RESUMEN
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 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/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/fisiologíaRESUMEN
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.
Asunto(s)
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/metabolismoAsunto(s)
Trastornos Histiocíticos Malignos/complicaciones , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Preescolar , Femenino , Trastornos Histiocíticos Malignos/diagnóstico , Humanos , Neoplasias Cutáneas/diagnóstico , Resultado del TratamientoAsunto(s)
Trastornos Histiocíticos Malignos/patología , Sarcoma/patología , Neoplasias Cutáneas/patología , Anciano , Antineoplásicos/uso terapéutico , Antígeno B7-2/análisis , Diagnóstico Diferencial , Estudios de Seguimiento , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/metabolismo , Humanos , Masculino , Sarcoma/química , Sarcoma/tratamiento farmacológico , Neoplasias Cutáneas/química , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Histiocytic sarcoma is a rare malignant neoplasm. It is well-known the association of Langerhans' cell histiocytosis with Hodgkin's disease but only few cases of histiocytic sarcoma associated with Hodgkin's disease was reported. We present the case of 20-years-old female patient with Hodgkin's disease with a sternal tumor mass which was diagnosed as histiocytic sarcoma. The diagnostic was established immunohistochemically, using a large battery of antibodies (S-100, CD 68, CD 34, CD 15, CD 30, Vim, NFAP) and by electron microscopy which revealed the lack of the Birbeck granules in the malignant proliferated histiocytes.
Asunto(s)
Trastornos Histiocíticos Malignos/patología , Enfermedad de Hodgkin/patología , Sarcoma/patología , Adulto , Femenino , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/cirugía , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/cirugía , Resultado del TratamientoRESUMEN
True histiocytic malignancies (THM) are controversial disorders that are being re-evaluated with modern cellular and molecular biology techniques. True histiocytic lymphoma (THL) is a low-incidence, poor-prognosis THM. It mainly affects the skin, gastrointestinal tract, and bone tissues. Occasionally, skin lesions are the presenting clinical features. A patient with initially cutaneous THL is described. This and other reported cases confirm that THM are a nosologic entity by themselves.