Mastocytosis: from a Molecular Point of View

Abstract

Mast cells (MCs) are physiologically activated by binding of stem cell factor (SCF) to the extracellular domains of the Kit receptor. This binding increases the proliferation and prolongs the survival of normal mature MCs, as well as intensifies the release of mediators. In mastocytosis, somatic mutations of the coding Kit gene cause autocrine dysregulation and lead to constitutive KIT activation even in the absence of its ligand SCF. Clinical symptoms are caused by MC-mediator release and/or infiltration of MCs into tissues. Aberrant KIT activation may result in increased production of MCs in the skin and extracutaneous organs. Depending on the affected organ(s), the disease can be divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and localized MC tumors. The updated classification of WHO discriminates between several distinct subvariants of CM and SM. While the prognosis in CM and indolent SM (ISM) is excellent with (almost) normal life expectancy, the prognosis in aggressive SM (ASM) and MC leukemia (MCL) is dismal. The symptoms may comprise urticaria, angioedema, flush, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain and are the results of MC infiltration and mediator release into target organs, i.e., the skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. Mastocytosis differs from a lot of other hematological disorders because its pathology is not only based on the lack of normal function of a specific pathway or of a specific cell type but additionally is a proliferative disease. Currently available treatments of mastocytosis include symptomatic, antimediator and cytoreductive targeted therapies.

Mast cell‐neural interactions contribute to pain and itch

“…MCAD is an umbrella diagnosis for mast cell‐associated conditions including mastocytosis and mast cell activation syndrome (MCAS) . Mastocytosis is a rare disease characterized by increased mast cell proliferation.…”

“…In chronic conditions, endogenous alterations in the tissue microenvironment with disease progression and organ pathology as well as use of drugs may stimulate mast cell differentiation, proliferation, and activation as described below for SCD and cancer. Targeting of c‐ kit with RTK inhibitors including imatinib mesylate and similar inhibitors is a promising strategy for the control of mast cell activity …”

Mast cells—Good guys with a bad image?

“…In humans, there is a differentiation between MC T (T as abbreviation for tryptase) that are localized at mucosal surfaces and express tryptase α and β, and MC CT (C as abbreviation for chymase; T as abbreviation for tryptase) , that that are localized in the skin, the peritoneum and connective tissues and express tryptases, chymases, and Cpa3. 54 Binding of SCF leads to receptor dimerization and initiates a signal cascade that is important for development, maturation, proliferation, and the survival of human and mouse MCs. 43,44 The content of proteases also influences the histochemical staining properties of these cells.…”

“…In rodents, MCs can be divided into mucosal-type MCs Cpa3, heparin and large amounts of histamine. 33,43,54 Low expression of c-Kit or low availability of SCF can be associated with blood disorders, low pigmentation, or fertility complications. Whereas CTMCs appear red in respond to a safranin staining, MMCs can be recognized by a blue color in respond to an alcian blue staining.…”

Frequency of isolated cutaneous involvement in adult mastocytosis: a cohort study

“…Mastocytosis is a rare disease characterized by the accumulation/proliferation of abnormal mast cells . Mastocytosis is categorized into isolated cutaneous mastocytosis (CM), where only the skin is infiltrated by abnormal mast cells, and systemic mastocytosis (SM), where at least one internal organ is infiltrated by abnormal mast cells . Isolated CM predominantly affects children and is rarely described in the adult population .…”