Mast Cell Disorders

Diagnosis

Indications for Testing

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

Criteria for Diagnosis of Systemic Mastocytosis (SM)

  • 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 nonmast cell-lineage disorder)
      • Bone marrow smear or extracutaneous tissue biopsy showing ≥25% of mast cells with atypical or spindle-shaped 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 assays
  • Serum tryptase concentration
    • Tryptase concentration correlates with total mast-cell burden in systemic mastocytosis
      • Tryptase concentration >20 ng/mL at least twice on separate occasions should be further evaluated for SM
      • Up to 20% of patients with SM have normal tryptase concentrations (usually more indolent forms [Afrin, 2014])
    • Increased tryptase concentration may indicate any of the following mast cell activation disorders
  • Serum and urine histamine concentrations
    • Histamine concentration may not be elevated
    • Increased concentration may indicate any of  the following
    KIT (D816V) gene mutation testing (bone marrow, blood, tissue)
    • Presence of mutation fulfills WHO minor criteria
    • Aids in prediction of response to tyrosine kinase inhibitor (TKI) therapy

Histology

  • SM
    • Skin or bone marrow biopsy (≥2 cm)
      • Recommended when tryptase is >20 ng/mL or high clinical suspicion exists for mastocytosis (eg, urticaria pigmentosa) in the presence of normal tryptase level
      • Definitive diagnosis (major criterion) when ≥15 mast cells (with ≥25% spindle shaped) in aggregate detected by immunohistochemistry tryptase staining
    • Immunohistochemistry (IHC) – 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 bone marrow
      • Low yield with peripheral blood, which usually contains no mast cells (except in mast cell leukemia)
      • Minor criteria include IHC-positive stains, KIT gene mutation, persistent elevation of tryptase, atypical or spindled appearance of ≥25% mast cells

Prognosis

  • Associated with worse 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
  • KIT D816V mutation – predicts mast cell disease will be unresponsive to TKI therapy

Differential Diagnosis

Clinical Background

Mastocytosis (mast cell disease, or MCD) is a rare disorder associated with mast cell hyperplasia and elevated levels of plasma histamine and tryptase. Mastocytosis 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, isolated mastocytoma, diffuse cutaneous erythroderma, and telangiectasia macularis eruptiva perstans
    • Systemic mastocytosis
      • Indolent systemic mastocytosis
        • Includes smoldering and isolated bone marrow
      • Systemic mastocytosis associated with clonal cell-lineage disease
        • Includes nonmast cell-lineage disease and mast cell disease-associated clonal hematologic nonmast cell-lineage disorder (MCD-AHNMD)
      • Aggressive systemic mastocytosis – may have eosinophilia
      • Mast cell leukemia
    • Mast cell sarcoma
    • Extracutaneous mastocytoma (extremely rare)
  • Mast cell activation classifications
    • Primary – mastocytosis, monoclonal mast cell activation syndrome
    • Secondary – allergic disorders, physical urticaria, chronic autoimmune urticaria, mast cell activation associated with neoplasm or chronic inflammation
    • Idiopathic – idiopathic anaphylaxis, idiopathic urticaria, idiopathic angioedema, mast cell activation syndrome

Pathophysiology

  • Mastocytosis
    • Mast cells are long-lived cells of hematopoietic origin that contain histamine and tryptase and are found in all human tissues
      • Disease process is marked by increased levels of both histamine and tryptase, with focal clustering of mast cells in tissue
    • D816V point mutation in the tyrosine kinase receptor domain of the KIT gene (regulating the KIT receptor) is present in most cases MCD
      • KIT receptor binds to stem cell factor, a cytokine that regulates development and growth of several cell types
      • KIT receptor mutation is a key factor in uncontrolled mast cell proliferation
  • Monoclonal mast cell activation syndrome
    • Demonstrates 1 or 2 criteria for mastocytosis (c-KIT or CD25 expression), but does not fully meet criteria for diagnosis
    • Serum testing for KIT D816V point mutation may be negative, but bone marrow specimens enriched for mast cells are positive
    • Baseline tryptase level may be normal or only mildly elevated
  • Mast cell activation syndrome
    • No evidence of mast cells in tissue or of KIT mutation
    • Evidence of mast cell activation during symptoms

