Coexistence of immunophenotypically normal and aberrant mast cells in patients with clonal mast cell diseases associates with more indolent subtypes and less severe disease characteristics

Aberrant antigen expression on mast cells (MCs) is one of the most accurate diagnostic markers for clonal MC diseases (CMCD). Although the coexistence of normal and pathologic MCs is frequently seen, the disease characteristics associated with it have been minimally investigated. We aimed to gain further insight into the relevance of partial aberrancy for establishing the diagnosis and risk stratification of systemic mastocytosis (SM) and monoclonal MC activation syndromes (MMAS). In patients with MMAS or SM, MC load, KIT D816V variant allele fraction (VAF), immunophenotype, mutational profile, basal serum tryptase (BST), and hematology parameters were evaluated to characterize the coexistence of normal and aberrant MCs. From 207 patients with CMCD, 75% of patients with MMAS, 67% with non-advanced SM (non-AdvSM), and 27% with advanced SM (AdvSM) exhibited partial aberrancy. This turned out to be one of the most discriminative parameters between indolent and advanced subtypes. Partial aberrancy was associated with less severe disease characteristics, that is, more indolent subtype, lower MC burden, KIT D816V VAF and BST, a mature MC immunophenotype, hematological parameters more closely corresponding to the normal-range values, and in a subgroup of patients with an SM-AHN, a less complex mutational profile. Assessing the coexistence of normal and pathologic MCs is a widely available, fast, and sensitive diagnostic and prognostic tool and may also be used in SM disease follow-up and treatment monitoring.