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1.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
3.
Semin Cell Dev Biol ; 86: 62-76, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29526544

RESUMO

The systemic histiocytoses encompass a clinically heterogeneous group of disorders leading to tissue damage secondary to the accumulation and infiltration of pathological cells thought to be derived from the dendritic or monocytic lineages with accompanying inflammation. For decades, whether or not the histiocytoses were inflammatory or neoplastic disorders was unclear, and their cellular origins have long been obscure and heavily debated. However, the rise of the molecular era led to the discovery of recurrent BRAFV600E mutations in approximately 50% of patients with Langerhans cell and non-Langerhans cell histiocytoses, which provided the first convincing evidence that these are indeed histiocytic neoplasms. This also supplied a molecular biomarker for potentially mapping the cell(s)-of-origin of these neoplasms. The purpose of this review will be to highlight the barrage of recent molecular advancements in the histiocytic neoplasms and discuss the impact these insights have had on our understanding of the molecular pathophysiology and cellular origins of these rare, enigmatic diseases.


Assuntos
Células Dendríticas/metabolismo , Células Dendríticas/patologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Transtornos Histiocíticos Malignos/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética
6.
Actas dermo-sifiliogr. (Ed. impr.) ; 108(7): 620-629, sept. 2017. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-166917

RESUMO

El descubrimiento de nuevos síndromes autoinflamatorios y nuevas mutaciones está avanzando a una velocidad vertiginosa en los últimos años. La segunda parte de la revisión está centrada en el estudio de los síndromes histiocítico-macrofágicos y de los síndromes vasculopáticos, incluyendo al final del texto una tabla con las alternativas terapéuticas de estos síndromes autoinflamatorios y sus mutaciones genéticas (AU)


The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives (AU)


Assuntos
Humanos , Transtornos Histiocíticos Malignos/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Vasculares Periféricas/genética , Mutação/genética , Doenças Hereditárias Autoinflamatórias/classificação , Vasculite Leucocitoclástica Cutânea/genética , Telangiectasia/genética , Complemento C1q/deficiência , Adenosina Desaminase/deficiência
7.
Hematol Oncol Clin North Am ; 31(4): 705-719, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28673397

RESUMO

Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Transtornos Histiocíticos Malignos/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/genética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Transtornos Histiocíticos Malignos/diagnóstico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genética , Proteínas ras/metabolismo
8.
Histopathology ; 70(6): 1000-1008, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28074480

RESUMO

AIMS: The aims of this study were to define whether diffuse cutaneous reticulohistiocytosis could be underpinned by somatic genetic alterations and represent a precursor of more aggressive forms of disease. METHODS AND RESULTS: A 59-year-old man with diffuse cutaneous reticulohistiocytosis experienced bone marrow localization of the disease, with associated systemic mastocytosis and acute myeloid leukaemia. Cytogenetic analyses of the bone marrow aspirate revealed the presence of a derivative chromosome giving rise to a partial trisomy of chromosome 1q and a partial monosomy of chromosome 9q. Therefore, we characterized the cutaneous lesions before and after chemotherapy by using an integrative approach combining histopathology, electron microscopy, and fluorescence in-situ hybridization. Histologically, the skin lesions belonged to the spectrum of diffuse cutaneous reticulohistiocytoses, as confirmed by immunohistochemistry and ultrastructural analyses. Fluorescence in-situ hybridization in the skin nodules confirmed the presence of the genetic alterations previously detected in the bone marrow. CONCLUSIONS: Here, we provide circumstantial evidence to suggest that at least a subset of cutaneous reticulohistiocytoses harbour clonal molecular alterations. Furthermore, we confirm that these lesions have the potential to arise in the setting of concurrent haematological disorders. In this hypothesis-generating study, two possible tumorigenesis models are proposed.


