Importance of adequate diagnostic work-up for correct diagnosis of advanced systemic mastocytosis.

Abstract Background Little is known about epidemiology of advanced systemic mastocytosis (advSM). Objectives We sought to investigate epidemiologic features and diagnostic pitfalls of advSM in Germany. Methods Therefore, 140 patients from a single German reference center of the European Competence Network on Mastocytosis between 2003 and 2018 were analyzed. Results Median age was 68 years (range 26-86), male vs. female ratio was 2:1. An elevated serum tryptase, a KIT D816 mutation and additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1 (S/A/R), were identified in 95%, 91% and 74% of patients, respectively. Median overall survival was 3.5 years (range 0.03-14.3; male vs. female 2.6 vs. 4.2 years, p=0.02). Two categories of misdiagnoses were identified in 51/140 (36%) patients: Firstly, systemic mastocytosis (SM) was overlooked in 28/140 (20%) patients primarily diagnosed with various subtypes of myeloid neoplasms. Secondly, 23/140 (16%) patients were diagnosed with supposed progression from indolent SM (ISM) to advSM; however, combination of an elevated KIT D816V variant allele frequency (VAF) in peripheral blood (n=22), monocytosis (n=9), eosinophilia (n=6) and/or mutations in S/A/R (n=10) suggest that distinct signs of potential advSM were overlooked in virtually all patients. Based on locally diagnosed patients in an area of 2.5 million inhabitants, but obviously without considering more, yet unrecognized cases, incidence and prevalence of advSM is at least 0.8 and 5.2, respectively, per 1 million inhabitants. Conclusions Adequate analyses of tryptase levels, bone marrow morphology and genetics in patients with myeloid neoplasms or SM would help to prevent the significant underdiagnosis of advSM.