What are the symptoms of mastocytosis versus mast cell activation syndrome (MCAS)?

Distinguishing Symptoms: Mastocytosis vs. Mast Cell Activation Syndrome

Both mastocytosis and mast cell activation syndrome (MCAS) share overlapping symptoms of mast cell mediator release, but mastocytosis is distinguished by the presence of skin lesions (in 85% of cases), evidence of mast cell infiltration in organs, and persistently elevated baseline tryptase >20 ng/mL, whereas MCAS presents with episodic systemic anaphylaxis affecting at least 2 organ systems without the pathologic mast cell burden or skin findings typical of mastocytosis. 1

Shared Symptoms of Mast Cell Mediator Release

Both conditions present with symptoms resulting from mast cell degranulation, including: 1

• Cutaneous manifestations: Flushing, pruritus, urticaria, and angioedema 1
• Gastrointestinal symptoms: Abdominal cramping, diarrhea, nausea, vomiting, and in severe cases malabsorption 1
• Cardiovascular symptoms: Hypotension, tachycardia, syncope, and in severe cases cardiovascular collapse 1
• Respiratory symptoms: Wheezing, dyspnea, and bronchospasm 1
• Neuropsychiatric symptoms: Headache, brain fog, and cognitive dysfunction 1
• Anaphylaxis: Life-threatening systemic reactions that can occur in both conditions 1

Distinguishing Features of Mastocytosis

Mastocytosis has several characteristic features that differentiate it from MCAS: 1, 2

Skin Involvement

• Mastocytosis in the skin (MIS) is present in 85% of systemic mastocytosis patients, manifesting as urticaria pigmentosa/maculopapular lesions, diffuse cutaneous mastocytosis, or mastocytomas 1, 2
• Cutaneous symptoms occur in 78% of patients with indolent systemic mastocytosis 2
• MCAS does not have characteristic skin lesions, though transient flushing and urticaria can occur during episodes 1

Laboratory Findings

• Persistently elevated baseline serum tryptase >20 ng/mL is a minor diagnostic criterion for mastocytosis 1
• Bone marrow biopsy shows multifocal, dense infiltrates of ≥15 mast cells in aggregates (major criterion) 1, 2
• KIT D816V mutation is present in most systemic mastocytosis cases 1
• Aberrant expression of CD25 ± CD2 on mast cells detected by flow cytometry or immunohistochemistry 1, 2

Organ Involvement

• Hepatomegaly and/or splenomegaly without organ dysfunction (B-findings) 1, 2
• High mast cell burden on bone marrow biopsy (>30% infiltration) 1
• In aggressive systemic mastocytosis, C-findings indicate organ damage: cytopenias, hepatic dysfunction with ascites and portal hypertension, skeletal involvement with pathologic fractures, splenic dysfunction with hypersplenism, or gastrointestinal malabsorption with weight loss 1, 2

Constitutional Symptoms

• Constitutional symptoms are uncommon in indolent systemic mastocytosis (only 15% of patients) 2
• Bone marrow mastocytosis variant has higher incidence of mediator-related symptoms (86% of patients) compared to other indolent forms 2

Distinguishing Features of MCAS

MCAS is defined by specific criteria that distinguish it from mastocytosis: 1

Clinical Presentation

• Episodic, spontaneous systemic anaphylaxis affecting at least 2 organ systems concurrently 1
• Symptoms are recurrent but not persistent 1, 3
• No characteristic skin lesions or persistent skin findings 1

Laboratory Findings

• Acute elevation of serum tryptase during symptomatic episodes, with increase of >20% + 2 ng/mL above baseline 1, 4
• Baseline tryptase may be <20 ng/mL or only transiently elevated 1
• Elevated mast cell mediators during episodes: histamine, prostaglandin D2, leukotriene C4, or their metabolites (N-methylhistamine, 11β-PGF2α, LTE4) 1
• Absence of WHO criteria for systemic mastocytosis: no multifocal mast cell infiltrates, no KIT D816V mutation (in primary MCAS), no aberrant CD25 expression 1, 3

Response to Treatment

• Symptoms improve with H1 and H2 antihistamines, leukotriene receptor antagonists, mast cell stabilizers, or COX/5-lipoxygenase inhibitors 1

Subtypes of MCAS

• Primary MCAS: Clonal mast cells with KIT mutations or aberrant CD25 expression, but not meeting full WHO criteria for systemic mastocytosis 1, 3
• Secondary MCAS: Underlying IgE-mediated allergy or other inflammatory trigger without clonal mast cells 1, 3
• Idiopathic MCAS: No identifiable trigger, allergy, or clonal mast cells 1, 3
• Hereditary alpha-tryptasemia: TPSAB1 gene duplications/triplications causing elevated baseline tryptase with symptoms including dysautonomia, functional GI symptoms, chronic pain, and joint hypermobility 1

Critical Diagnostic Pitfalls

• Timing of tryptase measurement is crucial: For MCAS diagnosis, tryptase must be drawn within 1-4 hours of symptom onset to capture the acute elevation 4
• Baseline tryptase must be established separately during asymptomatic periods to calculate the diagnostic increase 4
• Secondary causes must be excluded before diagnosing primary MCAS: allergies, drugs, infections, and other inflammatory conditions 1
• Bone marrow biopsy is required to definitively rule out systemic mastocytosis when evaluating suspected MCAS 1
• Many patients believe they have MCAS but actually have less severe mast cell activation or other underlying diseases that do not meet diagnostic criteria 5, 6

Diagnostic Algorithm

When a patient presents with suspected mast cell activation symptoms: 1, 2

1. Evaluate for systemic mastocytosis first with bone marrow biopsy, KIT D816V mutation testing, mast cell immunophenotyping (CD117, CD25, CD2), and baseline serum tryptase 1
2. If WHO criteria are met (1 major + 1 minor criterion, or ≥3 minor criteria), diagnose systemic mastocytosis and classify subtype based on B-findings and C-findings 1, 2
3. If WHO criteria are not met but symptoms are episodic and severe, measure acute tryptase during symptomatic episodes and mast cell mediators 1, 4
4. If acute tryptase elevation is documented (>20% + 2 ng/mL above baseline) with symptoms affecting ≥2 organ systems and response to antimediator therapy, diagnose MCAS 1
5. Exclude secondary causes including IgE-mediated allergies, drugs, infections, and consider hereditary alpha-tryptasemia testing if baseline tryptase is elevated 1, 4
6. Refer to specialized centers for complex or borderline cases 1, 2