Assuntos
Neoplasias da Medula Óssea/complicações , Transtornos Histiocíticos Malignos/complicações , Leucemia Mieloide Aguda/complicações , Mastocitose Sistêmica/complicações , Neoplasias Cutâneas/complicações , Medula Óssea/patologia , Neoplasias da Medula Óssea/genética , Neoplasias da Medula Óssea/patologia , Células Clonais/patologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
9.
Oncotarget ; 7(48): 78355-78362, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27823979

RESUMO

The 2008 World Health Organization (WHO) diagnostic criteria of histiocytic and dendritic cell neoplasms from hematopoietic and lymphoid tissues no longer required the absence of clonal B-cell/T-cell receptor gene rearrangements. It is true that the clonal B-cell/T-cell receptor gene rearrangements have been identified in rare cases of histiocytic and dendritic cell neoplasms, such as those with or following lymphoma/leukemia or in some sporadic histiocytic/dendritic cell sarcomas, but the clonal features of such group of tumor are still not clear. Here we investigated the clonal status of 33 samples including Langerhans cell histiocytosis (LCH), Langerhans cell sarcoma (LCS), follicular dendritic cell sarcoma (FDCS), interdigitating dendritic cell sarcoma (IDCS) and histiocytic sarcoma (HS). Among them, twenty-eight cases were sporadic without current or past lymphoma/leukemia. Three cases were found with a past history of T-cell lymphoma, one case was followed by extraosseous plasmacytoma, and one case was found with diffuse large B-cell lymphoma (DLBCL). Our results showed that there was a high frequency of clonal IG and T-cell receptor gene rearrangements in these cases. Notably, 4 cases of LCH and 2 cases of FDCS showed both B and T cell receptor gene rearrangements concurrently. One case of FDCS synchronous with DLBCL showed identical clonal IGH in both tumor populations and clonal TCRß in FDCS alone. No matter if the presence of clonal receptor gene rearrangements was associated with the tumor origin or tumorigenesis, it might serve as a novel tumor marker for developing target therapy.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Genes de Cadeia Pesada de Imunoglobulina , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T , Transtornos Histiocíticos Malignos/genética , Histiocitose de Células de Langerhans/genética , Cadeias kappa de Imunoglobulina/genética , Adolescente , Adulto , Idoso , Criança , Sarcoma de Células Dendríticas Foliculares/genética , Sarcoma de Células Dendríticas Foliculares/imunologia , Sarcoma de Células Dendríticas Foliculares/patologia , Sarcoma de Células Dendríticas Interdigitantes/genética , Sarcoma de Células Dendríticas Interdigitantes/imunologia , Sarcoma de Células Dendríticas Interdigitantes/patologia , Feminino , Predisposição Genética para Doença , Transtornos Histiocíticos Malignos/imunologia , Transtornos Histiocíticos Malignos/patologia , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/imunologia , Sarcoma Histiocítico/patologia , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Humanos , Sarcoma de Células de Langerhans/genética , Sarcoma de Células de Langerhans/imunologia , Sarcoma de Células de Langerhans/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
10.
Am J Surg Pathol ; 39(4): 573-80, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25768257

RESUMO

Fibroblastic reticular cell (FRC) neoplasms, which are one of the histiocyte tumor types, are very rare. Here we report a cytokeratin (CK)-positive FRC neoplasm having features of follicular dendritic cells in a 54-year-old woman with right axillary lymph node swelling. The resected lymph node showed multiple nodular aggregations simulating and replacing normal follicles. The tumor cells had a uniform, large and oval to polygonal shape, abundant cytoplasm, and various sizes of nuclei with central eosinophilic nucleoli and coarse nuclear chromatin. They were positive for CK AE1/AE3+CAM5.2, CK7, tenascin C, l-caldesomone, and CD21, weakly positive for S100, and negative for CD1a. Ultrastructurally, the tumor cells had long interdigitating microvillus-like cell processes and oval to elongated vesicular nuclei. In addition, the intercellular spaces contained accumulations of collagen, and some tumor cells had desmosomal-like junctions. These findings suggest that the present case is a CK-positive FRC tumor with follicular dendritic cell features.


