What are the clinical features and diagnostic tests for mastocytosis?

Clinical Features and Diagnosis of Mastocytosis

The diagnosis of mastocytosis requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses, with bone marrow biopsy and KIT D816V mutation testing being essential diagnostic procedures for suspected systemic disease. 1, 2

Classification of Mastocytosis

Mastocytosis is classified into two main categories:

1. Cutaneous Mastocytosis (CM):

   • Limited to skin involvement
   • Most common in children
   • Often regresses spontaneously by puberty
   • Requires histopathologic evidence of mast cell infiltration in the dermis without systemic involvement

2. Systemic Mastocytosis (SM):

   • Most common form in adults
   • Characterized by mast cell infiltration of one or more extracutaneous organs
   • Subtypes include:
     • Indolent SM (ISM)
     • Aggressive SM (ASM)
     • SM with Associated Hematologic Non-Mast Cell Lineage Disease (SM-AHNMD)
     • Mast Cell Leukemia (MCL)

Clinical Features

Cutaneous Manifestations

• Urticaria pigmentosa: Red-brown maculopapular lesions that urticate when rubbed (Darier's sign) 2
• Dermatographism: Skin writing phenomenon
• Pruritus: Common and can be severe
• Flushing: Occurs in 20-65% of patients
• Blistering/bullae: Can be hemorrhagic, especially in diffuse cutaneous mastocytosis 2

Systemic Symptoms

• Gastrointestinal: Abdominal pain, diarrhea (up to 40% of children), nausea, vomiting 2
• Cardiovascular: Hypotension, tachycardia, syncope 2
• Respiratory: Wheezing, shortness of breath 2
• Neurological: Headache, irritability, poor concentration 2
• Anaphylaxis: Can be triggered by various stimuli (Hymenoptera stings, foods, medications, physical factors) 2

Organ Involvement

• Organomegaly: Hepatomegaly, splenomegaly, lymphadenopathy 1, 2
• Bone involvement: Osteoporosis, pathological fractures 2
• Cytopenias: Due to bone marrow infiltration 2
• Constitutional symptoms: Weight loss, fatigue, fever 2

Diagnostic Approach

Initial Evaluation

• History and physical examination: Focus on:
  • Mast cell activation symptoms (flushing, pruritus, anaphylaxis)
  • Potential triggers
  • Examination for mastocytosis in the skin (MIS)
  • Spleen and liver size by palpation 1

Laboratory Studies

• Serum tryptase level:

  • 20 ng/mL suggests systemic disease

  • May be <20 ng/mL or only transiently elevated in some cases 1
• Complete blood count with differential: Look for monocytosis, eosinophilia, dysplasia 1
• Comprehensive metabolic panel: Include uric acid, LDH, and liver function tests 1
• Blood smear examination 1

Bone Marrow Studies

• Bone marrow aspirate and biopsy: Essential for diagnosis of SM 1, 2
  • Flow cytometry: CD34, CD117, CD25, CD2; CD30 (optional)
  • Immunohistochemistry: CD117, CD25, tryptase; CD30 (optional)
  • Cytogenetics
  • FISH: For associated hematologic neoplasm-related abnormalities

Molecular Testing

• KIT D816V mutation: By allele-specific PCR or alternative high-sensitivity method 1
• Additional KIT gene sequencing: If KIT D816V is negative 1
• Screen for FIP1L1-PDGFRA: If eosinophilia is present 1
• Myeloid mutation panel: For risk stratification in advanced disease 3

WHO Diagnostic Criteria

For Systemic Mastocytosis

Major criterion:

• Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow or other extracutaneous organs

Minor criteria:

1. 25% of mast cells in bone marrow or other extracutaneous organs show abnormal morphology (spindle-shaped)

2. KIT D816V mutation
3. Mast cells express CD2 and/or CD25
4. Serum total tryptase persistently >20 ng/mL

Diagnosis requires: 1 major + 1 minor criterion OR ≥3 minor criteria 1, 4

Diagnostic Algorithm

1. For suspected mast cell activation symptoms or adult-onset MIS:

   • Perform bone marrow biopsy or biopsy of organ with suspected extracutaneous involvement
   • Molecular testing for KIT D816V
   • Mast cell immunophenotyping using flow cytometry and/or immunohistochemistry 1

2. If WHO criteria for SM are fulfilled:

   • Determine SM subtype based on B-findings (burden of disease) and C-findings (organ damage)
   • Assess for associated hematologic neoplasm 1

3. If WHO criteria for SM are not fulfilled but MIS is present:

   • Consider primary mast cell activation syndrome (MCAS)
   • Consider other causes for mast cell activation (allergies, drugs, infections)
   • Consider idiopathic MCAS/anaphylaxis
   • Consider hereditary alpha-tryptasemia 1

Common Pitfalls and Caveats

1. Serum tryptase limitations:

   • May be <20 ng/mL in some SM cases
   • Can be transiently elevated in allergic reactions 1

2. Skin lesions:

   • Absence of skin lesions does not rule out SM
   • Adult-onset mastocytosis often presents without cutaneous involvement 5

3. Bone marrow sampling:

   • Patchy involvement may lead to false negatives
   • Multiple biopsies may be needed 6

4. KIT mutation testing:

   • Standard PCR may miss low-level mutations
   • Highly sensitive methods are recommended 7

5. Multidisciplinary approach:

   • Collaboration with sub-specialists (anesthesia for procedures/surgery, high-risk OB for pregnancy) is essential 1, 2

By following this diagnostic algorithm and being aware of the potential pitfalls, clinicians can accurately diagnose mastocytosis and determine the appropriate management strategy based on disease subtype and extent of involvement.