaken to evaluate the clinical significance of the expression of Bcl-2, p53 and LMP-1 in Hodgkin and Reed - Sternberg cells of patients with Hodgkin's lymphoma. The expression of these proteins in pre-treatment tissue biopsy specimens was correlated with presenting clinical features, failure-free survival (FFS) and overall survival (OS) in 83 patients with a confirmed Hodgkin's lymphoma treated in a single institution. HIV-positive patients were excluded. Patients were classified according to the International Prognostic Score (IPS) in low-risk (0 - 2 factors) and high-risk groups. The median age was 41 years (15 - 84), 41% were women, and 93% had advanced-stage disease (IIB - IVB). The expression of Bcl-2, p53 and LMP-1 was not associated with the complete remission rate, FFS or OS. The IPS risk group was the only factor significantly associated with OS. Patients with a high IPS had a lower 5 year OS (43% vs. 79%, P = 0.003). The expression of Bcl-2, p53 and LMP-1 did not add prognostic information to the IPS.

Expression of Epstein-Barr virus in patients with Hodgkin's disease: report of 64 cases from Rio de Janeiro, Brazil

O vírus Epstein-Barr (EBV) tem sido implicado na fisiopatogenia da doença de Hodgkin (DH) e a associação deste vírus com a DH está relacionada com as condições socioeconômicas da população estudada, com a idade e com o subtipo histológico celularidade mista (CM). A prevalência do EBV na DH é muito variável. Este estudo foi realizado com o objetivo de determinar a prevalência do EBV na DH em uma população brasileira. Foram estudados 64 casos de DH oriundos do Hospital Universitário utilizando-se o método de imunoistoquímica com anticorpo monoclonal contra a proteína latente da membrana (LMP1). O vírus foi encontrado em 35 dos 64 casos estudados (55 por cento) e sua presença correlacionou-se de maneira significativa com o subtipo histológico CM (OR = 9; IC 95 por cento = 1,66 - 66; p = 0,0015). Estes resultados confirmam que o EBV está relacionado com a DH em uma população brasileira.

Classificaçäo dos linfomas näo-Hodgkin: estudo morfológico e imunoistoquímico de 145 casos / Classification of non-Hodgkin's lymphoma: morphological and immunological study of 145 cases

A classificaçäo dos linfomas näo-Hodgkin tem sido, ao longo dos últimos trinta anos, motivo de controvérsia. Várias classificaçöes têm sido propostas em busca de um consenso entre patologistas e clínicos. Este trabalho teve como objetivo analisar criticamente três destas classificaçöes através do estudo retrospectivo de 145 casos de linfomas primários de gânglio linfático selecionados do Serviço de Anatomia Patológica do Hospital Universitário Clementino Fraga Filho, entre 1979 e 1995. Os casos revistos foram classificados pelas propostas da Working Formulation, de Kiel e da Real. Testes imunoistoquímicos com os anticorpos anti-CD45, anti-CD20, anti-CD45RO e anti-CD30 foram realizados. Cento e sete casos (73,7 por cento) apresentaram fenótipo B; 33 casos (22,7 por cento), fenótipo T; e quatro casos foram nulos (linfoma anaplásico de grandes células). Foi possível prever o fenótipo pela morfologia em 89,4 por cento dos casos. Os linfomas de alto grau predominaram (59,2 por cento), sendo o linfoma centroblástico o de maior freqüência (31,7 por cento ). Os linfomas foliculares representaram 29 casos (20 por cento), com maior incidência dos de grandes células (31 por cento) do que dos de pequenas células (27,5 por cento). Quando comparadas as três classificaçöes, observamos que determinados grupos da Working Formulation abrigam múltiplas entidades. Isto se deve ao fato de a classificaçäo da Working Formulation ser baseada somente em achados morfológicos e, por isso, deve ter seu uso desaconselhado. Já a classificaçäo de Kiel e a da Real devem ter o seu emprego estimulado, pois apresentam, além de uma boa análise histopatológica, um estudo imunológico que define entidades biológicas correlacionando-se, quando possível, com a célula de origem

Leucemia/linfoma de células T do adulto no Rio de Janeiro: estudo clinicopatológico de dez casos / Adult T-cell leukemia/lymphoma in Rio de Janeiro: clinical and pathological study of ten cases

Dez casos de leucemia/linfoma de células T do adulto, com sorologia positiva para o HTLV-I, diagnosticados entre 1989 e 1997, foram analisados quanto aos aspectos clínicos e histopatológicos. A doença caracterizou-se por adenomegalia generalizada,, emagrecimento, febre, elevaçäo da desidrogenase láctica, hipercalcemia e presença de linfócitos atípicos circulantes. Seis casos foram classificados como forma aguda, um deles evoluindo a partir de uma forma crônica ou arrastada, três casos comoforma linfomatosa e um caso como forma crônica. Ao exame histológico do glânglio linfático, houve grande polimorfismo celular, com presença de células bizarras na maioria dos casos. O estudo imunoistoquímico, realizado em sete casos, comprovou a linhagem T. Todos os casos biópsia ganglionar, exceto um, foram classificados como linfomas T pelomórficos de médias e grandes células (Kiel). A pele estava infiltrada em quatro casos e a medula óssea, em cinco. Escabiose e estrongiloidíase foram detectadas em dois casos. Os achados de necrópsia, em três casos, mostraram disseminaçäo da doença e infecçöes oportunísticas (candidíase, HPV e pneumocistose)