Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm

Mastocytosis Is characterized by accumulations of mast cells in various organs 1 . Most cases are indolent and confined to the skin, where discrete mast cell infiltrates are associated with increased epidermal melanin, a clinical picture known as urticaria pigmentosa (UP). Other forms of mastocytosis combine UP with aggressive involvement of other organs or with haematologic abnormalities 1–4 . It is not known whether all forms of mastocytosis are true neoplasms or whether some might represent reactive hyperplasias 5–7 . The c- KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT) that is critical to the development and survival of mast cells and melanocytes 8–11 . The ligand for KIT (KL) can stimulate mast cell development, proliferation, and mediator release 9,12–17 , as well as melanocyte proliferation and pigment production 18–20 . To determine the role of c- KIT in the pathogenesis of mastocytosis, we examined tissue and cells isolated from a patient with UP and aggressive systemic mastocytosis with massive splenic involvement. We found a mutation that results in constitutive activation and expression of c- KIT in mast cells of both skin and spleen. This is the first in situ demonstration of an activating c- KIT mutation in neoplastic cells. It also demonstrates the clonal and neoplastic nature of this form of mastocytosis.