Clinical, Biological, and Molecular Characteristics of Well-Differentiated Systemic Mastocytosis: a study in 18 Patients by Spanish Network on Mastocytosis (REMA)
Authors: Alvarez-Twose Iván , Sánchez-Muñoz Laura , Jara-Acevedo María , Teodosio Cristina , García-Montero Andrés , García-Cosio Mónica , Mollejo Manuela , Orfao Alberto , Escribano Luis María 
Published: April 2020

Abstract
BACKGROUND: Well-differentiated systemic mastocytosis (WDSM) has recently been described as a novel form of mast cell disease. WDSM is characterized by a marked increase of bone marrow (BM) mast cells, usually with compact aggregates, with normal phenotype and morphology as well as the absence of the typical D816V somatic KIT mutation.
OBJECTIVE: To describe and compare clinical, morphological, biological and molecular characteristics in a group of 18 patients who fullfilled criteria for WDSM with a group of 32 patients with indolent systemic mastocytosis (ISM).
PATIENTS AND METHODS: All the patients were diagnosed on the basis of BM aspirate and biopsy findings after they were thought to have a systemic mastocytosis. A rigorous skin examination together with a clinical work-up and a complete laboratory analysis including peripheral blood count, routine biochemistry and serum tryptase levels were performed. The Mann-Whitney U and the chi-square tests were used to assess the statistical differences of continuous and categorical variables, respectively.
RESULTS: WDSM patients were 4 males and 14 females with a median (range) age of 24 years (2–72) at diagnosis. Median (range) age at the time of the first observation of skin lesions was 2 years (0–41). In 16 of the 18 patients (89%), skin lesions appeared under the age of 14, five of them being younger than 1 year old. All the WDSM patients had skin involvement but the typical maculo-papular lesions were found only in 18% of patients while in the remaining 82% of cases, cutaneous lesions were plaques or nodules. Interestingly, 78% of WDSM patients had cutaneous neck involvement in contrast with only 13% in the ISM group (p&lt;0.001). There were no significant differences in mast cell mediators-related symptoms such as pruritus, flushing, abdominal pain or diahrrea between the two groups while anaphylactic reactions were significantly more frequent in the WDSM group than in the ISM group (59% vs 19%, p=0.004). Overall, bone loss was found in 38% and 37% of WDSM and ISM patients, respectively. Among all the biochemical parameters analyzed, only median serum cholesterol (mg/dL), ferritin (ng/mL) and tryptase levels (ng/mL) were significantly lower in patients with WDSM when compared to ISM patients (150 vs 168.5, p=0.043; 31.3 vs 56.6, p=0.004; 11 vs 31.6, p&lt;0.001; respectively). There were no significant differences in the median percentage of mast cells in the BM study as assesed by flow cytometry between both groups (0.055% in WDSM group and 0.08% in ISM group). In contrast, the presence of both fibrosis and lymphoid aggregates in the BM biopsy were more frequent in patients with ISM than in patients with WDSM (52% vs 0%, p&lt;0.001; 55% vs 14%, p=0.01; respectively). Somatic KIT mutation at codon 816 was found in 31 of the 32 ISM patients (97%) while only in one (6%) WDSM patient (p&lt;0.001). Additionally, 2 WDSM patients were found to carry variant mutations at codons other than at codon 816 (N819Y and I817V, respectively). From the remaining 15 WDSM patients, clonality of mast cell population was demonstrated by human androgen receptor (HUMARA) assay in the 5 female patients in whom the assay was made.
CONCLUSIONS: WDSM is a variant of systemic mastocytosis with several characteristics that are distinguishable from ISM, such as:
early onset of skin lesions, atypical skin involvement (plaques or nodules and cutaneous neck involvement), frequent anaphylactic episodes, lower serum tryptase levels than ISM despite no differences in BM mast cell infiltration, and infrequent detection of typical activating D816V KIT mutation.