RESUMEN
This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms, and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The diagnostic, clinicopathologic, cytogenetic, and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the World Health Organization classification of hematolymphoid neoplasms are highlighted.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Organización Mundial de la Salud , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Eosinofilia/patología , Eosinofilia/genética , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/clasificación , FenotipoRESUMEN
ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/análisis , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Quinasa de Linfoma Anaplásico/genética , Niño , Preescolar , Femenino , Trastornos Histiocíticos Malignos/complicaciones , Trastornos Histiocíticos Malignos/genética , Humanos , Lactante , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Histiocytic/dendritic cell tumors are rare in clinical practice. It is postulated that they originate from bone marrow stem cells. Accumulating evidence has established the existence of immunoglobulin gene and T-cell receptor gene rearrangements in these tumors. Cases of transdifferentiation across lineages from follicular lymphoma to histiocytic/dendritic cell tumors have also been reported. Herein, we report 2 adult males with histiocytic neoplasms coexisting with B-cell lymphoma. Laser capture microdissection and capillary electrophoresis polymerase chain reaction analysis revealed comparable immunoglobulin gene rearrangement in both patients. In one case, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Langerhans cell sarcoma, and histiocytic sarcoma coexisted in the lymph nodes. 11q22 deletion often present in CLL/SLL and expression of the BRAF V600E gene was detected in all the 3 components. In the other case, there diffuse large B-cell lymphoma and histiocytic sarcoma coexisted in the spleen. Forty-seven mutated genes commonly found in B-cell lymphoma were detected by next-generation sequencing. In the same line, DTX1, IRF8, KMT2D, MAP2K1, and TET2 genes were found to have similar mutation sites. The results of this study will contribute in providing new ideas for targeted treatment of these diseases.
Asunto(s)
Biomarcadores de Tumor/genética , Trastornos Histiocíticos Malignos/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Anciano , Análisis Mutacional de ADN , Células Dendríticas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Histiocitos/patología , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Primarias Múltiples/patología , LinajeRESUMEN
ALK-positive histiocytosis (APH) is a newly defined entity with specific histological features and a highly recurrent KIF5B-ALK gene fusion. APH is characterized by clonal proliferation of histiocytes and can present as either systemic or localized. It was first described in infants and then expanded to older children and adults. Although lung involvement has been shown in three systemic cases, localized lung lesions have not previously been reported. The ALK gene has many fusion partners in addition to KIF5B in APH. Here, we report a striking case of localized APH in the lung harboring a rare EML4-ALK rearrangement in a 52-year-old Chinese woman. Furthermore, we reviewed the previously published APH cases, analyzed the partner genes of the ALK fusions, and explored the role of patient ethnicity. We discovered a link between ethnicity and this rare disease.
Asunto(s)
Biomarcadores de Tumor/genética , Fusión Génica , Reordenamiento Génico , Trastornos Histiocíticos Malignos/genética , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Pueblo Asiatico/genética , China , Femenino , Predisposición Genética a la Enfermedad , Trastornos Histiocíticos Malignos/diagnóstico , Trastornos Histiocíticos Malignos/etnología , Trastornos Histiocíticos Malignos/cirugía , Humanos , Hallazgos Incidentales , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnología , Neoplasias Pulmonares/cirugía , Persona de Mediana Edad , Fenotipo , Neumonectomía , Resultado del TratamientoRESUMEN
Introduction: The classification of lymphomas is based on the postulated normal counterparts of lymphoid neoplasms and currently constitutes over 100 definite or provisional entities. As this number of entities implies, lymphomas show marked pathological, genetic, and clinical heterogeneity. Recent molecular findings have significantly advanced our understanding of lymphomas. Areas covered: The World Health Organization (WHO) classification of lymphoid neoplasms was updated in 2017. The present review summarizes the new findings that have been gained in the areas of mature T-cell neoplasms, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms since the publication of the 2017 WHO classification. Expert opinion: Although formal revisions to the WHO classification are published only periodically, our understanding of the pathologic, genetic, and clinical features of lymphoid neoplasms is constantly evolving, particularly in the age of -omics technologies and targeted therapeutics. Even in the relatively short time since the publication of the 2017 WHO classification, many significant findings have been identified in the entities covered in this review.
