155 - Histiocytoses

Abstract

The histiocytoses are characterized by the accumulation in various organs of abnormal cells having features reminiscent of macrophages or dendritic cells. These diseases are heterogeneous in their clinical behaviors and outcomes, but recent advances in molecular genetics have led to a new nosology that divides histiocytic diseases into five categories: L Group: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease, and indeterminate cell histiocytosis; C Group: non-Langerhans cell histiocytoses involving skin or mucosa and comprising both xanthogranuloma and nonxanthogranuloma subtypes; M Group: primary and secondary malignant histiocytoses; R Group: Rosai-Dorfman-Destombes disease and other noncutaneous, non-Langerhans cell histiocytoses; H Group: hemophagocytic lymphohistiocytosis and macrophage activation syndrome. The discovery of constitutive activation of the mitogen-activated protein kinase pathway, due largely to mutations in BRAF and MAP2K1, in Langerhans cell histiocytoses and Erdheim-Chester disease has led to clinical trials and observational studies describing major clinical responses to BRAF and MEK1 inhibitors. Targeted therapies based on gene mutations in other histiocytoses have also been effective. However, the role of these interventions in the standard treatment of these diseases awaits the results of ongoing clinical trials. In its familial form, hemophagocytic lymphohistiocytosis is associated with null germline mutations in genes encoding immune proteins such as perforin. Acquired hemophagocytic lymphohistiocytosis, triggered by malignancy, infection, or autoimmune disease, may be associated with hypomorphic alleles of these genes. Both forms are treated by immune suppression; hematopoietic stem cell transplantation may also be considered.