How is mastocytosis diagnosed?

Diagnosis of Mastocytosis

The diagnosis of mastocytosis requires a combination of clinical assessment (including Darier's sign), serum tryptase measurement, and histopathologic confirmation with tissue biopsy showing abnormal mast cell infiltration, supplemented by molecular testing for KIT D816V mutation and immunophenotyping. 1

Diagnostic Approach Based on Disease Type

Cutaneous Mastocytosis (Most Common in Children)

Initial Clinical Assessment:

• High index of suspicion in patients with new onset skin lesions (red-brown to yellow macules, plaques, or nodules) appearing before 6 months of age, typically distributed on trunk and extremities 1
• Darier's sign (urticaria development after stroking lesions) is positive in 89-94% of cases and is highly suggestive of mastocytosis 1, 2
• Assess for mast cell mediator-related symptoms: flushing, pruritus, abdominal pain, diarrhea, palpitations, angioedema, hypotension, or cyanosis 1, 3

Required Diagnostic Studies:

• Physical examination with Darier's sign testing 1
• Serum tryptase level 1
• Complete blood count with differential 1
• Skin biopsy processed with hematoxylin & eosin and Giemsa staining, plus immunostaining for tryptase and KIT 1
• Analysis of c-kit mutations within skin mast cells 1

When to Pursue Bone Marrow Studies: Bone marrow evaluation is indicated if any of the following are present: 1

• Significantly elevated tryptase levels
• Severe systemic symptoms
• Associated organomegaly
• No significant response to initial symptomatic therapy

Systemic Mastocytosis (Most Common in Adults)

Initial Evaluation:

• Assessment for mast cell activation symptoms or anaphylaxis 1
• Increased serum tryptase level (though may be <20 ng/mL or only transiently elevated) 1
• Examination for adult-onset skin lesions or absence of cutaneous involvement 1
• Screen for abnormal blood counts or B/C findings 1

Required Diagnostic Studies:

• Bone marrow biopsy or biopsy of organ with suspected extracutaneous involvement 1
• Molecular testing for KIT D816V mutation; if needed, additional KIT gene sequencing 1
• Mast cell immunophenotyping using flow cytometry and/or immunohistochemistry 1
• Screen for FIP1L1-PDGFRA if eosinophilia is present 1

WHO Diagnostic Criteria for Systemic Mastocytosis

The diagnosis requires at least 1 major criterion plus 1 minor criterion, OR at least 3 minor criteria: 1

Major Criterion:

• Multifocal compact tissue infiltration by mast cells (≥15 mast cells in aggregates) 4, 5

Minor Criteria:

1. Prominent spindling of mast cells (>25% spindle-shaped or atypical morphology) 4, 5
2. Atypical immunophenotype with coexpression of CD2 and/or CD25 (not expressed on normal/reactive mast cells) 4, 5
3. Activating KIT mutations (most commonly D816V in exon 17) 4, 5
4. Persistently elevated serum tryptase level (>20 ng/mL) 4, 5

Laboratory and Ancillary Studies

Baseline Laboratory Assessment:

• Serum tryptase level (age-dependent in children; levels >20 μg/L indicate increased mast cell burden) 1, 6
• Complete blood count with differential 1, 6
• Comprehensive metabolic panel 6
• Blood smear examination 6

Histopathologic Requirements:

• Tissue biopsy with hematoxylin & eosin and Giemsa staining 1
• Immunohistochemistry for tryptase and KIT 1
• Flow cytometry for aberrant mast cell immunophenotype (CD2/CD25 expression) 1

Critical Diagnostic Pitfalls

Common Diagnostic Challenges:

• Serum tryptase may be normal or only transiently elevated in some patients with mastocytosis, particularly cutaneous forms 1, 6
• Absence of skin lesions does not exclude systemic mastocytosis 7
• Mastocytosis should be suspected in cases of recurrent, unexplained, or severe insect-induced anaphylaxis even without typical skin findings 7
• Unexplained osteoporosis or hematological abnormalities with elevated baseline tryptase should prompt evaluation for mastocytosis 7

Multidisciplinary Approach

The diagnosis and management requires collaboration among: 1, 6

• Dermatologists
• Hematologists
• Gastroenterologists
• Pathologists
• Allergists/immunologists

Referral to specialized centers with expertise in mast cell disorders is strongly recommended 1, 6

Follow-Up After Diagnosis

• Schedule follow-up every 6 to 12 months once cutaneous mastocytosis is established 1, 6
• Counsel patients/parents about the possibility of evolution to systemic form (though rare in pediatric cases) 1
• Provide education about signs/symptoms and potential triggers of mast cell activation 1, 6