How should mastocytosis be diagnosed and managed, including workup, treatment options for cutaneous and systemic disease, and follow‑up?

Diagnosis and Management of Mastocytosis

Diagnostic Approach

Mastocytosis diagnosis requires a combination of histopathologic, clinical, laboratory, and molecular analyses based on 2017 WHO criteria, with the critical distinction being whether disease is confined to skin (cutaneous mastocytosis) or involves extracutaneous organs (systemic mastocytosis). 1

Initial Clinical Evaluation

When mastocytosis is suspected, look specifically for:

• Skin lesions with Darier's sign (urticaria developing after stroking lesions, positive in ~89% of cutaneous cases) 1, 2
• Mast cell activation symptoms: flushing, pruritus, urticaria, angioedema, abdominal cramping, diarrhea, nausea, hypotension, syncope, anaphylaxis 1, 3
• Organomegaly (hepatosplenomegaly suggests systemic disease) 2
• Constitutional symptoms (fatigue, weight loss, bone pain) 3

Essential Laboratory Workup

Obtain serum tryptase level as the initial screening test - persistently elevated baseline tryptase >20 ng/mL is a minor diagnostic criterion for systemic mastocytosis. 1, 3

Additional initial labs include: 1, 2

• Complete blood count with differential
• Comprehensive metabolic panel
• Blood smear examination

A critical pitfall: Serum tryptase may be normal or only transiently elevated in some patients, so normal tryptase does not exclude mastocytosis. 2

Diagnostic Criteria for Systemic Mastocytosis

Systemic mastocytosis requires either 1 major + 1 minor criterion, OR ≥3 minor criteria: 1, 3

Major criterion:

• Multifocal, dense infiltrates of ≥15 mast cells in aggregates in bone marrow or extracutaneous organs 1, 3

Minor criteria:

• 25% atypical/spindle-shaped mast cells in bone marrow 1, 3

• KIT D816V or other activating KIT mutation detected 1, 3
• Aberrant expression of CD25 ± CD2 on mast cells 1, 3
• Persistently elevated baseline serum tryptase >20 ng/mL 1, 3

When to Pursue Bone Marrow Biopsy

Perform bone marrow biopsy with immunophenotyping and KIT D816V mutation testing in adults with: 1, 3

• Suspected mast cell activation symptoms without skin lesions
• Adult-onset skin lesions (urticaria pigmentosa)
• Elevated serum tryptase >20 ng/mL
• Unexplained anaphylaxis (especially insect sting-induced)
• Unexplained osteoporosis with elevated tryptase 4

Do NOT routinely perform bone marrow biopsy in children with cutaneous mastocytosis, as pediatric cutaneous disease rarely involves bone marrow and typically resolves spontaneously. 1

The bone marrow evaluation must include: 1

• Histopathology for mast cell aggregates
• Molecular testing for KIT D816V mutation
• Mast cell immunophenotyping using flow cytometry and/or immunohistochemistry
• Screen for FIP1L1-PDGFRA if eosinophilia is present 1

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Classification and Prognosis

Cutaneous Mastocytosis (Pediatric-Predominant)

Cutaneous mastocytosis is diagnosed when abnormal mast cell infiltration is limited to the dermis with no evidence of systemic involvement. 1

Three subtypes exist: 1, 5

• Maculopapular cutaneous mastocytosis (urticaria pigmentosa) - most common presentation
• Diffuse cutaneous mastocytosis - rare, more severe
• Mastocytoma of skin - solitary lesions

Key prognostic point: 80-94% of pediatric cases improve or resolve spontaneously before puberty, with disease onset typically in the first year of life. 1 Referral to centers with expertise in cutaneous mastocytosis is strongly recommended. 1

Systemic Mastocytosis Subtypes (Adult-Predominant)

Indolent Systemic Mastocytosis (ISM):

• Low mast cell burden, no organ damage (C-findings absent) 3
• Excellent prognosis with median survival of 301 months 3
• 85% have skin involvement 3
• <1% risk of transformation to aggressive disease 3

Aggressive Systemic Mastocytosis (ASM):

• Presence of ≥1 C-finding (cytopenias, hepatic dysfunction, skeletal involvement with pathologic fractures, splenic dysfunction, GI malabsorption) 1, 3
• Significantly worse prognosis with median survival of 41 months 3
• Requires cytoreductive therapy consideration 3

Systemic Mastocytosis with Associated Hematologic Neoplasm (SM-AHN):

• Concurrent myeloid or lymphoid neoplasm 1
• Prognosis depends on the associated hematologic disease 6

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Management Strategy

Multidisciplinary Approach

All patients with mastocytosis require management by a multidisciplinary team including dermatologists, hematologists, gastroenterologists, pathologists, and allergists/immunologists, preferably at specialized centers. 1, 2

Treatment Goals

The primary treatment goals are: (1) suppressing mast cell mediator-related symptoms and (2) in advanced disease, reducing mast cell burden. 2

Management of Cutaneous Mastocytosis

For cutaneous mastocytosis, focus on symptom control and trigger avoidance: 2

First-line symptomatic therapy:

• H1 antihistamines (cetirizine, loratadine, fexofenadine) for pruritus, flushing, urticaria 3
• H2 antihistamines (famotidine, ranitidine) for gastrointestinal and vascular symptoms 3
• Topical corticosteroids for localized skin lesions 1

Second-line options for refractory symptoms:

• Oral cromolyn sodium 200 mg four times daily - FDA-approved for mastocytosis, particularly effective for gastrointestinal symptoms (diarrhea, abdominal pain), with clinical improvement typically within 2-6 weeks 7
• Leukotriene receptor antagonists (montelukast) 3
• Cyproheptadine (H1 blocker + serotonin antagonist) specifically for diarrhea 3

Critical management points:

• Educate patients/parents about trigger avoidance (temperature extremes, physical trauma, certain medications like NSAIDs, opiates, alcohol) 1, 2
• Provide emergency management plans for anaphylaxis with epinephrine auto-injectors 2
• Follow-up every 6-12 months 2

Management of Systemic Mastocytosis

Indolent Systemic Mastocytosis:

• Symptomatic management identical to cutaneous disease (H1/H2 antihistamines, cromolyn, leukotriene antagonists) 1
• No cytoreductive therapy needed 3
• Monitor for disease progression 1

Aggressive Systemic Mastocytosis:

• Consider cytoreductive therapy with novel targeted agents (tyrosine kinase inhibitors targeting KIT D816V mutation) 1, 8
• Symptomatic management for mediator-related symptoms 1
• Close monitoring for organ dysfunction 1

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Critical Pitfalls and Special Considerations

Common diagnostic pitfalls:

• Normal tryptase does not exclude mastocytosis - some patients have normal or only transiently elevated levels 2
• Absence of skin lesions does not rule out systemic mastocytosis - approximately 15% of systemic cases lack cutaneous involvement 3, 4
• Do not confuse with mast cell activation syndrome (MCAS), which lacks the pathologic mast cell burden, KIT mutations, and persistent tryptase elevation seen in mastocytosis 3

Perioperative/procedural considerations:

• Coordinate with anesthesiology for any invasive procedures or surgery due to anaphylaxis risk 1
• Premedicate with H1/H2 antihistamines and consider corticosteroids 1

Pregnancy management:

• Requires high-risk obstetric consultation 1
• Mast cell mediator symptoms may fluctuate during pregnancy 1

When to suspect mastocytosis in adults:

• Recurrent, unexplained, or severe insect sting-induced anaphylaxis 4
• Unexplained osteoporosis with elevated baseline tryptase 4
• Unexplained hematological abnormalities with elevated tryptase 4