Mast Cell Disease

Diagnosis

Indications for Testing

• Patient with clinical symptoms suggestive of allergic disease after other diseases ruled out (eg, asthma, atopic disease, chronic urticaria)

Criteria for Diagnosis

• Manifestation in an organ other than skin and either one major and one minor criterion or three minor criteria
  • Major criterion
    • Bone marrow or extracutaneous biopsy with multifocal, dense infiltration of mast cells (aggregates of >15 mast cells)
  • Minor criteria
    • Serum tryptase >20 ng/mL (not applicable in associated clonal hematologic non-mast cell-lineage disorder)
    • Bone marrow smear or extracutaneous tissue biopsy showing >25% of mast cells with atypical spindle-shape morphology
    • Evidence of CD2 or CD25 on mast cells in bone marrow, blood, or extracutaneous tissue
    • KIT D816V point mutation in bone marrow, blood or extracutaneous tissue

Laboratory Testing

•  Initial, nonspecific testing
  • CBC – may reveal eosinophilia on cell differential; cytopenias may occur
  • Liver function
• Serum tryptase concentration
  • Tryptase concentration correlates with total mast-cell burden in systemic mastocytosis
    • Tryptase concentration >20 ng/mL with a ratio of total tryptase to beta tryptase >20:1 suggests mastocytosis
    • Tryptase concentration in cutaneous mastocytosis may not be elevated
  • Increased tryptase concentration may occur in the following
    • Anaphylaxis
    • Asthma
    • Urticaria
• Histamine concentration
  • Histamine concentration may not be elevated; however, increased concentration in plasma and urine may indicate the following
    • Allergic response (anaphylaxis)
    • Carcinoid tumors, particularly of gastric origin
    • Myeloproliferative neoplasms
    • Urticaria pigmentosa or systemic mastocytosis
• FISH – if leukemia suspected

Histology

• Skin or bone marrow biopsy (≥2 cm)
  • Definitive diagnosis when ≥15 mast cells (≥25% will be spindle shaped) in aggregate are detected by immunohistochemistry tryptase staining
• Immunohistochemistry – CD2, CD25, CD117 (c-Kit), and mast cell tryptase on mast cells 
• Genetic testing – KIT D816V mutation found in >70% of patients with systemic mastocytosis
  • Recommend testing on extracutaneous tissue; low yield with peripheral blood, which contains no mast cells

Prognosis

• Elevated tryptase >200 ng/mL – dysmyelopoiesis (usually defined as >30% bone marrow mast cells)
• Evidence of impaired organ function
  • Cytopenia – absolute neutrophil count <1,000/µL; hemoglobin <10 g/dL, platelets <100,000/µL
  • Hepatomegaly with ascites and impaired liver function
  • Splenomegaly
  • Malabsorption
  • Skeletal lesions – osteolysis, osteoporosis
  • Life-threatening organopathy
• D816V mutation identifies MCD unresponsive to imatinib therapy

Differential Diagnosis

• Asthma
• Atopic disorders
• Chronic urticaria
• Anaphylaxis
• Carcinoid tumors
• VIPoma
• Autoimmune disorders
• Myelodysplastic syndrome/MPN
• Leukemia – monocytic subtype, tryptase (+) AML, chronic basophilic
• MPN-E (formerly termed chronic eosinophilic leukemia), monocytic leukemia
• Lymphoplasmacytic lymphoma

Clinical Background

Systemic mastocytosis, the most common mast cell disease (MCD), is a rare disorder associated with mast cell hyperplasia and elevated plasma histamine and tryptase levels. According to WHO (2008), MCD is classified as a myeloproliferative neoplasm (MPN).

Epidemiology

• Incidence – rare
• Age – usually in adults, except for cutaneous mastocytosis

Classification (WHO 2008)

• Cutaneous mastocytosis
  • Includes urticaria pigmentosa, maculopapular, diffuse and mastocytoma
• Systemic mastocytosis
  • Indolent systemic mastocytosis
    • Includes smoldering and isolated bone marrow
  • Systemic mastocytosis associated with clonal cell-lineage disease
    • Includes non-mast cell-lineage disease and MCD-AHNMD (associated clonal hematologic non-mast cell-lineage disorder) 
  • Aggressive systemic mastocytosis – may have eosinophilia
  • Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma (extremely rare)

Pathophysiology

• Mast cells are long-lived cells resident in vascularized tissue of many organs and contain histamine and tryptase
  • Disease process is marked by increased levels of both histamine and tryptase and with focal clustering of mast cells in tissue
• D816V mutation in the tyrosine kinase receptor domain of the KIT gene (c-KIT receptor) is the main cause of MCD
  • c-KIT receptor binds to stem cell factor, a cytokine that regulates development and growth of several cell types
  • c-KIT receptor mutation is a key factor in uncontrolled mast cell proliferation

Clinical Presentation

• Mediator release symptoms
  • Recurrent episodic flushing
  • Tachycardia
  • Nausea, emesis, diarrhea, hepatomegaly
  • Wheezing, hives and angioedema are very uncommon
  • Anaphylaxis
• Musculoskeletal involvement
  • Localized bone pain
  • Diffuse osteoporosis or osteopenia
  • Myalgia
  • Arthralgia
• Cutaneous mastocytosis
  • Urticaria pigmentosa – more common in children
    • Individual hyperpigmented and telangiectatic papules
    • Involves extremities, trunk and abdomen
    • Lesions exhibit Darier sign – urticarial response to mechanical stimulation
• Systemic disease
  • Hepatomegaly
  • Splenomegaly
  • Lymphadenopathy
  • Malabsorption
  • Extramedullary tissue involvement

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Histamine, Whole Blood 0070037 Method: Quantitative Enzyme-Linked Immunosorbent Assay
Histamine, Urine 0070038 Method: Quantitative Enzyme Immunoassay	Order when a more accurate and reliable determination of histamine production over a longer time period is required