Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal

Abstract

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of 'MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D(2), or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

Fig. 1

Diagnostic algorithm in patients with suspected MCA disorder. In a first step, the clinical checkpoint ‘MCA’ has to be established by MCA criteria. Then, the patient is examined for signs and symptoms of a clonal MC disorder, i.e. the presence of (mono)clonal MCs and signs and symptoms of an underlying comorbidity that would explain MCA, such as an allergy or chronic inflammation (secondary MCA). When MC clonality is proven, the exact variant of mastocytosis needs to be defined. If only 1 or 2 minor SM criteria are found and no cutaneous involvement is detected, the final diagnosis is (mono)clonal MCAS. Note here that the KIT mutation D816V already counts as a first minor SM criterion. If no underlying disease is detected in a patient with MCA, the final diagnosis is idiopathic MCAS. In some of the patients, the evaluation will show that both a primary MCAS and additional secondary MCAS (e.g. mastocytosis plus IgE-dependent allergy) are present (asterisk). Note that for both immunophenotyping of mast cells and KIT mutation analysis, adequate samples and methods sufficient for revealing defects in small cell numbers should be applied. With regard to KIT mutations, both the classical mutant KIT D816V, but also other KIT mutations in exon 17 should count as signs of MC (mono)clonality. SM_SY = SM with mediator-related symptoms requiring therapy, i.e. SM accompanied by primary MCA(S). MIS = Mastocytosis in the skin.