Clinical Information

Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPDs). These neoplasms are characterized by excessive proliferation of 1 or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B-cells are frequently part of the neoplastic clone.

Function-altering point mutations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT mutation is an adenine-to thymine base substitution (A->T) at nucleotide position 2468, which results in an aspartic acid-to-valine change in the protein (Asp816Val). Much less frequently, other mutations at this same location are found and occasional cases with mutations at other locations have also been reported. Mutations at the 816 codon are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation.

Detection of a mutation at the 816 codon is included as 1 of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization (WHO) classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPDs. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the mutation; some having positivity only in mast cells and others having positivity in additional myeloid and even lymphoid lineages. The mutation has not been reported in normal tissues.