Assuntos
Biomarcadores Tumorais/análise , Células Dendríticas Foliculares , Transtornos Histiocíticos Malignos , Queratinas/análise , Linfonodos , Células Estromais , Biomarcadores Tumorais/genética , Biópsia , Células Dendríticas Foliculares/química , Células Dendríticas Foliculares/ultraestrutura , Feminino , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/metabolismo , Transtornos Histiocíticos Malignos/patologia , Transtornos Histiocíticos Malignos/cirurgia , Humanos , Imuno-Histoquímica , Cariotipagem , Excisão de Linfonodo , Linfonodos/química , Linfonodos/cirurgia , Linfonodos/ultraestrutura , Microscopia Eletrônica , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Células Estromais/química , Células Estromais/ultraestrutura , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Vet Comp Oncol ; 7(2): 115-21, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19453365

RESUMO

A cohort study of 174 flat-coated retrievers was undertaken to establish the importance of cancer in flat coat mortality in terms of the prevalence of neoplasia in the breed and also the relative effect of cancer on lifespan in relation to other forms of mortality. Dogs aged 2-7 years were recruited in 1996 and followed until 2007. An annual health census was used to collect the data. Two dogs were lost to follow-up and 72 dogs (42%) died from confirmed neoplasia. Twenty dogs (11.6%) died of unconfirmed tumours and 61 (35%) died from non-neoplastic conditions. The cause of death was unknown for 19 dogs. Soft tissue sarcoma (especially histiocytic sarcoma) was the predominant cancer type, affecting 32 dogs (44% of neoplasms). Six dogs died with malignant melanoma and three with lymphoma. Median age at death was 9 years for dogs with tumours (eight for sarcoma patients) and 12 years for non-neoplastic fatalities. The results confirm that soft tissue sarcoma, particularly histiocytic sarcoma, is a major cause of mortality in this breed.


Assuntos
Doenças do Cão/mortalidade , Cabelo , Transtornos Histiocíticos Malignos/veterinária , Sarcoma/veterinária , Animais , Cruzamento , Estudos de Coortes , Doenças do Cão/epidemiologia , Doenças do Cão/genética , Cães , Feminino , Predisposição Genética para Doença , Transtornos Histiocíticos Malignos/epidemiologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/mortalidade , Masculino , Sarcoma/epidemiologia , Sarcoma/genética , Sarcoma/mortalidade , Reino Unido/epidemiologia
13.
Oncol Rep ; 18(4): 755-61, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17786332

RESUMO

p53 knockout mice have been utilized for the functional analysis of p53 in carcinogenic processes and for the evaluation of the carcinogenic potential of chemicals. In this study, we established that p53 knockout mice have an elevated susceptibility to the induction of histiocytic sarcoma (HS) by N-bis(2-hydroxy-propyl)nitrosamine (BHP). p53 heterozygous (+/-) and wild-type (+/+) mice were treated with 20 or 200 ppm BHP in their drinking water for 15 weeks or with 20 ppm BHP for 40 weeks. An additional group of p53 nullizygous (-/-) mice were treated with 20 ppm BHP for 15 weeks. In a 15-week experiment, hepatic HSs were unexpectedly observed in BHP-treated p53 (-/-) mice (30.8%) but not in p53 (+/-) and (+/+) mice and untreated (-/-) mice, indicating that a complete loss of p53 dramatically accelerates the genesis of HS. In a 40-week experiment, HSs were significantly increased in female p53 (+/-) mice (37.5%) as compared with female (+/+) mice (5.0%). Additionally, PCR-SSCP and sequencing analysis revealed a high frequency of p53 gene mutations in HSs, demonstrating the involvement of p53 gene mutations in HS development. Our data add to the understanding of the carcinogenic susceptibility of p53 knockout mice, and may help to elucidate the pathogenesis of HS development.


Assuntos
Carcinógenos/toxicidade , Genes p53/fisiologia , Transtornos Histiocíticos Malignos/induzido quimicamente , Nitrosaminas/toxicidade , Sarcoma Experimental/induzido quimicamente , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Homozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Sarcoma Experimental/genética , Sarcoma Experimental/patologia
14.
Przegl Lek ; 63(1): 47-52, 2006.
Artigo em Polonês | MEDLINE | ID: mdl-16892901

