What is the difference between Mast Cell Activation Syndrome (MCAS) and Systemic Mastocytosis?

Differences Between Mast Cell Activation Syndrome (MCAS) and Systemic Mastocytosis (SM)

Mast Cell Activation Syndrome (MCAS) and Systemic Mastocytosis (SM) are distinct mast cell disorders with different diagnostic criteria, though they can coexist in the same patient and share some clinical features.

Key Differences

Pathophysiology and Definition

• Systemic Mastocytosis (SM): A clonal neoplastic disorder characterized by abnormal proliferation and accumulation of mast cells in one or more extracutaneous organs (with or without skin involvement), most commonly diagnosed in adults 1
• Mast Cell Activation Syndrome (MCAS): A condition defined by recurrent episodes of mast cell mediator release causing systemic symptoms affecting at least two organ systems, without the required mast cell proliferation seen in SM 1

Diagnostic Criteria

Systemic Mastocytosis:

• Requires meeting the 2017 WHO criteria: one major criterion (multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organs) plus one minor criterion, OR three minor criteria 1
• Minor criteria include:
  • Abnormal mast cell morphology
  • Expression of CD25 and/or CD2 on mast cells
  • KIT D816V mutation
  • Baseline serum tryptase >20 ng/mL 1
• Requires bone marrow biopsy or biopsy of organ with suspected extracutaneous involvement 1

Mast Cell Activation Syndrome:

• Requires three criteria:
  • Recurrent episodes of systemic symptoms consistent with mast cell mediator release affecting ≥2 organ systems
  • Documented increase in mast cell mediators (typically tryptase >20% + 2 ng/mL above baseline) during symptomatic episodes
  • Response to medications targeting mast cell mediators or their receptors 1, 2
• Does not require the presence of abnormal mast cell accumulation 1

Genetic Features

• SM: Typically associated with somatic gain-of-function KIT mutations (especially KIT D816V) 1
• MCAS: May or may not have KIT mutations; can be classified as:
  • Primary MCAS: Associated with KIT mutations but not meeting full SM criteria
  • Secondary MCAS: Triggered by allergies, drugs, infections with no KIT mutations
  • Idiopathic MCAS: No identifiable trigger or mutation 1, 3

Clinical Management Approach

• SM: Often requires cytoreductive therapies for advanced forms, along with antimediator therapy for symptom control 1
• MCAS: Primarily managed with antimediator drugs (antihistamines, mast cell stabilizers) and avoidance of triggers 1

Clinical Overlap and Coexistence

• Both conditions can present with similar symptoms of mast cell activation including:

  • Skin: Pruritus, flushing, urticaria
  • Gastrointestinal: Diarrhea, abdominal cramping, nausea
  • Neurologic: Headache, cognitive issues
  • Cardiovascular: Blood pressure instability 1, 4

• SM patients frequently experience mast cell activation symptoms, and some may meet criteria for both SM and MCAS simultaneously 4

Diagnostic Approach

1. Measure serum tryptase (baseline and during symptomatic episodes)
2. Evaluate for KIT D816V mutation
3. Consider bone marrow biopsy when SM is suspected
4. Assess response to antimediator therapy 1, 2

Common Pitfalls in Diagnosis

• Failure to distinguish between these entities can lead to inappropriate treatment strategies 5
• Many patients self-diagnose with MCAS without meeting diagnostic criteria 5
• Overlapping symptoms with other conditions can complicate diagnosis 6, 3
• Baseline tryptase may be normal in both conditions, requiring careful timing of measurements during symptomatic episodes 1, 2

Summary of Distinctions

• SM is a neoplastic disorder with abnormal mast cell proliferation and specific histopathologic findings
• MCAS is a disorder of mast cell activation without requiring the same degree of mast cell proliferation
• SM diagnosis requires tissue biopsy (typically bone marrow)
• MCAS diagnosis is based on clinical symptoms, mediator release, and response to therapy 1, 4