Differential Diagnosis for Mast Cell-Related Disorders
Case Summary
This case involves distinguishing between systemic mastocytosis and mast cell activation syndrome (MCAS), two related but distinct disorders involving pathological mast cell activity. Both conditions present with symptoms of mast cell mediator release, but differ in their underlying pathophysiology, diagnostic criteria, and clinical implications.
Single Most Likely Diagnosis
Mast Cell Activation Syndrome (MCAS)
- More common than systemic mastocytosis in the general population
- Characterized by episodic symptoms of mast cell mediator release without clonal proliferation
- Normal or only slightly elevated baseline tryptase (<20 ng/mL typically)
- No evidence of mast cell infiltration on bone marrow biopsy
- Requires documentation of elevated mediators during symptomatic episodes
Other Likely Diagnoses
Systemic Mastocytosis (SM)
- Clonal proliferation of abnormal mast cells in one or more organs
- Elevated baseline serum tryptase (typically >20 ng/mL)
- Bone marrow biopsy shows multifocal dense infiltrates of mast cells (≥15 cells in aggregates)
- KIT D816V mutation present in >90% of cases
- May have skin involvement (urticaria pigmentosa/maculopapular cutaneous mastocytosis)
Indolent Systemic Mastocytosis (ISM)
- Most common subtype of systemic mastocytosis
- Relatively benign course with good prognosis
- Meets WHO criteria for SM but without organ dysfunction
- May coexist with cutaneous mastocytosis
Hereditary Alpha Tryptasemia (HαT)
- Genetic condition with increased baseline tryptase due to extra copies of TPSAB1 gene
- Can mimic or coexist with MCAS
- Elevated baseline tryptase without clonal mast cell disease
- Family history often positive
Do Not Miss Diagnoses
Aggressive Systemic Mastocytosis (ASM)
- Life-threatening variant with organ dysfunction (cytopenia, hepatosplenomegaly, malabsorption)
- Requires immediate recognition and treatment
- Poor prognosis without intervention
- C-findings present (organ dysfunction due to mast cell infiltration)
Mast Cell Leukemia (MCL)
- Extremely rare but rapidly fatal
- ≥20% mast cells in bone marrow aspirate smear
- Circulating mast cells in peripheral blood
- Requires urgent hematology consultation
Systemic Mastocytosis with Associated Hematologic Neoplasm (SM-AHN)
- Concurrent myeloid or lymphoid malignancy
- May present with cytopenias or other hematologic abnormalities
- Requires comprehensive hematologic workup
- Treatment must address both conditions
Anaphylaxis (secondary to other causes)
- Severe allergic reactions can mimic mast cell disorders
- IgE-mediated reactions to foods, medications, or insect stings
- Missing the trigger can lead to fatal anaphylaxis
- Requires identification of allergen and avoidance strategies
Rare Diagnoses
Smoldering Systemic Mastocytosis (SSM)
- Intermediate between ISM and ASM
- High mast cell burden but no C-findings
- B-findings present (organomegaly, high tryptase >200 ng/mL, dysplasia)
- Requires close monitoring for progression
Monoclonal Mast Cell Activation Syndrome (MMAS)
- Overlap syndrome with features of both MCAS and SM
- Clonal mast cells present but doesn't meet full SM criteria
- May have KIT mutation without meeting WHO criteria for SM
Cutaneous Mastocytosis (CM) without systemic involvement
- Isolated skin involvement, more common in children
- No systemic symptoms or organ involvement
- Generally good prognosis with spontaneous resolution in children
Carcinoid Syndrome
- Neuroendocrine tumor producing serotonin and other mediators
- Can mimic mast cell mediator release symptoms (flushing, diarrhea)
- Elevated 5-HIAA in urine
- Requires imaging to identify tumor
Pheochromocytoma
- Catecholamine-secreting tumor
- Episodic symptoms similar to mast cell activation (flushing, tachycardia, hypertension)
- Elevated plasma or urine metanephrines
- Can be life-threatening if undiagnosed
Key Differentiating Features
Systemic Mastocytosis:
- Elevated baseline tryptase (>20 ng/mL)
- Positive bone marrow biopsy with mast cell aggregates
- KIT D816V mutation
- Meets WHO diagnostic criteria
Mast Cell Activation Syndrome:
- Normal or minimally elevated baseline tryptase
- Episodic symptoms with documented mediator elevation during attacks
- Negative bone marrow or insufficient criteria for SM
- Diagnosis of exclusion after ruling out SM and secondary causes