RESUMO

Hemophagocytic syndrome (HS) is a rare but life-threatening disease caused by inappropriate activation of T-lymphocytes and histiocytes, hipercytokinemia and hemophagocytosis. The most common symptoms are fever, hepatosplenomegaly, unspecific neurological abnormalities, pancytopenia, coagulopathy, hiperferritinemia and lipid abnormalities. HS is classified into two forms: primary, inherited (Familial Hamophagocytic Lymphohistiocytosis--FHL) and secondary (associated with infection, malignancy, autoimmune disease). In spite of the fact that diagnostic guidelines are available it often remains unrecognised. Prognosis of HS depends on the form of disease and in case of secondary HS on the underlying disease. Development of the treatment protocols (HLH-94, HLH-2004) which combine immunochemiotherapy with hematopoietic stem cell transplantation has strongly improved prognosis in HS especially in the primary form. Three-year overall survival for children with HS is now over 50%. Early diagnosis and appropriate therapy is crucial for effectiveness of the treatment. Popularisation of the knowledge about the syndrome, diagnostic guidelines and treatment protocols can contribute to more frequent appropriate recognition of HS and to improvement of the treatment results.


Assuntos
Transtornos Histiocíticos Malignos/diagnóstico , Histiocitose de Células não Langerhans/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Criança , Diagnóstico Diferencial , Transtornos Histiocíticos Malignos/epidemiologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/imunologia , Histiocitose de Células não Langerhans/epidemiologia , Histiocitose de Células não Langerhans/genética , Histiocitose de Células não Langerhans/imunologia , Humanos , Síndrome , Linfócitos T/imunologia , Linfócitos T/patologia
15.
Am J Vet Res ; 67(4): 633-41, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16579756

RESUMO

OBJECTIVE: To evaluate canine histiocytic sarcoma cell lines and tumor samples for dysregulation of the Kit/stem-cell factor (SCF), Flt3/Flt3 ligand (Flt3L), and Met/hepatocyte growth factor (HGF) receptor tyrosine kinase signaling pathways, as these are known to contribute to the differentiation and survival of normal dendritic cells as well as malignant transformation of dendritic cells in mouse models. SAMPLE POPULATION: 4 histiocytic sarcoma tumor cell lines and 35 formalin-fixed histiocytic sarcoma specimens obtained from dogs. PROCEDURE: Histiocytic sarcoma cell lines were evaluated for expression of Kit/SCF, Flt3/Flt3L, and Met/HGF by use of reverse transcriptase-PCR procedures. Histiocytic sarcoma cell lines and tumor samples were evaluated for mutations in Kit, Flt3, and Met by use of PCR analysis of genomic DNA, followed by both sequencing and fluorescent PAGE for deletions or internal tandem duplications. The ability of the multi-targeted split-kinase inhibitor SU11654 to block proliferation and induce apoptosis of histiocytic sarcoma cell lines was also evaluated. RESULTS: No mutations in Kit, Flt3, and Met were identified in any of the cell lines or tumor samples evaluated. Furthermore, SU11654 did not induce cell-cycle arrest or apoptosis of histiocytic sarcoma lines, even at supratherapeutic doses. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that dysregulation of Kit/SCF, Flt3/Flt3L, and Met/HGF signaling pathways is unlikely to occur in histiocytic sarcomas of dogs and that inhibitors of the Kit, Flt3, and Met pathways are unlikely to provide clinical benefit to dogs with histiocytic sarcomas.


Assuntos
Doenças do Cão/genética , Transtornos Histiocíticos Malignos/veterinária , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-met/genética , Sarcoma/veterinária , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Clonagem Molecular , Análise Mutacional de DNA , Primers do DNA , Cães , Éxons , Transtornos Histiocíticos Malignos/genética , Reação em Cadeia da Polimerase , Sarcoma/genética , Fator de Células-Tronco/genética
16.
Mod Pathol ; 18(5): 693-704, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15696128

