Mastocytosis: Pathology, genetics, and current options for therapy

Abstract

Mast cell disorders are defined by an abnormal accumulation of tissue mast cells (MCs) in one or more organ systems. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Cutaneous mastocytosis (CM) is a benign disease of the skin and may regress spontaneously. Systemic mastocytosis (SM) is a persistent disease in which a somatic c-kit mutation at codon 816 is usually detectable in MCs and their progenitors. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. The WHO discriminates five categories of SM: indolent SM (ISM), aggressive SM (ASM), SM with associated clonal hematological non-MC-lineage disease (AHNMD), and mast cell leukemia (MCL). The c-kit mutation D816V is quite common and may be found in all SM-categories. In SM-AHNMD, additional genetic abnormalities have been reported, whereas no additional defects are yet known for ASM or MCL. Patients with ISM and CM are treated with "mediator-targeting" drugs, whereas patients with ASM or MCL are candidates for cytoreductive therapy. The use of "Kit-targeting" tyrosine kinase inhibitors such as STI571 (Imatinib, Gleevec), has also been suggested. However, the D816V mutation of c-kit is associated with relative resistance against STI571. Therefore, these patients require alternative targeted drugs or new drug-combinations. In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established. Examples include the use of STI571 in patients with SM plus hypereosinophilic syndrome (SM-HES) and the FIPL1/PDGFRA fusion gene target, or chemotherapy for eradication of AML in patients with SM-AML.

Utility of the World Heath Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow

“…However, serum tryptase levels can be transiently elevated in severe allergic reactions, as well as in patients with myeloid neoplasms. 23 Serum tryptase levels 420 ng/ml have been reported in 39% of de novo acute myeloid leukemia, 44% of secondary acute myeloid leukemia, and in patients with myelodysplastic and myeloproliferative diseases. One study reported that approximately 5% of acute myeloid leukemia cases had serum tryptase levels 4200 ng/ml.…”

“…In subsequent publications by the same authors, the phrase concerning the validity of serum tryptase in the diagnostic work-up has been changed from 'associated myeloid disorder' to 'systemic mastocytosis with associated clonal hematologic non-mast-cell disease' which by definition includes other entities beyond myeloid disorders. 3,23 Myeloid disorders account for 80-90% of cases of systemic mastocytosis with associated clonal hematologic non-mast-cell disease myelodysplastic syndrome/myeloprolifertive disorder being most common. Of the associated lymphoid malignancies, plasma cell myeloma is most frequent.…”

Anesthetic considerations in pediatric mastocytosis: a review

“…Tryptase is a protease specific for and present in all mast cells, and serum levels may correlate with mast cell burden, especially after activation [1,4,13,35,38,39]. In a significant number of both children and adults with mastocytosis confined to the skin, however, the serum tryptase level may be normal (1-15 ng/mL) [13,40]. It is unclear if children whose tryptase levels remain normal should be monitored past adolescence.…”

“…After a Gastric hypersecretion H 2 -antagonists [12,20,54,86] Proton pump inhibitors [12,86] Abdominal pain Disodium cromolyn [12,15,20,54,86] H 2 -antagonists [30,86] Glucocorticoids [12] Prostaglandin-D2 Flushing Acetylsalicylic acid b [4,43] NSAIDs b [4,43,86] Syncope Acetylsalicylic acid b [20,43] NSAIDs b [4,20,43] Heparin Hemorrhage, surgical Protamine c [3,12,90] Fibrinogen, coagulation factors c [12] Hemorrhage, gastric H 2 -antagonists [12,15] Proton pump inhibitors [12,54] Thromboxane Bronchoconstriction, vasoconstriction Antileukotrienes [30] Leukotrienes Vasoconstriction/vasodilation, increased capillary permeability Antileukotrienes [15,30] Tryptase Fibrinolysis Fresh frozen plasma c [89] Antifibrinolytics c [89] a Mast cell stabilizer hypothesized to counter effects of epinephrine b Aspirin and/or NSAIDs should be administered under controlled conditions only c Clinical efficacy unclear mastocytosis-related anaphylaxis-like incident, serum tryptase levels may return to normal but again increase as mast cell burden increases [39]. Paradoxically, children with mastocytosis, particularly those with mild disease, may have normal serum tryptase levels [35,40]…”

“…It is speculated that mastocytosis may be vertically transmitted in a heterozygous fashion, involving de novo mutation at the gamete and/or post-zygotic level [94]. Although not generally regarded as heritable, autosomal recessive and dominant transmission with incomplete penetrance have also not been ruled out [14,40,93].…”