Clinical Presentation

  • Mediator release symptoms
    • Recurrent episodic flushing
    • Tachycardia, hypotension
    • Nausea, emesis, dyspepsia, diarrhea, hepatomegaly
    • Wheezing, hives, anaphylaxis, and angioedema are very uncommon
  • Musculoskeletal involvement
    • Localized bone pain
    • Diffuse osteoporosis or osteopenia
    • Myalgias
    • Arthralgias
    • Increased reaction to Hymenoptera stings
  • Cutaneous mastocytosis classification
    • Usually found during childhood
    • Urticaria pigmentosa (UP) – more common in children
      • Individual brown macules or papules
      • Involves extremities, trunk, and abdomen
      • Lesions exhibit Darier sign – urticarial response to mechanical stimulation
    • Isolated mastocytoma
      • One or multiple reddish-brown plaques or nodules
      • Darier sign can be elicited
      • Involves extremities
    • Diffuse cutaneous erythrodermic mastocytosis
      • Rare
      • Thickened red-brown skin with orange peel texture
      • Bullae and blisters
    • Telangiectasia macularis eruptiva perstans
      • Rarest form
      • Brownish erythematous, macules, telangiectasia
      • Involves chest, extremities
      • Darier sign usually absent
  • Systemic disease associated with
    • Hepatomegaly
    • Splenomegaly
    • Lymphadenopathy
    • Malabsorption
    • Extramedullary tissue involvement
  • Patients with mast cell activation disorders will not have UP

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Helpful in prognostication of mastocytosis

May be helpful in differentiating nonallergic disease from mastocytosis allergic disease

   
Tryptase 0099173
Method: Quantitative Fluorescent Enzyme Immunoassay

Measure total tryptase to confirm mast cell activation in diseases such as

  • Mastocytosis
  • Anaphylaxis
  • Urticaria
  • Asthma

Useful in determining cause of sudden, unexplained death

Useful in prognosis of systemic mastocytosis

Best results with specimens collected 15 minutes to 3 hours after suspected cause of mast cell activation

May take 1 hour to elevate in allergic reaction; will return to normal levels after 6 hours

Assay measures total tryptase and does not distinguish between alpha and beta protein types

 
Histamine, Plasma 0070036
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Aid in evaluation of patient with allergic signs and symptoms; not used for diagnosis

   
Mast Cell Tryptase by Immunohistochemistry 2003993
Method: Immunohistochemistry

Aid in histologic diagnosis of mast cell disease

Stained and returned to client pathologist; consultation available if needed

   
KIT (D816V) Mutation by PCR 0040137
Method: Polymerase Chain Reaction

Aid in diagnosis of mastocytosis

Provide prognostic and predictive information for tyrosine kinase inhibitor (TKI) therapy planning

Clinical sensitivity – occurs in >80% of systemic mastocytosis cases

Analytical sensitivity – 0.3% allelic burden

Mutations other than D816V (including other variants) will not be detected

Mutations below analytical sensitivity will not be detected

 
Eosinophilia Panel by FISH 2002378
Method: Fluorescence in situ Hybridization

Diagnose and classify specific eosinophilic myeloid neoplasms

  • AML with inv(16) or t(16;16)
  • Myeloid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

Provide significant prognostic and predictive information for individuals presenting with acute or chronic leukemia with eosinophilia

Monitor therapeutic response

   
CD2 by Immunohistochemistry 2003505
Method: Immunohistochemistry

Aid in histologic diagnosis of mast cell disease

Stained and returned to client pathologist; consultation available if needed

   
CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

Aid in histologic diagnosis of mast cell disease

Stained and returned to client pathologist; consultation available if needed

   
CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry

Aid in histologic diagnosis of mast cell disease

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Rule out hepatic involvement

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; direct bilirubin; total protein; total bilirubin

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