Differentiating Systemic Mastocytosis from Mast Cell Activation Syndrome
The key distinction is that systemic mastocytosis (SM) meets WHO diagnostic criteria with pathologic evidence of clonal mast cell infiltration in bone marrow or other organs, while mast cell activation syndrome (MCAS) presents with mast cell activation symptoms but does NOT fulfill WHO criteria for SM. 1
Diagnostic Algorithm
Step 1: Evaluate for Systemic Mastocytosis First
When a patient presents with suspected mast cell activation symptoms, you must perform:
- Bone marrow biopsy with immunophenotyping (CD117, CD25, CD2, tryptase) 1
- KIT D816V mutation testing using allele-specific PCR or high-sensitivity methods 1
- Serum tryptase level (baseline, not during acute episode) 1
- Flow cytometry to detect aberrant CD25/CD2 expression on mast cells 1
Step 2: Apply WHO Diagnostic Criteria for SM
SM is diagnosed when:
- 1 major criterion + 1 minor criterion, OR
- ≥3 minor criteria are present 1
Major criterion: Multifocal, dense infiltrates of ≥15 mast cells in aggregates in bone marrow or extracutaneous organs 1
Minor criteria: 1
25% atypical/spindle-shaped mast cells in bone marrow
- KIT D816V or other activating KIT mutation detected
- Aberrant expression of CD25 ± CD2 on mast cells
- Persistently elevated baseline serum tryptase >20 ng/mL (in absence of associated myeloid neoplasm)
Step 3: If WHO Criteria NOT Met, Consider MCAS
MCAS is diagnosed when all 3 criteria are present: 2, 3
- Clinical symptoms of recurrent, episodic, systemic mast cell activation (flushing, pruritus, hypotension, GI symptoms, anaphylaxis)
- Biochemical evidence: Acute tryptase increase to >20% + 2 ng/mL above baseline within 1-4 hours of symptom onset 2
- Response to antimediator therapy (H1/H2 antihistamines, mast cell stabilizers, leukotriene inhibitors) 2, 3
Critical Distinguishing Features
Baseline Serum Tryptase
- SM: Persistently elevated baseline tryptase >20 ng/mL in most cases 1
- MCAS: Baseline tryptase may be <20 ng/mL or normal; only transiently elevated during acute episodes 1, 2
Bone Marrow Findings
- SM: Dense mast cell infiltrates (≥15 cells in aggregates), spindle-shaped morphology, aberrant CD25/CD2 expression 1
- MCAS: Normal mast cell morphology and immunophenotype, no clonal markers 1, 2
KIT D816V Mutation
Skin Involvement
- SM: Mastocytosis in skin (urticaria pigmentosa) present in ~85% of indolent SM cases 1
- MCAS: No characteristic skin lesions of mastocytosis 1, 2
Common Pitfalls to Avoid
Do not diagnose MCAS without excluding SM first. The diagnostic algorithm explicitly requires bone marrow evaluation to rule out SM before considering MCAS 1. This is critical because SM requires different management and has prognostic implications.
Beware of hereditary alpha-tryptasemia (HαT). This genetic condition causes elevated baseline tryptase and mast cell activation symptoms but is distinct from both SM and MCAS 1. Consider TPSAB1 gene testing if baseline tryptase is elevated without meeting SM criteria 1.
Tryptase timing matters. For MCAS diagnosis, you need both baseline tryptase AND acute tryptase drawn within 1-4 hours of symptom onset 2. A single elevated tryptase during symptoms without knowing the baseline is insufficient.
Secondary causes must be excluded. Before diagnosing primary MCAS, rule out allergies, drugs, infections, and other inflammatory conditions that can cause secondary mast cell activation 1, 3.
When Diagnostic Uncertainty Exists
If bone marrow shows subtle findings or low mast cell burden that doesn't clearly meet WHO criteria, use the Spanish Network on Mastocytosis score as a predictive model to determine if repeat bone marrow studies are warranted 2. This helps identify patients with clonal mast cell disorders at low frequencies who might otherwise be misclassified as MCAS.
Referral to specialized centers with expertise in mastocytosis is strongly recommended for complex or borderline cases 1, 5.