Differential Diagnosis for Distinguishing Mast Cell Activation Syndrome from Systemic Mastocytosis
Case Summary
This case involves differentiating between two related mast cell disorders: Mast Cell Activation Syndrome (MCAS) and Systemic Mastocytosis (SM). Both conditions involve abnormal mast cell activation and mediator release, but differ in their pathophysiology, diagnostic criteria, and clinical implications. The key distinction lies in whether there is clonal proliferation and accumulation of mast cells (mastocytosis) versus functional mast cell activation without clonal expansion (MCAS).
Single Most Likely Diagnosis
Mast Cell Activation Syndrome (MCAS)
- More common than systemic mastocytosis in the general population
- Characterized by episodic mast cell mediator release without clonal mast cell proliferation
- Normal or only slightly elevated serum tryptase (typically <20 ng/mL)
- No KIT D816V mutation
- Absence of multifocal mast cell infiltrates on bone marrow biopsy
- Symptoms respond to mast cell stabilizers and mediator blockers
Other Likely Diagnoses
Systemic Mastocytosis (SM)
- Clonal proliferation of abnormal mast cells in one or more extracutaneous organs
- Persistently elevated baseline serum tryptase (typically >20 ng/mL)
- KIT D816V mutation present in >90% of cases
- Bone marrow biopsy shows multifocal dense mast cell infiltrates (≥15 mast cells in aggregates)
- May have cutaneous involvement (urticaria pigmentosa/maculopapular cutaneous mastocytosis)
- WHO diagnostic criteria include major and minor criteria
Hereditary Alpha Tryptasemia (HαT)
- Genetic condition with increased copies of TPSAB1 gene encoding alpha-tryptase
- Elevated baseline tryptase without mast cell proliferation
- Can coexist with MCAS or SM and confound diagnosis
- Family history of elevated tryptase
- May present with MCAS-like symptoms
Do Not Miss Diagnoses
Aggressive Systemic Mastocytosis (ASM)
- Life-threatening subtype with organ dysfunction (cytopenia, hepatosplenomegaly, malabsorption)
- Requires urgent treatment with cytoreductive therapy
- C-findings present: cytopenia, hepatomegaly with impaired function, ascites, skeletal lesions
- Poor prognosis if untreated
Mast Cell Leukemia (MCL)
- Extremely rare but rapidly fatal
- ≥20% mast cells in bone marrow aspirate smear or ≥10% in peripheral blood
- Aggressive clinical course with multi-organ failure
- Requires immediate recognition and treatment
Systemic Mastocytosis with Associated Hematologic Neoplasm (SM-AHN)
- Concurrent myeloid or lymphoid malignancy
- May present with cytopenias, organomegaly
- Requires treatment of both conditions
- Worse prognosis than indolent SM
Anaphylaxis (idiopathic or secondary)
- Can be the presenting feature of both MCAS and SM
- Recurrent unexplained anaphylaxis warrants mast cell disorder workup
- Hymenoptera venom allergy more severe in mastocytosis patients
- Missing diagnosis risks fatal anaphylactic episodes
Rare Diagnoses
Monoclonal Mast Cell Activation Syndrome (MMAS)
- Clonal mast cell disorder that doesn't meet full SM criteria
- KIT D816V positive but lacks sufficient bone marrow findings
- Intermediate between MCAS and SM
- Controversial entity, not universally recognized
Cutaneous Mastocytosis (CM) without systemic involvement
- Mast cell proliferation limited to skin
- More common in children, often resolves spontaneously
- Adults require evaluation to exclude systemic disease
- Includes urticaria pigmentosa, diffuse cutaneous mastocytosis, mastocytoma
Carcinoid Syndrome
- Neuroendocrine tumor with serotonin and other mediator release
- Can mimic mast cell disorders with flushing, diarrhea, bronchospasm
- Elevated 24-hour urinary 5-HIAA
- Imaging shows primary tumor (usually GI or bronchial)
Pheochromocytoma
- Catecholamine-secreting tumor
- Episodic hypertension, headache, sweating, palpitations
- Elevated plasma or urinary metanephrines
- Imaging localizes adrenal or extra-adrenal tumor
Key Distinguishing Features
| Feature | MCAS | Systemic Mastocytosis |
|---|---|---|
| Baseline Tryptase | Usually <20 ng/mL | Usually >20 ng/mL |
| KIT D816V | Negative | Positive (>90%) |
| Bone Marrow | Normal or scattered mast cells | Dense multifocal infiltrates |
| Mast Cell Burden | Low | High |
| Skin Lesions | Absent | Often present (UP) |