Mast Cell Disorders


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 – differential may reveal eosinophilial; cytopenias may occur
    • Liver function assays
  • Serum tryptase concentration
    • Tryptase concentration correlates with total mast-cell burden in systemic mastocytosis
      • Evaluation for SM if 
        • Tryptase concentration >20 ng/mL at least twice on separate occasions
        • Event-related typtase level increased by 20% above baseline level plus 2 ng/mL
      • Up to 20% of patients with SM have normal tryptase concentrations (usually more indolent forms [Afrin, 2014])
      • Not specific for mast cell disorder – also elevated in chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)
    • 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
  • Molecular testing
    • KIT (D816V) gene mutation testing (bone marrow, blood, extracutaneous lesion specimen)
      • Initial testing may be blood – if elevated perform bone marrow testing
      • Presence of mutation fulfills WHO minor criteria
      • Aids in prediction of response to tyrosine kinase inhibitor therapy (TKIs)
    • If eosinophilia present – consider PDGFRA testing if KIT mutation absent
    • If KIT and PDGFRA testing are negative or tryptase is borderline – consider mast cell activation disorder
      • 24-hour urine specimen for methylhistamine, PGD2, 11β prostaglandin F2α


  • SM
    • Skin or bone marrow biopsy (≥2 cm) recommended when
      • Tryptase is >20 ng/mL
      • High clinical suspicion exists for mastocytosis in the presence of normal tryptase level (eg, urticaria pigmentosa)
      • Definitive diagnosis (major criterion) when ≥15 mast cells (with ≥25% spindle shaped) in aggregate detected by immunohistochemistry tryptase staining on biopsy
    • Immunohistochemistry (IHC) – CD2, CD25, CD117 (c-Kit), and mast cell tryptase on mast cells
      • May use immunophenotyping/flow cytometry for CD2, CD25
    • Genetic testing – KIT D816V mutation found in ~80% of patients with systemic mastocytosis (Theoharides, 2015)
      • Bone marrow specimen recommended for detection
      • Low yield with peripheral blood, which usually contains no mast cells (except in mast cell leukemia)


  • Worse prognosis associated with
    • Tryptase >200 ng/mL (associated with dysmyelopoiesis, 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/impaired liver function
      • Splenomegaly
      • Malabsorption
      • Skeletal lesions – osteolysis, osteoporosis
      • Life-threatening organopathy
  • KIT D816V mutation – predicts unresponsiveness to TKIs

Differential Diagnosis

Clinical Background

Mastocytosis (mast cell disease) 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) and varies from a skin-limited disease that resolves in children to an aggressive, systemic disorder associated with multi-organ dysfunction.


  • Incidence – mastocytosis (rare)
  • Age – usually adults; exception is cutaneous mastocytosis (children)


  • WHO 2008
    • Cutaneous mastocytosis
      • Includes urticaria pigmentosa, solitary mastocytoma of skin, diffuse cutaneous erythroderma, and telangiectasia macularis eruptiva perstans
      • Three variants – maculopapular, diffuse cutaneous, mastocytoma of the skin
    • Indolent systemic mastocytosis
      • Includes smoldering and isolated bone marrow mastocytosis subtypes
    • Systemic mastocytosis associated with clonal hematological nonmast-cell lineage disease
      • Includes nonmast cell-lineage disease and mast cell disease-associated clonal hematologic nonmast cell-lineage disorder (SM-AHNMD)
    • Aggressive systemic mastocytosis – may have eosinophilia
      • Organ damage
    • Mast cell leukemia (MCL)
      • >20% atypical mast cells in bone marrow or ≥10% immature mast cells in peripheral blood
      • Rare variant – aleukemic MCL
    • Mast cell sarcoma
    • Extracutaneous mastocytoma – extremely rare
      • No evidence of systemic mastocytosis
  • Mast cell activation classification
    • 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


  • Mastocytosis
    • Mast cells are long-lived cells of hematopoietic origin that contain histamine and tryptase and are found in all human tissues
      • Mastocytosis is characterized by increased levels of histamine and tryptase, plus 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
      • Other point mutations may be present (<5%) – V560G, D815K, D816Y, D816F, D816H, D820G
      • 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
    • Other recent mutations – TET2, NRAS (pathogenic role unknown)
  • Monoclonal mast cell activation syndrome
    • 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
    • Absence of mast cells in tissue and 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 – spontaneous regression with age is common
    • 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 do 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
Tryptase 0099173
Method: Quantitative Fluorescent Enzyme Immunoassay

Aids in evaluation of mast cell activation in disorders such as mastocytosis, anaphylaxis, urticarial, asthma

Useful in determining cause of sudden, unexplained death

Prognosis of systemic mastocytosis

Not generally used acutely except where diagnosis is unclear

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

Aids in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation disorders

Mast Cell Tryptase by Immunohistochemistry 2003993
Method: Immunohistochemistry

Aids 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

Aids in diagnosis of mastocytosis

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

Clinical sensitivity – found in >80% of systemic mastocytosis

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

Diagnoses and classifies specific eosinophilic myeloid neoplasms

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

Provides  prognostic and predictive information for acute or chronic leukemia with eosinophilia

Monitors therapeutic response

Analytic sensitivity/specificity − >95%

Detects only rearrangements targeted by the probes

PDGFRB gene on 5q33 and FGFR1 gene on 8p11 have multiple translocation partners; translocation partners are not identified by this test

Histamine, Urine 0070038
Method: Quantitative Enzyme Immunoassay

Aids in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation

Order when a more accurate and reliable determination of histamine production over a longer time period is required

Should be a 24 hour specimen

CD2 by Immunohistochemistry 2003505
Method: Immunohistochemistry

Aids in histologic diagnosis of mast cell disease

Stained and returned to client pathologist; consultation available if needed

CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

Aids 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

Initial screening test in tumor that is morphologically and clinically suspicious for GIST

Aids 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
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

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Initial screening for hepatobiliary inflammation

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

Aids in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation disorders