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.
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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
Canine histiocytic proliferative disorders include aggressive and fatal diseases, such as histiocytic sarcoma (HS) and histiocytosis (SyH). The molecular mechanisms underlying cell proliferation need to be elucidated for the development of effective treatments. In the present study, mRNA expression levels were comprehensively analysed in cell lines derived from localized HS, disseminated HS, SyH and Langerhans cell histiocytosis (LCH) in dogs. Based on the results obtained, the growth inhibitory effects of palbociclib, a CDK4/6 inhibitor, were verified with the cell lines in vitro and in xenograft mouse model. Hierarchical clustering and principal component analysis plots of mRNA expression profiles divided the cell lines into three groups: a localized HS group, disseminated HS/SyH group, and LCH. The results of an ingenuity pathway analysis suggested that the MAPK signalling pathway was activated in the localized HS and LCH cell lines, and the PI3K signalling pathway in the disseminated and localized HS cell lines. In all cell lines, the expression of the tumour suppressor genes TP53, CDKN2A and CDKN1A was down-regulated, whereas that of Rb was preserved. In vitro assessments revealed the growth inhibitory effects of palbociclib in all cell lines examined. In a xenograft mouse model using a cell line from disseminated HS, palbociclib exerted significant growth inhibitory effects. These results suggest the potential of palbociclib as a therapeutic drug candidate for the treatment of malignant histiocytic proliferative disorders of the dog.
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Enfermedades de los Perros , Trastornos Histiocíticos Malignos , Sarcoma Histiocítico , Histiocitosis de Células de Langerhans , Enfermedades de los Roedores , Animales , Línea Celular , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/patología , Perros , Trastornos Histiocíticos Malignos/patología , Trastornos Histiocíticos Malignos/veterinaria , Sarcoma Histiocítico/veterinaria , Histiocitosis de Células de Langerhans/patología , Histiocitosis de Células de Langerhans/veterinaria , Humanos , Ratones , Piperazinas , Piridinas , ARN Mensajero/genéticaRESUMEN
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.
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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.
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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
PURPOSE: Histiocytic and dendritic cell neoplasms are rare hematologic tumors. This study aimed to describe the epidemiologic features of the entire spectrum of histiocytic and dendritic cell neoplasms, including clinicopathological variables and patient outcomes. MATERIALS AND METHODS: We comprehensively reviewed 274 patients who were diagnosed with histiocytic and dendritic neoplasms at Severance Hospital, Seoul, South Korea between 1995 and 2018. RESULTS: The most common neoplasm was Langerhans cell histiocytosis (LCH), followed by dermal xanthogranuloma. Among non-LCH sarcomas, histiocytic sarcoma (HS) showed a relatively high prevalence, followed by follicular dendritic cell sarcoma (FDCS). Disseminated juvenile xanthogranuloma (DJG), Erdheim-Chester disease (ECD), indeterminate dendritic cell tumor (IDCT), and interdigitating dendritic cell sarcoma (IDCS) rarely occurred. Generally, these tumors presented in childhood, although the non-LCH sarcoma (HS/FDCS/IDCS/IDCT) group of tumors and ECD occurred in late adulthood. Multiorgan involvement and advanced Ann-Arbor stage, as well as recurrence and death of disease, were not uncommon. The non-LCH sarcoma group had the worst overall survival, compared to the DJG, ECD, and LCH groups. CONCLUSION: Our findings indicate that histiocytic and dendritic cell neoplasms exhibit heterogeneous epidemiologic characteristics and that some patients may have unfavorable outcomes, especially those with non-LCH sarcoma.
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Células Dendríticas/patología , Histiocitos/patología , Trastornos Histiocíticos Malignos/patología , Sarcoma Histiocítico/patología , Adulto , Niño , Sarcoma de Células Dendríticas Foliculares/epidemiología , Sarcoma de Células Dendríticas Foliculares/patología , Femenino , Trastornos Histiocíticos Malignos/epidemiología , Sarcoma Histiocítico/epidemiología , Histiocitosis de Células de Langerhans/epidemiología , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Prevalencia , República de Corea/epidemiología , Seúl , Xantogranuloma Juvenil/epidemiología , Xantogranuloma Juvenil/patologíaRESUMEN
Multinucleated giant cells (MGCs) are a prominent histological feature of various mesenchymal neoplasms and are often considered a criterion of malignancy. Mesenchymal neoplasms with MGCs for which the cell lineage is unclear generally are referred to as giant cell sarcomas. Here we characterize the gross, histologic, and immunohistochemical features of 90 giant cell sarcomas in domestic pet rabbits. Based on the anatomic location and histologic and immunohistochemical findings, 18 cases were classified as histiocytic sarcomas (HS) and 72 cases as anaplastic sarcomas (AS). At postmortem examination, HS was either localized HS (n = 7) always affecting the lungs, or disseminated HS (n = 10) that affected the lungs (n = 10), liver (n = 6), kidneys (n = 4), pleura (n = 2), mediastinum (n = 2), heart (n = 4), skeletal muscle (n = 1), adipose tissue (n = 1), and lymph node (n = 1). Additionally, one cecal biopsy was consistent with HS. Microscopically, HS were characterized by sheets of neoplastic polygonal to round cells that contained single to several, often greatly enlarged nuclei as well as abundant cytoplasm. HS were always positive for CD204 and always negative for SMA and desmin. In contrast, AS arose most commonly from the skin or subcutis (n = 62) and rarely the skeletal muscle (n = 8) or abdominal organs (n = 2). In 29% of extra-abdominal AS, the tumor deeply invaded into surrounding connective tissue, skeletal muscle, tendons, and bone causing pathological fractures. Five of 9 postmortem cases metastasized to various organs often including the lungs. Microscopically, AS were characterized by sheets of spindle or pleomorphic cells admixed with variable numbers of MGCs. Immunohistochemically, AS were always negative for CD204 and often (71%) positive for SMA and/or desmin.
