Mast Cell Disorders

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

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

Histology

  • 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)

Prognosis

  • 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

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.

Epidemiology

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

Classification

  • 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

Pathophysiology

  • 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

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.

Tryptase 0099173
Method: Quantitative Fluorescent Enzyme Immunoassay

Limitations

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

Mast Cell Tryptase by Immunohistochemistry 2003993
Method: Immunohistochemistry

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

Limitations

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

Limitations

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

KIT D816V Mutation Detection by PCR for Gleevec Eligibility in Aggressive Systemic Mastocytosis (ASM) 2012207
Method: Polymerase Chain Reaction

Limitations

The effectiveness of this device for this use has not been demonstrated

Federal Law restricts this device to sale by or on the order of a licensed practitioner

CD2 by Immunohistochemistry 2003505
Method: Immunohistochemistry

CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

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

Related Tests

Guidelines

General References

Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract. 2014; 2(3): 252-7.e1; quiz 258. PubMed

Bunimovich O, Grassi M, Baer MR. Systemic mastocytosis: classification, pathogenesis, diagnosis, and treatment. Cutis. 2009; 83(1): 29-36. PubMed

Chiu A, Orazi A. Mastocytosis and related disorders. Semin Diagn Pathol. 2012; 29(1): 19-30. PubMed

George TI, Horny H. Systemic mastocytosis. Hematol Oncol Clin North Am. 2011; 25(5): 1067-83, vii. PubMed

Gotlib J, Akin C. Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders. Semin Hematol. 2012; 49(2): 128-37. PubMed

Jabbar KJ, Medeiros J, Wang SA, Miranda RN, Johnson MR, Verstovsek S, Jorgensen JL. Flow cytometric immunophenotypic analysis of systemic mastocytosis involving bone marrow. Arch Pathol Lab Med. 2014; 138(9): 1210-4. PubMed

Klco JM, Vij R, Kreisel FH, Hassan A, Frater JL. Molecular pathology of myeloproliferative neoplasms. Am J Clin Pathol. 2010; 133(4): 602-15. PubMed

Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MBoe, Broesby-Olsen S, Mastocytosis Centre, Odense University Hospital (MastOUH). Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014; 89(5): 493-8. PubMed

Ozdemir D, Dagdelen S, Erbas T. Systemic mastocytosis. Am J Med Sci. 2011; 342(5): 409-15. PubMed

Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. Am J Hematol. 2012; 87(4): 401-11. PubMed

Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015; 90(3): 250-62. PubMed

Patnaik MM, Rindos M, Kouides PA, Tefferi A, Pardanani A. Systemic mastocytosis: a concise clinical and laboratory review. Arch Pathol Lab Med. 2007; 131(5): 784-91. PubMed

Pettigrew D, Teuber SS, Kong JS, Gershwin E. Contemporary challenges in mastocytosis. Clin Rev Allergy Immunol. 2010; 38(2-3): 125-34. PubMed

Ravi A, Butterfield J, Weiler CR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11β-prostaglandin2α. J Allergy Clin Immunol Pract. 2014; 2(6): 775-8. PubMed

Soucie E, Brenet F, Dubreuil P. Molecular basis of mast cell disease. Mol Immunol. 2015; 63(1): 55-60. PubMed

Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015; 373(2): 163-72. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Schumacher JA, Elenitoba-Johnson KS J, Lim MS. Detection of the c-kit D816V mutation in systemic mastocytosis by allele-specific PCR. J Clin Pathol. 2008; 61(1): 109-14. PubMed

Medical Reviewers

Last Update: February 2016