What are the diagnostic criteria and treatment options for mastocytosis?

Diagnosis and Treatment of Mastocytosis

The diagnosis of mastocytosis requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses based on the 2017 WHO Criteria Classification, with treatment approaches varying significantly between cutaneous and systemic forms of the disease. 1

Diagnostic Criteria

General Diagnostic Approach

• Initial evaluation should include assessment for mast cell activation symptoms, examination for skin lesions, and serum tryptase level measurement 1
• Diagnosis requires high index of suspicion in patients with new onset skin lesions with or without mast cell mediator-related symptoms 1
• Darier's sign (urticaria development after stroking lesions) is positive in approximately 89% of patients with cutaneous mastocytosis 1

Diagnostic Studies for Suspected Mastocytosis

• Complete history and physical examination focusing on mast cell activation symptoms, potential triggers, skin examination, and organomegaly assessment 1
• Laboratory studies:
  • Serum tryptase level (may be <20 ng/mL or transiently elevated) 1
  • Complete blood count with differential 1
  • Comprehensive metabolic panel with uric acid, LDH, and liver function tests 1
  • Examination of blood smear for monocytosis, eosinophilia, or dysplasia 1

Definitive Diagnosis

• Cutaneous Mastocytosis (CM):

  • Requires clinical and histopathologic findings of abnormal mast cell infiltration of the dermis 1
  • No evidence of systemic mast cell infiltration in bone marrow or other organs 1
  • Skin biopsy with hematoxylin & eosin, giemsa staining, and immunostaining for tryptase and KIT 1

• Systemic Mastocytosis (SM):

  • Requires at least 1 major + 1 minor or ≥3 minor WHO criteria 1
  • Major criterion: multifocal clusters of abnormal mast cells in bone marrow or other extracutaneous organs 2
  • Minor criteria include:
    • Elevated serum tryptase level
    • Abnormal mast cell CD25 expression
    • Presence of KIT D816V mutation 2
  • Diagnostic procedures:
    • Bone marrow biopsy or biopsy of organ with suspected extracutaneous involvement 1
    • Molecular testing for KIT D816V by allele-specific PCR or alternative high-sensitivity method 1
    • Mast cell immunophenotyping using flow cytometry (CD117, CD25, CD2) and/or immunohistochemistry 1
    • Cytogenetic studies 1
    • Screen for FIP1L1-PDGFRA if eosinophilia is present 1

Classification of Mastocytosis

• Cutaneous Mastocytosis (CM):

  • Maculopapular cutaneous mastocytosis/urticaria pigmentosa (most common in children) 1
  • Diffuse cutaneous mastocytosis 1
  • Mastocytoma of skin 3

• Systemic Mastocytosis (SM):

  • Indolent systemic mastocytosis (ISM) 3
  • SM with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) 3
  • Aggressive systemic mastocytosis (ASM) 3
  • Mast cell leukemia (MCL) 3
  • Mast cell sarcoma (rare) 3

Treatment Approaches

General Treatment Principles

• Treatment goals include suppressing mast cell mediator-related symptoms and, in advanced cases, reducing mast cell burden 1
• Management requires a multidisciplinary team approach (dermatologists, hematologists, gastroenterologists, pathologists, allergists/immunologists) 1
• Referral to centers with expertise in mastocytosis is strongly recommended 1

Treatment Based on Disease Type

Cutaneous Mastocytosis

• Focus on symptom control and avoidance of triggers 1
• Education of patients/parents and care providers about the disease and potential triggers 1
• Most pediatric cases improve or resolve spontaneously (75% of mastocytomas and 56% of urticaria pigmentosa) 1
• Cytoreductive therapy is strongly discouraged except in rare life-threatening variants 1

Indolent/Smoldering Systemic Mastocytosis

• Patients generally have normal life expectancy 2
• Treatment focused on:
  • Anaphylaxis prevention
  • Symptom control
  • Osteoporosis treatment 2
• Cromolyn sodium is indicated for symptom management and has been associated with improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching 4

Advanced Systemic Mastocytosis

• Requires mast cell cytoreductive therapy to improve organ dysfunction 2
• Treatment options include:
  • KIT inhibitors such as midostaurin (FDA approved) or avapritinib (investigational) 2
  • Cladribine or interferon-α as alternative options 2
  • For SM with associated hematologic neoplasm, treatment primarily targets the associated neoplasm 2
  • Allogeneic stem cell transplant may be considered for relapsed/refractory advanced SM 2

Symptom Management

• Cromolyn sodium oral solution has shown clinical improvement in gastrointestinal symptoms (diarrhea, abdominal pain) and cutaneous manifestations (urticaria, pruritus, flushing) 4
• Improvement typically occurs within 2-6 weeks of treatment initiation 4
• H1 and H2 antihistamines (e.g., chlorpheniramine plus cimetidine) may provide similar benefit to cromolyn sodium for both cutaneous and systemic symptoms 4

Important Considerations and Pitfalls

• Absence of skin lesions does not rule out systemic mastocytosis, especially in adults 5
• Mastocytosis should be suspected in cases of recurrent, unexplained, or severe insect-induced anaphylaxis 5
• Serum tryptase levels may be normal or only transiently elevated in some patients 1
• Differential diagnoses including myeloproliferative neoplasms, basophilic and eosinophilic leukemias may be difficult to distinguish from mastocytosis 6
• Mast cell hyperplasia (reactive) must be differentiated from indolent systemic mastocytosis 6
• In aggressive and leukemic variants, mast cells may be very atypical and devoid of metachromatic granules, potentially leading to misdiagnosis 6
• Regular follow-up (every 6-12 months) is recommended for patients with cutaneous mastocytosis 1
• Patients should be counseled about potential triggers of mast cell activation and provided with emergency management plans 1