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Células Gigantes/patología , Conejos , Sarcoma/veterinaria , Animales , Autopsia/veterinaria , Biomarcadores de Tumor , Biopsia/veterinaria , Trastornos Histiocíticos Malignos/patología , Trastornos Histiocíticos Malignos/veterinaria , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/veterinaria , Inmunohistoquímica/veterinaria , Metástasis de la Neoplasia/patología , Sarcoma/patologíaRESUMEN
No disponible
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Humanos , Masculino , Persona de Mediana Edad , Hiperparatiroidismo Primario/etiología , Hiperparatiroidismo Primario/cirugía , Neoplasias de las Paratiroides/complicaciones , Hiperparatiroidismo Primario/diagnóstico por imagen , Paratiroidectomía , Tomografía Computarizada por Rayos X , Trastornos Histiocíticos Malignos/patologíaRESUMEN
Histiocytic and dendritic cell neoplasms are very rare, belonging to a group that share morphologic, immunophenotypic, and ultrastructural characteristics of mature histiocytic/dendritic neoplasms. Histiocytic and dendritic cell neoplasms may arise de novo or in association with B-cell, T-cell, or myeloid neoplasms. Recent molecular findings, particularly the discoveries of the mutations in the RAS-RAF-MEK-ERK pathway, have greatly advanced the diagnosis and treatment options. Histiocytic and dendritic cell neoplasms may closely resemble each other, non-hematopoietic neoplasms, and even reactive processes. Therefore, it is essential to understand the clinicopathologic characteristics, differential diagnoses, and pitfalls of each entity.
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Células Dendríticas/patología , Trastornos Histiocíticos Malignos/patología , Diagnóstico Diferencial , Humanos , PronósticoRESUMEN
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.
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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/genéticaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células Dendríticas/patología , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Terapia Recuperativa , Animales , Abejas , Médula Ósea/patología , Bortezomib/administración & dosificación , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Traumatismos del Antebrazo/complicaciones , Trastornos Histiocíticos Malignos/complicaciones , Trastornos Histiocíticos Malignos/patología , Humanos , Mordeduras y Picaduras de Insectos/complicaciones , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , FN-kappa B/fisiología , Proteínas de Neoplasias/fisiologíaAsunto(s)
Carcinoma de Células en Anillo de Sello/patología , Neoplasias de los Párpados/patología , Trastornos Histiocíticos Malignos/patología , Anciano , Biopsia , Neoplasias de los Párpados/diagnóstico por imagen , Humanos , Inmunohistoquímica , Masculino , Tomografía Computarizada Multidetector/métodosRESUMEN
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/genéticaRESUMEN
This article focuses on cutaneous hematopoietic neoplasms that are more likely to be encountered in the pediatric age-group and includes both lymphoproliferative and histiocytic disorders. The cutaneous hematologic disorders in children have a different epidemiologic profile to what is seen during adulthood. Although mycosis fungoides is the most frequent form of cutaneous lymphoma in adults, it is very rare in children. Because lymphoblastic leukemias and lymphomas are more frequent in the pediatric setting, cutaneous leukemic infiltrates are relatively common in this age-group. Similarly, histiocytic disorders are more common in children, particularly Langerhans cell histiocytosis and juvenile xanthogranuloma. Notably, the histiocytic disorders have undergone significant modifications on their nomenclature in the basis of the molecular characteristics that are present in them. A summary of the most frequent cutaneous hematopoietic disorders in children will be discussed further in this review.
