What is the pathophysiology of mastocytosis?

Pathophysiology of Mastocytosis

Mastocytosis results from clonal proliferation of abnormal mast cells driven primarily by activating mutations in the KIT proto-oncogene (most commonly D816V), leading to accumulation of these cells in skin and/or extracutaneous organs, with clinical manifestations arising from both pathologic tissue infiltration and inappropriate release of mast cell mediators. 1

Molecular and Genetic Basis

The fundamental pathophysiologic defect involves dysregulation of the c-kit receptor and its ligand stem cell factor (SCF), which normally promotes mast cell growth and differentiation. 2

• The KIT D816V mutation is present in most systemic mastocytosis cases and represents an imatinib-resistant activating point mutation typically involving exon 17 3
• This mutation causes constitutive activation of the KIT receptor tyrosine kinase, independent of ligand binding, driving uncontrolled mast cell proliferation 1
• The clonal nature of the disease involves both mature mast cells and their CD34+ progenitors 3
• Neoplastic mast cells display an atypical immunophenotype with aberrant coexpression of CD2 and/or CD25, antigens not found on normal or reactive mast cells 3

Cellular Proliferation and Tissue Infiltration

Abnormal mast cells accumulate in multifocal, dense infiltrates primarily affecting skin and bone marrow, with numbers reaching up to 10 times normal skin levels. 1

• In cutaneous forms, mast cells aggregate around blood vessels in the papillary dermis, sometimes associated with eosinophils 1
• Electron microscopy reveals both round and spindle-shaped cells that stain with tryptase and chymase, often in sheet-like distribution 1
• In nodular forms and mastocytomas, infiltration extends through the entire dermis into subcutaneous tissues 1
• Mast cell numbers are elevated even in non-lesional skin of affected patients compared to normal controls 1
• Systemic forms involve bone marrow with multifocal compact tissue infiltration (≥15 mast cells in aggregates), which constitutes the major diagnostic criterion 3

Mediator Release and Clinical Manifestations

Clinical symptoms arise from both constitutive and triggered release of preformed and newly synthesized mast cell mediators, including histamine, prostaglandin D2, leukotrienes, platelet-activating factor, heparin, and proteolytic enzymes. 2, 4

Cutaneous Manifestations

• Darier's sign (urtication and flare upon rubbing lesions) results from local release of histamine, leukotrienes, and prostaglandins 1
• Flushing, pruritus, redness, and swelling occur spontaneously or with triggers in 20-65% of patients 1
• The extent of skin involvement does not directly correlate with symptom severity—even single mastocytomas can produce significant systemic symptoms 1

Systemic Mediator Effects

• Gastrointestinal symptoms (abdominal pain, diarrhea) affect up to 40% of children and result from direct mediator effects on gut motility and secretion 1
• Cardiovascular manifestations include vasodilation, hypotension, and rarely hypovolemic shock from massive mediator release 1
• Anaphylactic reactions can occur in all forms of mastocytosis, triggered by hymenoptera stings, foods, drugs, or physical stimuli 5

Severe Complications in Diffuse Cutaneous Mastocytosis

• Blistering and bullae contain chondroitin sulfate (acting as local anticoagulant), PAF, PGD2, and histamine 1
• Hemorrhagic bullae, prolonged bleeding, and life-threatening hypotensive episodes result from the large burden of mediators released and absorbed systemically 1

Pathophysiologic Heterogeneity

The disease spectrum ranges from benign cutaneous forms with spontaneous regression to aggressive systemic variants with organ dysfunction and poor prognosis. 4, 3

• Cutaneous mastocytosis (predominantly pediatric) typically remains confined to skin with benign course and tendency toward spontaneous regression 4, 3
• Indolent systemic mastocytosis involves skin and bone marrow with low mast cell burden and excellent prognosis (median survival 301 months) 6
• Aggressive systemic mastocytosis demonstrates organ damage (C-findings) from pathologic infiltration, including cytopenias, hepatic dysfunction, skeletal involvement, and malabsorption 6
• Mast cell leukemia represents uncontrolled proliferation with immature morphology, often without cutaneous lesions, and carries very poor prognosis 4, 3

Key Pathophysiologic Distinctions

The critical pathophysiologic difference between mastocytosis and mast cell activation syndrome (MCAS) is the presence versus absence of clonal mast cell proliferation with tissue infiltration. 6

• Mastocytosis involves pathologic mast cell burden with multifocal infiltrates, KIT mutations, and persistently elevated baseline tryptase >20 ng/mL 6
• MCAS involves abnormally activatable mast cells with lower activation threshold but without clonal proliferation or tissue infiltration 7, 6
• Both conditions share mediator-related symptoms, but only mastocytosis demonstrates the structural tissue changes and genetic mutations 6