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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., (Copyright © 2011 S. Karger AG, Basel.)

Hypereosinophilic syndrome (HES) includes heterogeneous hematological disorders that are characterized by distinctive blood and tissue eosinophilia. In addition to classical HES criteria, the World Health Organization proposed a set of criteria that distinguish chronic eosinophilic leukemia (CEL) from HES. As such, the fusion gene FIP1L1/PDGFRA was found as a cause of CEL in a significant proportion of patients initially diagnosed as having HES. Several investigations have tried to dissect the mechanism of leukemogenesis; eosinophilia and signaling induced by FIP1L1/PDGFRalpha in cell lines, bone marrow mast cells, primary human eosinophils and in murine myeloproliferative disorder models. In this review, we introduce the current knowledge on the relationship between FIP1L1/PDGFRalpha and cell signaling, eosinophil proliferation, survival and activation and mastocytosis specially focusing on the evidence learned from murine models., (Copyright 2009 S. Karger AG, Basel.)

Background: Patients with systemic mastocytosis have increased numbers of mast cells in the bone marrow and other organs, such as the liver, spleen, gastrointestinal tract and skin. Symptoms result from the local and remote effects of mediator release from mast cells and from the local effects of increased mast cell numbers in various organs. Patients with mast cell activation experience many of the same clinical symptoms as do patients with systemic mastocytosis from chronic or spontaneous release of mast cell mediators. We report 4 patients with mast cell activation symptoms from selective release of prostaglandin (PG) D(2), but not histamine, and their improvement with aspirin therapy., Methods: Bone marrow biopsy specimens obtained from 4 patients with symptoms suggestive of mastocytosis were examined by tryptase immunostaining. Baseline levels of serum tryptase and urinary 11beta-PGF(2)(alpha) and N-methylhistamine were obtained. In 2 of the 4 patients, urinary 11beta-PGF(2)(alpha) and N-methylhistamine samples were also measured during acute symptoms., Results: Baseline increase in urinary excretion of the PGD(2) metabolite 11beta-PGF(2)(alpha) was found in 2 patients. In the remaining 2 patients, baseline levels of urinary 11beta-PGF(2)(alpha) and N-methylhistamine were normal, but during acute symptoms, the excretion of 11beta-PGF(2)(alpha) increased markedly. Treatment with aspirin resulted in normalization of 11beta-PGF(2)(alpha) excretion in the 2 patients with elevated baseline levels and in prevention of symptoms in all 4 patients., Conclusions: These results suggest that mast cell activation may be manifested by a selective excessive release of PGD(2). These patients respond to administration of aspirin but not to antihistamines., (2008 S. Karger AG, Basel.)

Background: The serum tryptase level is used as a diagnostic marker in mastocytosis and is considered to reflect the burden of (neoplastic) mast cells (MC)., Methods: In the present study, serum tryptase levels were measured in patients with mastocytosis by fluoroenzyme immunoassay and compared with the extent of infiltration of the bone marrow (BM) by neoplastic MC, determined by tryptase immunohistochemistry. Sixteen patients with cutaneous mastocytosis (CM) and 43 patients with systemic mastocytosis (SM) were examined., Results: In most patients with CM (defined by the absence of dense compact MC infiltrates in tryptase-stained BM sections), normal or near-normal serum tryptase levels (median 10 ng/ml, range 2-23 ng/ml) were measured. By contrast, in the vast majority of patients with SM, elevated serum tryptase levels (median 67 ng/ml) were found. In addition, there was a significant correlation between the grade of infiltration of the BM by neoplastic MC and tryptase levels in patients with SM (r = 0.8). Moreover, enzyme levels differed significantly among the groups of patients with different types of SM. The highest levels (>900 ng/ml) were detected in the patient with MC leukemia, 2 patients with slowly progressing SM and high MC burden (smoldering SM) and 1 patient with indolent SM. In contrast, in all 3 patients with isolated BM mastocytosis (no skin lesions and no signs of multiorgan involvement), serum tryptase levels were <20 ng/ml., Conclusions: In summary, our data suggest that the measurement of serum tryptase is a reliable noninvasive diagnostic approach to estimate the burden of MC in patients with mastocytosis and to distinguish between categories of disease., (Copyright 2002 S. Karger AG, Basel)

The diagnosis of mastocytosis is based on histological evidence of a focal increase in tissue mast cells. Immunohistochemical staining with antitryptase antibodies is strongly recommended in all cases of suspected mastocytosis because mast cell infiltrates may be small and scanty. Mastocytosis may be difficult to distinguish from other hematological malignancies, in which an increase in mast cells is frequently seen. The expression of the T cell-associated antigen CD2 has been shown to be exclusively found on neoplastic mast cells in mastocytosis. The demonstration of expression of vascular endothelial growth factor by mast cells is consistent with the finding of angiogenesis which is commonly seen in tissue infiltrates of mastocytosis., (Copyright 2002 S. Karger AG, Basel)

Human mast cells are myeloid cells derived from human pluripotential CD34+ stem cells. Normal mast cells exhibit a myeloid immunophenotype characterized by the expression of CD117, CD33 and Fc epsilon RI in the absence of reactivity for CD14, CD15 and lymphoid-lineage-associated antigens. Multiparametric flow-cytometric studies have shown that mast cells from mastocytosis display unique immunophenotypic characteristics, including coexpression of CD2 and CD25 antigens together with abnormally high levels of the activation-related antigens CD35, CD63 and CD69 among others. Such aberrant immunophenotypic features are of great relevance in the diagnosis and differential diagnosis of the disease, flow-cytometric immunophenotyping of mast cells representing the most sensitive method for the diagnosis of tissue involvement in mastocytosis. From the pathogenetic point of view, the immunophenotypical patterns described suggest the existence of profound changes regarding the adhesion and activation status of mast cells in mastocytosis and may represent a useful tool for a better understanding of some pathophysiological aspects of the disease., (Copyright 2002 S. Karger AG, Basel)