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Neoplasias Hematológicas/patología , Trastornos Histiocíticos Malignos/patología , Trastornos Linfoproliferativos/patología , Neoplasias Cutáneas/patología , Niño , Diagnóstico Diferencial , Neoplasias Hematológicas/diagnóstico , Trastornos Histiocíticos Malignos/diagnóstico , Humanos , Trastornos Linfoproliferativos/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms. We correlated EZH2 expression with that of p-ERK1/2, MYC, and p-STAT3, potential regulators of EZH2, and found that 60-80% of these cases showed strong p-ERK1/2 expression, and only a minority of cases showed positivity for MYC or p-STAT3 in neoplastic cells. In cases of follicular dendritic cell sarcoma, Langerhans cell histiocytosis, histiocytic sarcoma, and interdigitating dendritic cell sarcoma with strong EZH2 expression, 90%, 89%, 70%, and 100% of cases showed co-expression of p-ERK1/2 with EZH2, respectively, while only a small percentage of these cases showed MYC or p-STAT3 co-expression with EZH2 (≤30%). These findings suggest that the p-ERK1/2 signaling cascade, but not the p-STAT3 and MYC signaling cascades, may regulate EZH2 expression in histiocytic and dendritic cell neoplasms, and that EZH2 and the p-ERK1/2 signaling cascade could serve as therapeutic targets for the treatment of these neoplasms. Interestingly, only a minority of cases of blastic plasmacytoid dendritic cell neoplasm exhibited high EZH2 expression, and only a minority of these cases showed p-ERK1/2 co-expression, suggesting that alternative mechanisms may contribute to tumorigenesis in this aggressive neoplasm.
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Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Trastornos Histiocíticos Malignos/metabolismo , Histiocitosis de Células de Langerhans/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Transducción de Señal/fisiología , Biomarcadores de Tumor/análisis , Trastornos Histiocíticos Malignos/patología , Histiocitosis de Células de Langerhans/patología , Humanos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Indeterminate cell histiocytosis is a rare disease belonging to the group of malignant histiocytic diseases. The disease predominantly affects the skin. The disease appeared in the described patient at the age of 80 years. Morphs began to develop on the skin and rapidly spread over the whole body including the face. Only the hands and feet were left uncovered. The patients skin samples were taken from 2 sites for histological examination. The resulting conclusion was indeterminate cell histiocytosis. The treatment we chose was analogous to the procedures for Langerhans cell histiocytosis. We chose PUVA phototherapy as the first-line treatment. This treatment is frequently efficient for skin forms of Langerhans cell histiocytosis. In the described case, however, PUVA phototherapy did not influence the disease activity at all. As the second-line treatment, we used low-energy electron beam irradiation in the total dose of 36.2 Gy. This treatment had a positive impact, morphs began to diminish and slowly disappear from the skin. But they have not disappeared completely, therefore we assessed the treatment effect of the radiotherapy itself as partial remission of the disease. Within the third-line treatment, we used 2-chlorodeoxyadenosine in a dose of 5 mg/m2/per day, administered via subcutaneous injection over 5 consecutive days in monthly intervals. There were three cycles of this treatment administered overall. The treatment with 2-chlorodeoxyadenosine was tolerated without any adverse effects. The patient aged 82 years was only administered 3 cycles of 2-chlorodeoxyadenosine. When after the 3rd cycle the skin was free from any pathological morphs and only some pigmentation spots remained, we finished the treatment. The skin expressions of indeterminate cell histiocytosis completely disappeared after electron beam irradiation and the following administration of 3 cycles of 2-chlorodeoxyadenosine. The remission was short, however, after 6 months the disease recurred and the treatment is planned to resume. We assume the disease regresses following administration of 2-chlorodeoxyadenosine, but more than 3 treatment cycles will probably be needed to reach a longer-term response.Key words: electron beam irradiation - indeterminate cell histiocytosis - 2-chlorodeoxyadenosine.
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Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Trastornos Histiocíticos Malignos/terapia , Terapia PUVA/métodos , Radioterapia/métodos , Neoplasias Cutáneas/terapia , Anciano de 80 o más Años , Trastornos Histiocíticos Malignos/patología , Humanos , Inyecciones Subcutáneas , Masculino , Neoplasias Cutáneas/patologíaRESUMEN
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
Information about histiocytic disease in cats is limited. The aim of this study was to document clinical findings and outcome in feline histiocytic disorders, and characterize the expression of PDGFRß and KIT in order to identify potential treatment targets. Morphologically diagnosed feline histiocytic tumours were reviewed and characterized by immunohistochemistry (IHC). Five cases of feline progressive histiocytosis (FPH), eight histiocytic sarcomas (HS) and two haemophagocytic histiocytic sarcomas (HaeHS) were confirmed. PDGFRß was variably positive in most histiocytic cases, while KIT was negative in all. Clinical presentation, treatment and outcome were also evaluated. Partial responses were recorded in measurable disease with tyrosine kinase inhibitors and lomustine, and radiotherapy achieved long-term control in some cases. Survival times were shortest in HaeHS and disseminated disease. PDGFRß, but not KIT, may represent a therapeutic target in feline histiocytic disorders but more studies are needed to investigate other potential treatment targets.
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Enfermedades de los Gatos/metabolismo , Trastornos Histiocíticos Malignos/veterinaria , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Animales , Biomarcadores de Tumor , Enfermedades de los Gatos/diagnóstico , Enfermedades de los Gatos/patología , Gatos , Bases de Datos como Asunto , Femenino , Trastornos Histiocíticos Malignos/metabolismo , Trastornos Histiocíticos Malignos/patología , Trastornos Histiocíticos Malignos/terapia , Inmunohistoquímica/veterinaria , Masculino , Estadificación de Neoplasias , Resultado del Tratamiento , Reino UnidoRESUMEN
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
The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.