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) Beca use neoplastic mast cells expressing specific c-kit mutations may be suscep tible to different forms of therapy,(10, 11) we decided to reconsider previ ous classification schemes for mastocytosis in light of the developing know ledge of c-kit mutations and their relationship to different clinical forms of the disease. In this article, a classification system based on a combin ation 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 r esearchers and to practitioners caring for patients and that is flexible en ough to accommodate current and future molecular genetic data regarding the pathogenesis of mastocytosis. This scheme can be related to previous class ification systems for retrospective with adult-onset mastocytosis. In patie nts with atypical pediatric-onset disease, the mutation can be found in mul tiple cell lineages, indicating involvement of an early, multipotent cell i n 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 prese nt in canine mast cell neoplasms.(10, 11, 14) Taken together, these data su ggest that c-kit activation mutations have a causal role in essentially ail cases of sporadic adult mastocytosis and in cases of pediatric mastocytosi s with diffuse cutaneous mastocytosis and atypical urticaria pigmentosa. Th e clinical correlate of these activating mutations is disease which is pers istent or progressive and which may require therapy that specifically inhib its 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 acti vation loop mutations are more resistant to inhibition than are juxtamembra ne mutations,(11) subclassification based on specific types of mutations wi ll be important to slide therapy.