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Linfoma de Burkitt/clasificación , Infecciones por Virus de Epstein-Barr/clasificación , Neoplasias Hematológicas/clasificación , Trastornos Histiocíticos Malignos/clasificación , Enfermedad de Hodgkin/clasificación , Linfoma de Células T/clasificación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Linfoma de Burkitt/inmunología , Células Dendríticas/inmunología , Células Dendríticas/patología , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/inmunología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Trastornos Histiocíticos Malignos/diagnóstico , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/inmunología , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Macrófagos/inmunología , Macrófagos/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Terminología como Asunto , Organización Mundial de la SaludRESUMEN
Canine histiocytic malignancies (HM) are rare across the general dog population, but overrepresented in certain breeds, such as Bernese mountain dog and flat-coated retriever. Accurate diagnosis relies on immunohistochemical staining to rule out histologically similar cancers with different prognoses and treatment strategies (e.g., lymphoma and hemangiosarcoma). HM are generally treatment refractory with overall survival of less than 6 months. A lack of understanding regarding the mechanisms of disease development and progression hinders development of novel therapeutics. While the study of human tumors can benefit veterinary medicine, the rarity of the suggested orthologous disease (dendritic cell sarcoma) precludes this. This study aims to improve the understanding of underlying disease mechanisms using genome-wide DNA copy number and gene expression analysis of spontaneous HM across several dog breeds. Extensive DNA copy number disruption was evident, with losses of segments of chromosomes 16 and 31 detected in 93% and 72% of tumors, respectively. Droplet digital PCR (ddPCR) evaluation of these regions in numerous cancer specimens effectively discriminated HM from other common round cell tumors, including lymphoma and hemangiosarcoma, resulting in a novel, rapid diagnostic aid for veterinary medicine. Transcriptional analysis demonstrated disruption of the spindle assembly complex, which is linked to genomic instability and reduced therapeutic impact in humans. A key signature detected was up-regulation of Matrix Metalloproteinase 9 (MMP9), supported by an immunohistochemistry-based assessment of MMP9 protein levels. Since MMP9 has been linked with rapid metastasis and tumor aggression in humans, the data in this study offer a possible mechanism of aggression in HM.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Perfilación de la Expresión Génica , Genoma/genética , Trastornos Histiocíticos Malignos/genética , Huso Acromático/patología , Animales , Trastornos de los Cromosomas , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/genética , Perros , Trastornos Histiocíticos Malignos/diagnóstico , Trastornos Histiocíticos Malignos/veterinaria , Humanos , Inmunohistoquímica/métodos , Metaloproteinasa 9 de la Matriz/metabolismoRESUMEN
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.
Asunto(s)
Azetidinas/uso terapéutico , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/enzimología , Histiocitosis/tratamiento farmacológico , Histiocitosis/enzimología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Piperidinas/uso terapéutico , Azetidinas/farmacología , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Histiocitosis/genética , Histiocitosis/patología , Humanos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mutación , Piperidinas/farmacología , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-raf/genéticaRESUMEN
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.
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Células Dendríticas/metabolismo , Células Dendríticas/patología , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Macrófagos/metabolismo , Macrófagos/patología , Trastornos Histiocíticos Malignos/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genéticaAsunto(s)
Transformación Celular Neoplásica/genética , Células Dendríticas/metabolismo , Células Dendríticas/patología , Genes de Retinoblastoma , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/metabolismo , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Alelos , Biopsia , Médula Ósea/metabolismo , Evolución Clonal , Progresión de la Enfermedad , Silenciador del Gen , Humanos , Masculino , Persona de Mediana Edad , Secuenciación del ExomaRESUMEN
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)
Asunto(s)
Humanos , Trastornos Histiocíticos Malignos/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Vasculares Periféricas/genética , Mutación/genética , Enfermedades Autoinflamatorias Hereditarias/clasificación , Vasculitis Leucocitoclástica Cutánea/genética , Telangiectasia/genética , Complemento C1q/deficiencia , Adenosina Desaminasa/deficienciaRESUMEN
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.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Trastornos Histiocíticos Malignos/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/genética , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Trastornos Histiocíticos Malignos/diagnóstico , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
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.
