Histiocytic neoplasms in the era of personalized genomic medicine

Abstract

Purpose of Review Since the discovery of BRAFV600E mutations in histiocytic neoplasms, diverse kinase alterations have been uncovered in BRAFV600E-wildtype histiocytoses. The purpose of this review is to outline recent molecular advances in histiocytic neoplasms and discuss their impact on the pathogenesis and treatment of these disorders. Recent Findings Activating kinase alterations discovered in BRAFV600E-wildtype Langerhans (LCH) and non-Langerhans cell histiocytoses (non-LCH) result in constitutive activation of the mitogen-activated protein kinase (MAPK) and/or PI3K/AKT pathways. These kinase alterations include activating mutations in ARAF, MAP2K1, NRAS, KRAS, and PIK3CA kinases in LCH and non-LCH; BRAF, ALK, and NTRK1 fusions, as well as the ETV3-NCOA2 fusion in non-LCH; and mutations in the MAP3K1 and HRAS kinases in LCH and histiocytic sarcoma, respectively. These discoveries have refined the understanding of the histiocytoses as clonal, myeloid neoplasms driven by constitutive MAPK signaling and identified molecular therapeutic targets with promising clinical responses to RAF and MEK inhibition. Summary Genomic analyses over the last 6 years have identified targetable kinase alterations in BRAFV600E-wildtype histiocytic neoplasms. However, despite this progress, the molecular pathogenesis and therapeutic responsiveness of non-BRAFV600E kinase alterations are still poorly defined in these disorders.

JAG2 signaling induces differentiation of CD14+ monocytes into Langerhans cell histiocytosis-like cells

“…Skin LCH frequently presents as refractory eczematous rash, whereas bone LCH usually causes osteolytic bone lesions with associated soft‐tissue masses . Genomic analysis has recently redefined our view of histiocytoses and LCH is now commonly defined as a clonal neoplasm driven by constitutive activation of MAPK signaling . In 50–60% of cases, the MAPK activation is driven by the BRAF V600E mutation …”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…Recurrent mutations activating MAPK signaling are present in the majority of patients with Langerhans cell histiocytosis (LCH) and ErdheimChester disease (ECD; newly added as a distinct entity in the 2016 WHO revision 114 ) with ;50% of patients having a BRAFV600E mutation 170 while BRAFV600 wild-type patients harbor mutually exclusive MAP2K1, ARAF, NRAS, or KRAS mutations (reviewed recently by Durham et al 171 ). Rare in-frame activating deletions in BRAF 172 as well activating BRAF, ALK, and NTRK1 fusions have also been identified in BRAFV600 wild-type cases.…”

Sarcoma histiocítico: presentación de un caso probable

“…Esta entidad corresponde a un tipo de desorden histiocitario que pertenece a un grupo de enfermedades con clínica y pronósticos heterogéneos. Las neoplasias histiocitarias se dividen en dos grupos: histiocitosis de células de Langerhans e histiocitosis no Langerhans [15] , perteneciendo el sarcoma histiocítico a éste último. Se define por la acumulación de histiocitos, células derivadas de monocitos de la médula ósea que migran desde la sangre periférica a diferentes tejidos, aunque la proliferación local también se ha descrito [16] .…”

“…Diagnóstico: Compatible con afectación de médula por Sarcoma Histiocítico. [15] . Su etiología es desconocida, se ha visto algunos casos asociados en pacientes con tumores mediastinales de células germinales ya que en presencia de estos tumores hay células pluripotenciales capaces de dar lugar a colonias de macrófagos y otros tipos de células [17] .…”

“…El marcador ki67 se describe como variable. También se ha descrito al ser un desorden histiocitario no Langerhans como inmunorreactivo para factor XIIIa y CD14, algunos expresan S100 [15) . La citometría de flujo tiene múltiples reportes en la literatura donde reconocen su importancia e incluso se han descrito casos de su utilización como único orientador hacia este diagnóstico [18,25] .…”