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Mast Cell Activation Disease: a Concise Practical Guide for Diagnostic Workup and Therapeutic Options

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Mast Cell Activation Disease: a Concise Practical Guide for Diagnostic Workup and Therapeutic Options Molderings et al. Journal of Hematology & Oncology 2011, 4:10 http://www.jhoonline.org/content/4/1/10 JOURNAL OF HEMATOLOGY & ONCOLOGY REVIEW Open Access Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options Gerhard J Molderings1*, Stefan Brettner2, Jürgen Homann3, Lawrence B Afrin4 Abstract Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells’ mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient’s presentation. Introduction tissue responses to mast cell mediators released both The term mast cell activation disease (MCAD) denotes spontaneously and in response to trigger stimuli. a collection of disorders characterized by (1) accumula- A rare variant of MCAD is mast cell leukemia (MCL; tion of pathological mast cells in potentially any or all Table 1). This aggressive mast cell neoplasm is defined organs and tissues and/or (2) aberrant release of variable by increased numbers of mast cells in bone marrow subsets of mast cell mediators. A classification has been smears (≥20%) and by circulating mast cells (reviewed in proposed which differentiates several types and sub- [2]). Patients typically suffer from rapidly progressive classes of MCAD (Table 1). The traditionally recognized organopathy involving the liver, bone marrow and other subclass termed systemic mastocytosis (SM) includes dis- organs. The bone marrow typically shows a diffuse, orders characterized by certain pathological immunohis- dense infiltration with mast cells. In typical MCL, mast tochemical and mutational findings (the WHO criteria; cells account for more than 10% of blood leukocytes. In Table 2; [1,2]) which are divided into several subtypes a smaller group of patients, pancytopenia occurs and (Table 1). On the other hand, mast cell activation syn- mast cells account for less than 10% (aleukemic variant drome (MCAS) presents a complex clinical picture of of MCL). The prognosis in MCL is poor. Most patients multiple mast cell mediator-induced symptoms, failure survive less than 1 year and respond poorly to cytore- to meet the WHO criteria for diagnosis of SM, and ductive drugs or chemotherapy. exclusion of relevant differential diagnoses [1,3-5]. Mast cell activation disease in general has long been Symptoms observed in patients with MCAS are little, if thought to be rare. However, although SM and MCL as any, different from those seen in patients with SM [6-8]. defined by the WHO criteria are truly rare, recent find- Patients present variable and often fluctuating patterns ings suggest MCAS is a fairly common disorder. Evi- of symptoms (Table 3; [9-15]) which depend on the dence has been presented for a causal involvement of pathologically active mast cells not only in the patho- genesis of SM and MCAS but also in the etiology of * Correspondence: [email protected] idiopathic anaphylaxis [16-18], interstitial cystitis [19], 1 Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud- some subsets of fibromyalgia [20,21] and some subsets Str. 25, D-53127 Bonn, Germany Full list of author information is available at the end of the article of irritable bowel syndrome [22-24]. © 2011 Molderings et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Molderings et al. Journal of Hematology & Oncology 2011, 4:10 Page 2 of 8 http://www.jhoonline.org/content/4/1/10 Table 1 Classification of mast cell activation disease Table 2 Criteria proposed to define mast cell activation (modified from [2-4]) disease (for references, see text) Mast cell activation disease Criteria to define mast cell WHO criteria to define systemic (MCAD) activation syndrome mastocytosis Mast cell activation syndrome Major criteria Major criterion (MCAS) 1. Multifocal or disseminated Multifocal dense infiltrates of mast Systemic mastocytosis (SM) dense infiltrates of mast cells in cells (>15 mast cells in aggregates) defined by the WHO criteria • Indolent systemic mastocytosis bone marrow biopsies and/or in in bone marrow biopsies and/or in • Isolated bone marrow mastocytosis sections of other extracutaneous sections of other extracutaneous • Smoldering systemic mastocytosis organ(s) (e.g., gastrointestinal