Mast Cell Disease


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
  • Histamine concentration
    • Histamine concentration may not be elevated; however, increased concentration in plasma and urine may indicate the following
  • KIT (D816V) mutation testing
    • Fulfills minor criteria
    • Aids in prediction of response to tyrosine kinase inhibitor (TKI) therapy
  • FISH – testing to identify mutations
  • MPN subtypes, features, and diagnostic criteria

    MPN Subtypes, Features, and Diagnostic Criteria

    WHO Classification



    AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

    • Presents as AML
    • Myeloid sarcomas may be present at initial diagnosis or relapse
    • Morphology – acute myelomonocytic leukemia with increased eosinophils containing immature eosinophilic granules in the bone marrow
      • Peripheral eosinophilia is unusual
      • Diagnosis of AML even if blasts <20%
    • Genetics
      • inv(16)(p13.1q22)or t(16;16)(p13.1;q22) found in most cases
        • inv(16)(p13.1q22) is found in vast majority
        • FISH or PCR may be necessary to document this genetic alteration
      • Secondary cytogenetic abnormalities – +22, +8, del(7q)
      • KIT mutations may be present

    Myeloid and lymphoid neoplasms with PDGFRA rearrangement

    • Most frequently presents as CEL, but may present as AML, T-LBL, or both
      • Acute transformation can follow CEL presentation
    • Organ infiltration by eosinophils
      • Heart
      • Lungs
      • CNS
      • GI tract
    • Splenomegaly in majority of patients
    • Pronounced male predominance
    • Morphology
      • Peripheral blood and bone marrow eosinophilia (markedly elevated)
      • Typically <20% blasts in peripheral blood and bone marrow
      • Increased bone marrow mast cells common
    • Genetics
      • Absence of BCR-ABL1 fusion gene
      • Most commonly associated with FIP1L1-PDGFRA fusion
        • FISH or PCR is usually necessary to document this genetic alteration; cytogenetic studies are normal
      • Other fusion genes have rarely been identified

    Myeloid and lymphoid neoplasms with PDGFRB rearrangement

    • Presents with features of chronic myelomonocytic leukemia (usually with eosinophilia)
    • Splenomegaly in majority of patients
    • Male predominance, but much less marked than PDGFRA 002D-associated neoplasms
    • Morphology
      • Peripheral leukocytosis
      • Hypercellular BM with typically <20% blasts
      • Increased bone marrow mast cells common
    • Genetics
      • Most common translocation-t(5;12)(q31-33;p13) resulting in formation of ETV6-PDGFRB

    Myeloid and lymphoid neoplasms with FGFR1 abnormalities

    • Often presents with peripheral eosinophilia in the context of lymphadenopathy and lymphoblastic leukemia/lymphoma
    • Slight male predominance
    • Morphology
      • AML, ALL, CEL (usually associated with peripheral blood or bone marrow eosinophilia)
    • Genetics
      • Presence of t(8;13)(p11;q12) or a variant translocation at the 8p11 breakpoint leading to FGFR1 rearrangement
      • Secondary cytogenetic abnormalities – trisomy 21 most often observed


  • 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


  • 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 unresponsiveness to imatinib therapy

Differential Diagnosis

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).


  • 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 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)


  • 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, 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
  • Cutaneous mastocytosis
    • Urticaria pigmentosa – 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
    • 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
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 on samples 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; bilirubin, direct; protein, total; bilirubin, total

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