Mast Cell Disorders

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Content

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

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

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

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

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

Comments

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

Comments

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

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 M. 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 T, 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 K, Medeiros J, Wang S, Miranda R, Johnson M, Verstovsek S, Jorgensen J. Flow cytometric immunophenotypic analysis of systemic mastocytosis involving bone marrow. Arch Pathol Lab Med. 2014; 138(9): 1210-4. PubMed

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

Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller M, 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 M, Rindos M, Kouides P, 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 S, Kong J, Gershwin E. Contemporary challenges in mastocytosis. Clin Rev Allergy Immunol. 2010; 38(2-3): 125-34. PubMed

Ravi A, Butterfield J, Weiler C. 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 T, 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 J, Elenitoba-Johnson K, Lim M. Detection of the c-kit D816V mutation in systemic mastocytosis by allele-specific PCR. J Clin Pathol. 2008; 61(1): 109-14. PubMed

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Last Update: February 2016