tract organ(s) (CD117-, tryptase- and • Systemic mastocytosis with an biopsies; CD117-, tryptase- and CD25-stained) associated clonal hematologic non- CD25-stained) mast cell lineage disease 2. Unique constellation of clinical • Aggressive systemic mastocytosis complaints as a result of a Mast cell leukemia (MCL) pathologically increased mast cell activity (mast cell mediator release syndrome) Minor criteria Minor criteria Pathogenesis 1. Mast cells in bone marrow or 1. Mast cells in bone marrow or Mutations in kinases (particularly in the tyrosine kinase other extracutaneous organ(s) other extracutaneous organ(s) Kit) and in enzymes and receptors (JAK2, PDGFRa, show an abnormal morphology show an abnormal morphology (>25%) in bone marrow smears or (>25%) in bone marrow smears or RASGRP4, Src-kinases, c-Cbl-encoded E3 ligase, hista- in histologies in histologies mine H4 receptor) which are crucially involved in the 2. Mast cells in bone marrow 2. Mast cells in bone marrow regulation of mast cell activity have been identified as express CD2 and/or CD25 express CD2 and/or CD25 necessary to establish a clonal mast cell population, but 3. Detection of genetic changes in 3. c-kit mutation in tyrosine kinase other abnormalities yet to be determined must be added mast cells from blood, bone at codon 816 in mast cells in marrow or extracutaneous organs extracutaneous organ(s) for the development of a clinically symptomatic disease for which an impact on the state ([7,8,25,26]; further references therein). The observations of activity of affected mast cells in that the same KIT mutation (e.g. D816V) can be asso- terms of an increased activity has ciated with both good prognosisaswellasprogression been proved. 4. Evidence of a pathologically 4. Serum total tryptase >20 ng/ml to advanced disease [27] and that the D816V mutation increased release of mast cell (does not apply in patients who has also been detected in healthy subjects [28] highlight mediators by determination of the have associated hematologic non- the potential role of other factors in determining the content of mast-cell lineage disease) progression/outcome of the disease. Recent findings sug- • tryptase in blood gest that the immunohistochemical and morphological • N-methylhistamine in urine alterations which constitute the WHO criteria for SM • heparin in blood (formation of mast cell clusters; spindle-shaped mor- • chromogranin A in blood phology of mast cells; expression of CD25 on mast cells; • other mast cell-specific Table 2) are causally related to and specific for the mediators (e.g., leukotrienes, prostaglandin D2) occurrence of a mutation in codon 816 of tyrosine The diagnosis mast cell activation syndrome is made if both major criteria or kinase Kit in the affected mast cells [6,29-31]. Another the second criterion and at least one minor criterion are fulfilled. According to aspect that limits the diagnostic value of this mutation the WHO criteria [1], the diagnosis systemic mastocytosis is established if the major criterion and at least one minor criterion or at least three minor criteria is that during progression of SM the Kit mutant D816V are fulfilled. may disappear ([32]; own unpublished observation). Taken together, the recent genetic findings suggest that theclinicallydifferentsubtypes of MCAD (encompass- mast cells and the great heterogeneity of aberrant med- ing SM, MCL, and MCAS) should be more accurately iator expression patterns, symptoms can occur in vir- regarded as varying presentations of a common generic tually all organs and tissues (Table 3). Moreover, root process of mast cell dysfunction than as distinct symptoms often occur in a temporally staggered fashion, diseases [4,7,8,11]. waxing and waning over years to decades. Symptoms often initially manifest during adolescence or even child- Clinical diagnostics hood or infancy but are recognized only in retrospect as MCAD is first suspected on clinical grounds, based on MCAD-related. Clinical features and courses vary recognition of compatible mast cell mediator-related greatlyandrangefromveryindolentwithnormallife symptoms and, in some, identification of typical skin expectancy to highly aggressive with reduced survival lesions. The clinical presentation of MCAD is very times. Physical examination should include inspection diverse, since due to
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