Clinical Information

Systemic mastocytosis (SM) is a hematopoietic neoplasm that is now recognized as a distinct entity in the current World Health Organization and International Consensus Classifications. SM is characterized by a proliferation of neoplastic mast cells in the bone marrow and rarely in extramedullary sites. SM may present with variable degrees of clinical severity and can sometimes be associated with a non-mast cell hematologic neoplasm. SM is diagnosed using a combination of major and minor criteria, encompassing morphologic, biochemical and molecular genetic features. An important minor criterion is the presence of an activating somatic mutation in the KIT gene, encoding the tyrosine kinase receptor for stem cell factor, which is a critical growth factor in early myeloid cell proliferation and development. In SM, the most common KIT alteration is a missense change in exon 17 at codon 816, p.Asp816Val (D816V). Much less frequently, other missense mutations involving the D816 codon or adjacent amino acids are encountered and rarely, KIT genetic alterations can occur in other exons. A subset of acute myeloid leukemias (AML) with core-binding factor gene fusions can also acquire activating KIT gene mutations, including D816V in many cases. Detection of KIT D816V is critical to help establish a diagnosis of SM and is optimally determined by molecular testing. Because mast cell lesions are typically sparse and fibrotic in bone marrow and circulating tumor mast cells are in low abundance, highly sensitive and specific assays are required for optimal detection of KIT D816V. This can be achieved using quantitative allele-specific polymerase chain reaction (PCR) or droplet digital PCR (ddPCR) methods. The presence of KIT D816V mutation in the appropriate clinical and pathologic context is highly supportive of SM. In addition, although the D816V in SM is insensitive to targeted therapy with imatinib, other tyrosine kinase inhibitors such as avapritinib have demonstrated significant therapeutic efficacy in advanced SM, indicating that this mutation may also be a theranostic marker for these patients.