A proposed classification of mastocytosis incorporating molecular genetics

Recent studies have suggested that mutations in c-kit are a probable cause of some forms of mastocytosis.(10) C-kit is a proto-oncogene that encodes a receptor tyrosine kinase (kit), which is the receptor for stem cell factor (SCF, also known as mast cell growth factor).(2, 4, 5, 8, 12, 17, 19) Because neoplastic mast cells expressing specific c-kit mutations may be susceptible to different forms of therapy,(10, 11) we decided to reconsider previous classification schemes for mastocytosis in light of the developing knowledge of c-kit mutations and their relationship to different clinical forms of the disease. In this article, a classification system based on a combination of molecular, genetic, and clinical features is outlined. The goal is to develop a classification, as shown in Box 1, that will be relevant to researchers and to practitioners caring for patients and that is flexible enough to accommodate current and future molecular genetic data regarding the pathogenesis of mastocytosis. This scheme can be related to previous classification systems for retrospective with adult-onset mastocytosis. In patients with atypical pediatric-onset disease, the mutation can be found in multiple cell lineages, indicating involvement of an early, multipotent cell in the development of mastocytosis.(1, 14) Furthermore, although the authors have not detected juxtamembrane mutations in human material other than the HMC-1 cell line, they have found a number of juxtamembrane mutations present in canine mast cell neoplasms.(10, 11, 14) Taken together, these data suggest that c-kit activation mutations have a causal role in essentially ail cases of sporadic adult mastocytosis and in cases of pediatric mastocytosis with diffuse cutaneous mastocytosis and atypical urticaria pigmentosa. The clinical correlate of these activating mutations is disease which is persistent or progressive and which may require therapy that specifically inhibits activated kit. Detecting and defining the specific type of mutation in an individual patient is useful, especially for pediatric patients, because it allows assignment into a prognostic category. Furthermore, because activation loop mutations are more resistant to inhibition than are juxtamembrane mutations,(11) subclassification based on specific types of mutations will be important to slide therapy.