Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology

Abstract

Mastocytosis is a rare disease characterized by abnormal expansion and accumulation of tissue mast cells (MC) in one or multiple organs. In most adult patients, systemic mastocytosis (SM) is diagnosed. Based on histopathological findings and organ damage, SM is divided into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM), and MC leukemia (MCL). The clinical course and prognosis vary greatly among these groups of patients. In all variants of SM and most patients, neoplastic cells display the KIT mutation D816V. This suggests that additional KIT-independent molecular defects cause progression. Indeed, additional oncogenic lesions, including RAS- and TET2 mutations, have recently been identified in advanced SM. In patients with SM-AHNMD, such additional lesions are often detectable in the 'AHNMD-component' of the disease. Clinically relevant symptoms of SM result from i) malignant MC infiltration and the subsequent organ damage seen in advanced SM and/or ii) the release of pro-inflammatory and vasoactive mediators from MC, found in all disease-variants. Therapy of SM has to be adjusted to the individual situation in each patient. In ISM, the aim is to control mediator release and mediator effects. In advanced SM, a major goal is to control MC expansion by using conventional drugs or novel targeted drugs directed against mutant forms of KIT and/or other pro-oncogenic kinase-targets. In rapidly progressing ASM, MCL and drug-resistant AHNMD, chemotherapy and subsequent stem cell transplantation has to be considered.

Keywords: KIT mutations; Mastocytosis; mast cells; rare disease; targeted therapy.