RESUMO

Histiocytic sarcoma (HS) is a rare but controversial hematopoietic neoplasm. In the past, malignancies have been misclassified as histiocytic tumors due to overlapping histologic features and inadequate phenotypic data. CD163, a recently characterized hemoglobin scavenger receptor, appears to be a 'specific' marker of histiocytic lineage and a promising diagnostic tool for evaluating histiocytic neoplasms. Five cases of HS were studied to further elucidate the clinicopathologic features of these rare tumors and to demonstrate the diagnostic utility of CD163. Criteria for diagnosis included histologic and immunohistochemical evidence of histiocytic differentiation, CD45 positivity, and exclusion of lymphoid, epithelial, melanocytic and dendritic cell phenotype. Sites of disease included the colon (two cases), palate, inguinal lymph node, and testis. The clinical course was aggressive in 4/5 patients (survival=2-15 months). One patient with localized disease of the palate, survived 17 years after diagnosis. All patients with poor survival had tumors > or =3.5 cm. Histologically, all cases showed diffuse architecture with large, discohesive polygonal cells. Spindling of cells was focally noted. Hemophagocytosis was identified in 3/5 cases. A prominent inflammatory background was present in 4/5 tumors. All cases were immunoreactive for CD45, CD163, CD68, and lysozyme. S-100 was focally positive in 4/5 cases. Antibodies for melanocytic, epithelial, lymphoid, and dendritic cell markers were negative. Molecular studies showed monoclonal IgH gene rearrangements in three cases. Our findings suggest that HS is an uncommon neoplasm frequently extranodal in presentation and aggressive in behavior, with rare exceptions. Stage of disease and possibly tumor size are significant prognostic indicators. Molecular studies remain controversial in the diagnosis. The morphologic and phenotypic features are relatively uniform; however, the diagnosis requires exclusion of more common neoplasms by extensive immunophenotypic studies. CD163 appears to be a specific histiocytic marker and is important in establishing the diagnosis of HS.


Assuntos
Transtornos Histiocíticos Malignos/patologia , Sarcoma/patologia , Adulto , Idoso , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Feminino , Rearranjo Gênico , Histiócitos/química , Histiócitos/patologia , Histiócitos/ultraestrutura , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Antígenos Comuns de Leucócito/análise , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Superfície Celular/análise , Sarcoma/genética , Sarcoma/metabolismo
17.
Leuk Lymphoma ; 41(3-4): 429-33, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11378558

RESUMO

We describe a patient with a neoplasm derived from the histiocytic-monocytic lineage associated with t(2;5) detected by FISH. The patient presented with bone marrow involvement, no organomegaly and subsequently developed a leukaemic picture. The clinical course was aggressive and the patient died four months from diagnosis. Cell morphology, immunophenotype (CD30-, EMA-, Lisozyme+, cy CD68+ and CD45+) and DNA analysis showing germ-line configuration of the Ig/TCR chain genes ruled out the diagnosis of anaplastic large cell lymphoma (ALCL). This unusual case ilustrates that t(2;5) is not exclusive for ALCL but may be found in a few cases of rare neoplasms derived from the histiocytic-monocytic cells.


Assuntos
Cromossomos Humanos Par 2 , Cromossomos Humanos Par 5 , Transtornos Histiocíticos Malignos/diagnóstico , Transtornos Histiocíticos Malignos/genética , Leucemia Monocítica Aguda/diagnóstico , Leucemia Monocítica Aguda/genética , Translocação Genética , Idoso , Antígenos CD/análise , Diagnóstico Diferencial , Evolução Fatal , Transtornos Histiocíticos Malignos/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Leucemia Monocítica Aguda/patologia , Masculino
18.
Clin Genet ; 53(4): 298-302, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9650769

RESUMO

We describe a patient with a congenital malignant blood disorder and a constitutional de novo chromosomal rearrangement that includes four breakpoints. By conventional cytogenetic analysis an obviously reciprocal balanced translocation with the breakpoints 1p36 and 5q11.2 was diagnosed. Due to a suspicious dark band in the breakpoint area of 1p a more detailed analysis of the breakpoints was performed using microdissection and reverse chromosome painting. This revealed a small inversion at 1p36 that must have occurred prior to the reciprocal translocation. The three breakpoints in chromosome 1 (1p36.11, 1p36.21 and 1p36.31) are within or close by regions known to contain tumor suppressor genes. The chromosomal rearrangement might have resulted either in a submicroscopic deletion, in loss of heterozygosity of one or more imprinted genes, or in gene position effects as possible explanations for the clinical course of our patient.


Assuntos
Cromossomos Humanos Par 1 , Cromossomos Humanos Par 5 , Transtornos Histiocíticos Malignos/genética , Translocação Genética , Eritrócitos , Feminino , Transtornos Histiocíticos Malignos/congênito , Humanos , Lactente , Fagocitose
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