Pathophysiology
- Systemic mastocytosis is a clonal neoplasm characterized by:
- Abnormal proliferation and accumulation of mast cells in multiple organs (bone marrow, liver, spleen, GI tract, skin, etc.)
- Most cases are driven by a gain-of-function mutation in the KIT gene, particularly:
- KIT D816V → leads to constitutive activation of the mast cell receptor → uncontrolled proliferation and histamine release
Clinical Manifestations
Symptoms vary based on mast cell activation and organ infiltration:
- Cutaneous (skin) symptoms:
- Flushing, pruritus, urticaria pigmentosa (brownish macules or plaques)
- Systemic/mast cell mediator-related:
- Flushing, hypotension, anaphylaxis (can be spontaneous or triggered)
- Headache, palpitations
- Gastrointestinal symptoms:
- Abdominal pain, diarrhea, nausea, peptic ulcers (due to excess histamine)
- Bone involvement:
- Bone pain, fractures, osteoporosis
- Hematologic or organ dysfunction:
- Hepatosplenomegaly, cytopenias (in advanced/aggressive forms)
Diagnosis of systemic mastocytosis requires:
Major Criterion (1):
- Multifocal dense infiltrates of ≥15 mast cells in bone marrow or other extracutaneous organs
- Minor Criteria (need ≥3 if major is absent, or ≥1 with the major):
- 25% of mast cells are spindle-shaped or atypical in morphology
-
- Detection of KIT D816V mutation
- Mast cells express CD2 and/or CD25 (aberrant immunophenotype)
- Serum tryptase level >20 ng/mL (unless there’s another cause)
Diagnosis = 1 major + 1 minor, or ≥3 minor criteria
Treatment Options
Depends on severity and subtype (indolent vs aggressive):
- Avoid triggers (temperature extremes, alcohol, NSAIDs, venoms)
- Symptomatic therapy:
- Antihistamines (H1 & H2 blockers) – for flushing, GI symptoms
- Cromolyn sodium – stabilizes mast cells
- Epinephrine autoinjector – for anaphylaxis
- Advanced disease (aggressive SM or associated hematologic neoplasm):
- Midostaurin – multikinase TKI that targets KIT D816V
- Avapritinib – more selective KIT inhibitor
- Interferon-α or cladribine – cytoreductive therapy
- Stem cell transplant – in select advanced/aggressive cases