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Demystifying the diagnostic criteria of indolent systemic mastocytosis

Systemic mastocytosis (SM) is a rare neoplasm resulted from a clonal proliferation of abnormal mast cells (MCs) in extra‐cutaneous organs. Previously considered a subgroup of myeloproliferative neoplasms, SM is now classified as distinct disease category due to its unique clinical and pathological features. The clinical scenario of SM can be very heterogeneous, ranging from cutaneous lesions, MC degranulation symptoms, such as diarrhea and vomiting, osteoporosis and episodic anaphylactoid attacks, to multiorgan dysfunction due to MC infiltration. Major criterion for diagnosis of SM is the detection of multifocal dense infiltrates of mast cells (≥15 MCs in aggregates) in the bone marrow (BM) and/or other extra‐cutaneous organs. Identification of KIT D816V mutation counts as a minor diagnostic criterion, together with a persistently elevated serum tryptase level (>20 ng/mL), aberrantMCexpression of CD25 and/or CD2 and abnormal morphology of >25% of all MCs. If the major plus one minor criterion or at least three minor criteria are fulfilled, the diagnosis of SM can be established. In the updated World Health Organization (WHO) classification of hematological malignancies, SM is sub‐classified into five categories: indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic (non‐MC lineage) neoplasm (SM‐AHN), aggressive SM (ASM) and mast cell leukemia (MCL). Clinical features related to MC burden and aggressiveness of the disease are classified as ‘B’ and ‘C’ findings, respectively: the former includes >30% of MC infiltration on BM biopsy and serum total tryptase level >200 ng/mL, signs of dysplasia or myeloproliferation in non‐MC lineage, hepatomegaly with normal liver function, splenomegaly without hypersplenism, and/or lymphadenopathy; the latter encompasses liver impairment or hypersplenism, cytopenias (absolute neutrophil count <1 � 10/L, hemoglobin <10 g/dl, or platelets <100 � 10/L), hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, splenomegaly with hypersplenism, malabsorption with weight loss from gastrointestinal tract MC infiltrates. ISM is characterized by the absence of ‘C’ findings and the presence of less than 2 ‘B’ findings, SSM is defined if 2 or more ‘B’ findings and no ‘C’ findings are detected, the aggressive subgroup in presence of ‘C’ findings. Differently from other SM categories, ISM consists in a low MC burden disease, predominantly characterized by MC mediator release symptoms, frequently with skin involvement. Patients with ISM have typically a normal life expectancy, although anaphylaxis could represent a life‐threatening condition. Treatment goals for ISM patients are primarily directed towards prevention of anaphylaxis with avoidance of symptom triggers, management of severe episodes of anaphylaxis, and control of systemic MC mediator–release symptoms, including osteoporosis. PatientswithMCdegranulation symptomswhodonotmeet all the diagnostic criteria for SM could be diagnosed with ‘monoclonal mast cell activation syndrome’ (MMAS). This condition is characterized by the association of MC activation symptoms or anaphylaxis and/or increased serum tryptase level (also <20 ng/ml or only transiently elevated), in combination with the presence of MC clonality markers (abnormal MC expression of CD25 or KITmutation). It is matter of discussion if MMAS or cutaneous mastocytosis with BM MC clonality might be considered as ‘pre‐diagnostic ISM’. Herein, we report our monocentric experience, as SM referral Centre, about ISM and ‘pre‐diagnostic ISM’, which we defined as MMAS or cutaneous mastocytosis with MC clonality which does not fulfill all SM diagnostic criteria. Our aim was to compare clinical aspects, laboratory features and outcome between these two patient groups. Diagnosis was performed according to WHO 2008 diagnostic criteria for cases diagnosed from 2008 to 2016, and according to WHO 2016 for those diagnosed after 2016. KIT D816V analysis was performed using digital PCR. All statistical analyses considered clinical and laboratory parameters at the time of diagnosis. Patient group with categorical variables were compared using χ test, while differences in the distribution of continuous variables were analyzed by Mann‐Whitney test. Values of p < 0.05 were considered significant. All calculations were performed using IBM‐SPSS v. 21.0. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. Among 200 mastocytosis followed at our Centre through a multidisciplinary approach from 2010 to 2020, we identified 71 ISM patients and 29 ‘pre‐diagnostic ISM’. At diagnosis, median age was 51 years (range 22–86) for ISM and 49 years (range 22–74) for ‘pre‐ diagnostic ISM’; the median symptom durations before diagnosis were 9 and 7 years for ISM and ‘pre‐diagnostic ISM’, respectively.