What is the difference between mast cell activation syndrome (MCAS) and mastocytosis?

Differences Between Mast Cell Activation Syndrome and Mastocytosis

Mast cell activation syndrome (MCAS) and mastocytosis are distinct mast cell disorders with different underlying pathophysiology, diagnostic criteria, and clinical implications for morbidity and mortality.

Key Distinctions

Underlying Pathophysiology

• Mastocytosis: A clonal neoplastic disorder characterized by abnormal proliferation and accumulation of mast cells in tissues, typically associated with a somatic gain-of-function (GOF) KIT D816V mutation 1
• MCAS: A disorder of mast cell hyperactivation without necessarily increased mast cell numbers, defined by recurrent episodes of systemic symptoms from mast cell mediator release 1

Diagnostic Criteria

Mastocytosis

• Requires demonstration of abnormal mast cell accumulation in tissues
• Diagnosed by WHO criteria including:
  • Major criterion: Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organs
  • Minor criteria: Abnormal mast cell morphology, KIT D816V mutation, aberrant CD25 expression on mast cells, serum tryptase >20 ng/mL 1
• Classified into cutaneous mastocytosis and systemic mastocytosis (SM) with several subtypes

MCAS

• Diagnosed by three criteria:
  1. Recurrent episodes of symptoms affecting ≥2 organ systems
  2. Documented increase in validated mast cell mediators during symptomatic episodes
  3. Response to medications targeting mast cell mediators 1
• No requirement for mast cell accumulation or specific mutations

Clinical Presentation

Mastocytosis

• Often presents with skin lesions (urticaria pigmentosa/cutaneous mastocytosis)
• May have persistent elevated baseline serum tryptase
• Can have organ infiltration causing dysfunction (hepatomegaly, splenomegaly, bone lesions)
• Risk of progression to more aggressive forms in systemic disease 1

MCAS

• Episodic symptoms with normal baseline between attacks
• No skin lesions specific to the disorder
• Serum tryptase may be normal at baseline or only transiently elevated during attacks
• No progressive organ infiltration 1

Classification Relationship

Mastocytosis can be considered a subtype of primary MCAS, as patients with mastocytosis often experience mast cell activation symptoms. However, not all MCAS patients have mastocytosis 1, 2.

Primary MCAS includes:

• Systemic mastocytosis
• Clonal MCAS (KIT mutations but not meeting full SM criteria)
• Hereditary α-tryptasemia 1

Secondary MCAS includes:

• Allergic/IgE-mediated reactions
• Other inflammatory disorders 2

Idiopathic MCAS:

• No identifiable trigger, mutation, or underlying disease 1

Diagnostic Approach

When evaluating a patient with suspected mast cell disorder:

1. Document recurrent systemic symptoms affecting ≥2 organ systems
2. Measure mast cell mediators during symptomatic episodes
3. Test response to antimediator therapy
4. If MCAS criteria are met, evaluate for:
   • KIT D816V mutation in peripheral blood or bone marrow
   • Bone marrow biopsy if mastocytosis is suspected
   • Increased TPSAB1 α-tryptase copy number for hereditary α-tryptasemia 1

Treatment Implications

• Mastocytosis: May require cytoreductive therapy in advanced forms; higher risk of severe anaphylaxis; requires long-term monitoring for disease progression 1
• MCAS without mastocytosis: Focus on symptom control with antimediator drugs; generally better prognosis without risk of progression to aggressive disease 1

Prognosis

• Mastocytosis: Variable depending on subtype; indolent SM has normal life expectancy while advanced forms have worse outcomes
• MCAS: Generally good prognosis with appropriate symptom management; some clonal MCAS cases may progress to SM 1

Common Pitfalls

• Misdiagnosing MCAS in patients with vague, non-specific symptoms without documented mediator release
• Failing to evaluate for underlying mastocytosis in patients with MCAS
• Not recognizing that increased mast cell numbers in tissue biopsies alone (without meeting diagnostic criteria) is insufficient for diagnosing either condition 1, 3

Remember that both conditions can significantly impact quality of life and carry risk of severe or life-threatening anaphylaxis, requiring proper diagnosis and management to reduce morbidity and mortality.