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Neoplasias de la Médula Ósea/complicaciones , Trastornos Histiocíticos Malignos/complicaciones , Leucemia Mieloide Aguda/complicaciones , Mastocitosis Sistémica/complicaciones , Neoplasias Cutáneas/complicaciones , Médula Ósea/patología , Neoplasias de la Médula Ósea/genética , Neoplasias de la Médula Ósea/patología , Células Clonales/patología , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/genética , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Genes Codificadores de la Cadena gamma de los Receptores de Linfocito T , Trastornos Histiocíticos Malignos/genética , Histiocitosis de Células de Langerhans/genética , Cadenas kappa de Inmunoglobulina/genética , Adolescente , Adulto , Anciano , Niño , Sarcoma de Células Dendríticas Foliculares/genética , Sarcoma de Células Dendríticas Foliculares/inmunología , Sarcoma de Células Dendríticas Foliculares/patología , Sarcoma de Células Dendríticas Interdigitantes/genética , Sarcoma de Células Dendríticas Interdigitantes/inmunología , Sarcoma de Células Dendríticas Interdigitantes/patología , Femenino , Predisposición Genética a la Enfermedad , Trastornos Histiocíticos Malignos/inmunología , Trastornos Histiocíticos Malignos/patología , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/inmunología , Sarcoma Histiocítico/patología , Histiocitosis de Células de Langerhans/inmunología , Histiocitosis de Células de Langerhans/patología , Humanos , Sarcoma de Células de Langerhans/genética , Sarcoma de Células de Langerhans/inmunología , Sarcoma de Células de Langerhans/patología , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/análisis , Células Dendríticas Foliculares , Trastornos Histiocíticos Malignos , Queratinas/análisis , Ganglios Linfáticos , Células del Estroma , Biomarcadores de Tumor/genética , Biopsia , Células Dendríticas Foliculares/química , Células Dendríticas Foliculares/ultraestructura , Femenino , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/metabolismo , Trastornos Histiocíticos Malignos/patología , Trastornos Histiocíticos Malignos/cirugía , Humanos , Inmunohistoquímica , Cariotipificación , Escisión del Ganglio Linfático , Ganglios Linfáticos/química , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/ultraestructura , Microscopía Electrónica , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Células del Estroma/química , Células del Estroma/ultraestructura , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Granulocitos/patología , Trastornos Histiocíticos Malignos/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Síndrome de Sweet/patología , Translocación Genética , Trastornos Histiocíticos Malignos/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Enfermedades de los Perros/mortalidad , Cabello , Trastornos Histiocíticos Malignos/veterinaria , Sarcoma/veterinaria , Animales , Cruzamiento , Estudios de Cohortes , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/genética , Perros , Femenino , Predisposición Genética a la Enfermedad , Trastornos Histiocíticos Malignos/epidemiología , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/mortalidad , Masculino , Sarcoma/epidemiología , Sarcoma/genética , Sarcoma/mortalidad , Reino Unido/epidemiologíaRESUMEN
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.
Asunto(s)
Carcinógenos/toxicidad , Genes p53/fisiología , Trastornos Histiocíticos Malignos/inducido químicamente , Nitrosaminas/toxicidad , Sarcoma Experimental/inducido químicamente , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Trastornos Histiocíticos Malignos/genética , Trastornos Histiocíticos Malignos/patología , Homocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Sarcoma Experimental/genética , Sarcoma Experimental/patologíaRESUMEN
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.