Differential Diagnosis for Mast Cell Disorders
Case Summary
This case involves distinguishing between systemic mastocytosis and mast cell activation syndrome (MCAS), two related but distinct mast cell disorders that can present with overlapping symptoms including flushing, pruritus, urticaria, gastrointestinal symptoms, and anaphylaxis. The key challenge is differentiating these conditions based on diagnostic criteria, mast cell burden, and clonal markers.
Single Most Likely Diagnosis
Systemic Mastocytosis (SM)
- Most likely if there is evidence of clonal mast cell proliferation with elevated serum tryptase (>20 ng/mL), KIT D816V mutation, and/or bone marrow biopsy showing multifocal dense mast cell infiltrates (>25% spindle-shaped or atypical mast cells)
- Presence of urticaria pigmentosa or other skin lesions (Darier's sign positive) strongly suggests SM
- Meets WHO diagnostic criteria with major and minor criteria
- More objective diagnostic findings compared to MCAS
Other Likely Diagnoses
Mast Cell Activation Syndrome (MCAS)
- Diagnosis of exclusion when symptoms of mast cell activation are present but WHO criteria for SM are not met
- Episodic symptoms with evidence of mast cell mediator release (elevated tryptase during episodes, elevated histamine metabolites, or prostaglandin D2)
- Response to mast cell-directed therapy
- Normal or minimally elevated baseline tryptase (<20 ng/mL typically)
- No clonal markers or significant mast cell infiltration on biopsy
Indolent Systemic Mastocytosis (ISM)
- Subtype of SM with good prognosis
- Meets WHO criteria but without organ dysfunction (C-findings)
- May have minimal symptoms similar to MCAS
- Baseline tryptase persistently >20 ng/mL with clonal markers
Do Not Miss Diagnoses
Aggressive Systemic Mastocytosis (ASM)
- Life-threatening variant with organ dysfunction (hepatomegaly, splenomegaly, malabsorption, cytopenias, pathologic fractures)
- Requires urgent treatment and specialist management
- Presence of C-findings (organ damage from mast cell infiltration)
- Poor prognosis if untreated
Mast Cell Leukemia (MCL)
- Extremely rare but rapidly fatal
20% mast cells in bone marrow aspirate or >10% in peripheral blood
- Aggressive course with multi-organ failure
- Requires immediate hematology/oncology intervention
Systemic Mastocytosis with Associated Hematologic Neoplasm (SM-AHN)
- Concurrent myeloproliferative or myelodysplastic disorder
- May present with cytopenias, organomegaly
- Requires treatment of both conditions
- Worse prognosis than ISM alone
Anaphylaxis from Other Causes
- IgE-mediated allergic reactions, food allergies, drug reactions
- Idiopathic anaphylaxis
- Could be misattributed to mast cell disorder
- Missing true allergen could lead to fatal exposure
Rare Diagnoses
Monoclonal Mast Cell Activation Syndrome (MMAS)
- Clonal mast cell disorder that doesn't meet full SM criteria
- Presence of KIT D816V mutation but insufficient bone marrow findings
- Intermediate between MCAS and SM
- Controversial entity, not universally recognized
Hereditary Alpha-Tryptasemia (HαT)
- Genetic condition with increased baseline tryptase
- Can coexist with MCAS or SM and confound diagnosis
- Familial elevated tryptase without clonal disease
- May predispose to mast cell activation symptoms
Cutaneous Mastocytosis (CM) without Systemic Involvement
- Mast cell proliferation limited to skin
- More common in children, often resolves
- No systemic symptoms or organ involvement
- Requires monitoring for progression to SM
Carcinoid Syndrome
- Can mimic mast cell disorders with flushing and diarrhea
- Elevated 5-HIAA in urine, not tryptase
- Imaging shows neuroendocrine tumor
- Different treatment approach required
Key Distinguishing Features
Systemic Mastocytosis:
- Baseline tryptase typically >20 ng/mL
- KIT D816V mutation present
- Bone marrow: multifocal mast cell aggregates
- CD25 and/or CD2 expression on mast cells
Mast Cell Activation Syndrome:
- Baseline tryptase usually <20 ng/mL
- No KIT mutation
- Normal or minimal bone marrow findings
- Diagnosis requires symptom documentation, mediator elevation, and response to therapy