Laboratory evaluation of patients with suspected systemic mastocytosis (SM) includes: (1) morphologic review of bone marrow biopsies and aspirates, (2) molecular testing for the presence of the KIT mutation and (3) immunophenotypic analysis of mast cells and other hematopoietic elements by flow cytometry. Recently, we have developed RT-PCR/RFLP assay for detection of the most prevalent KIT mutation in mastocytosis patients (D816V).The D816V mutation results in constitutive activation of the receptor tyrosine kinase and is believed to be involved in disease pathogenesis. We have also developed a flow cytometric assay for immunophenotypic analysis of mast cells, since it has been recently described that neoplastic mast cells display aberrant immunophenotype, most notably, aberrantly coexpress CD117 with CD25 and/or CD2. So far, the results of our analysis show complete concordance between diagnosis of systemic mastocytosis, the presence of KIT D816V point mutation, and aberrant expression of CD25 antigen on mast cells. Expression of CD2 antigen on mast cells is detected in 57% of patients with systemic mastocytosis. Aberrant expression of CD25 and CD2 is not detected in normal marrow mast cells. ? The identification of the KIT D816V mutation in patients with systemic mastocytosis has lately gained a major prognostic significance, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. Imatinib was shown to be ineffective in patients carrying KIT D816V mutation, but effective in cases with some other mutations. Therefore, it is of paramount importance to correctly identify SM patients with KIT D816V mutation. Although most patients with SM do not have peripheral blood eosinophilia, both bone marrow and peripheral blood eosinophilia have been reported in D816V mutation-positive patients. In these cases, the broad and overlapping clinical manifestations between the patients with D816V KIT-associated systemic mastocytosis with eosinophilia and patients with chronic eosinophilic leukemia (CEL) associated with FIP1L1/PDGFRA fusion gene present diagnostic challenge. The increase in activated eosinophils and mast cells is seen in both disorders, and has led to confusion in the nomenclature. It is of paramount importance, however, to distinguish between these two groups of patients because of differences in clinical sequelae, prognoses and selection of treatment. This has profound consequences for patients with these disorders, since the FIP1L1/PDGFRA and D816V mutations respond dramatically differently to therapy. Most notably, the FIP1L1/PDGFRA fusion kinase, but not D816V KIT mutation, is inhibited by imatinib. We thus sought to identify clinical and laboratory features that could be used to distinguish these two diagnoses. We compared 12 patients with D816V-positive systemic mastocytosis with eosinophilia with 17 patients with FIP1L1/PDGFRA-positive CEL. Distinguishing features were used to create a risk factor scoring system. This system correctly classified 16/17 FIP1L1/PDGFRA-positive CEL patients, and all 12 systemic mastocytosis with eosinophilia patients. Thirty-four FIP1L1/PDGFRA-positive patients described in the literature were also classified using this system, and although a complete set of data was not available for any of the historical patients, 21 were correctly classified. These results reinforce the hypothesis that the FIP1L1/PDGFRA gene fusion and D816V-KIT mutation cause distinct clinical syndromes. This novel diagnostic approach should prove helpful in clinical practice in the evaluation of patients with increased mast cells burden and peripheral eosinophilia.
| Maric, Irina; Robyn, Jamie; Metcalfe, Dean D et al. (2007) KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol 120:680-7 |
