Mast Cell Disorders

Mast cell disorders (MCDs) are a diverse group of conditions characterized by inappropriate mast cell (MC) activation and/or the proliferation and accumulation of abnormal MCs throughout the body.   These conditions range in severity from benign, nonclonal disorders to malignant clonal diseases that rapidly progress and may involve the skin (eg, cutaneous mastocytosis [CM]) or extracutaneous organs (eg, systemic mastocytosis [SM]). Symptoms result from the release of MC mediators (eg, tryptase and histamine) and/or end organ damage.  The diagnostic approach depends on the type of MCD. Laboratory testing involves measuring serum tryptase and performing KIT gene mutational analysis on bone marrow and/or peripheral blood.

Quick Answers for Clinicians

Who should be tested for mast cell disorders?

Individuals who have clinical symptoms of allergic disease AND an elevated serum total tryptase level should be evaluated for systemic mastocytosis (SM). Adult patients with mastocytosis skin lesions (often called urticaria pigmentosa) should also be evaluated for SM. Pediatric patients with urticaria pigmentosa typically have cutaneous mastocytosis only and do not need further testing, unless symptoms suggest systemic disease.

Which markers are used in mast cell disorder testing?

Serum tryptase is an important initial test in the evaluation of patients with a suspected mast cell disorder  and is the most specific marker of mast cell activation available. KIT mutational analysis, preferably performed by allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR) on the peripheral blood, is also necessary to predict response to therapy.

When should a person be tested?

When evaluating an individual for nonclonal mast cell activation syndrome (NC-MCAS), an increase in the serum level of tryptase above baseline and within a narrow window of time (generally 1-2 hours) after a symptomatic episode is the preferred method for providing evidence of mast cell involvement. Alternatively, if a clonal process is suspected, serum tryptase can be tested at any time. KIT mutational testing can also be performed at any time. 

Which testing algorithms are related to this topic?

Indications for Testing

Individuals presenting with symptoms consistent with mast cell activation (eg, flushing, loose stools or diarrhea, anaphylaxis) and/or characteristic skin lesions and in whom secondary causes of mast cell activation have been investigated and excluded should be considered for MCD testing.

Classification

MCDs are categorized as clonal and nonclonal disorders:

Clonal Mast Cell Disordersa
Disorder Description
CM Typically a skin-only disease that affects young children <2 years of age and spontaneously resolves during childhood
SM Chronic and systemic disease that predominantly affects adults and frequently involves the bone marrow and virtually any other organ (eg, skin, spleen, liver, gastrointestinal tract)
Indolent SM Most adults with SM have the indolent form of the disease
Smoldering SM Less aggressive than advanced SM
SM with an associated hematological neoplasm Aggressive clinical course and poor prognosis; as a group, these 3 disorders are referred to as advanced SM
Aggressive SM
Mast cell leukemia
MMAS Recurrent anaphylaxis, without skin lesions, and evidence of mast cell clonality not meeting criteria for SM
Nonclonal Disorders
Secondary MCAS MCAS is secondary to another disorder, such as collagen vascular disease
Idiopathic MCAS Exact cause of the MCAS is not known
aAll clonal mast cell disorders may also have MCAS (primary MCAS).

MCAS, mast cell activation syndrome; MMAS, monoclonal mast cell activation syndrome

Sources: Valent, 2017 ; Arock, 2015 ; Jennings, 2018 

Diagnostic Criteria

Proposed Criteria for the Diagnosis of Mast Cell Activation Syndrome
  • Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems (eg, skin, gastrointestinal, cardiovascular)
  • Decrease in the frequency or severity or resolution of symptoms with antimediator therapy (eg, histamine receptor antagonists, mast cell stabilizers)
  • Evidence of an elevation in a validated urinary or serum markera of mast cell activation
  • Primary (clonal) and secondary disorders of mast cell activation have been excluded
aTotal serum tryptase is the recommended marker of choice; 24-hour urine histamine metabolites and 11-beta-prostaglandin F2 are less specific.

Source: Akin, 2010 

WHO 2017 Diagnostic Criteria of SM
Major criteriona
  • Multifocal dense infiltrates of MCs (≥15 MCs in aggregates) in BM biopsies and/or in sections of other extracutaneous organ(s)

Minor criteria

  • >25% of all MCs are atypical cells (type I or type II) on BM smears or are spindle shaped in MC infiltrates detected on sections of visceral organs
  • KIT point mutation at codon 816 in bone marrow or another extracutaneous organ
  • Mast cells in bone marrow, blood, or other extracutaneous organs express CD25 with or without CD2
  • Serum total tryptase persistently exceeds 20 ng/mLb
aEither the presence of 1 major and 1 minor criteria OR 3 minor criteria establish the diagnosis of SM.

bUnless there is an associated clonal myeloid disorder, in which case this parameter is not valid.

MC, mast cells; BM, bone marrow

Source: Horny, 2017 

Clinical Presentation

Clinical presentation varies greatly depending on the affected organ systems. Some presentations, including anaphylaxis, result from the inappropriate release of mast cell mediators and are frequently associated with a set of characteristic triggers.

In clonal disease (eg, advanced SM), further testing may be prompted by findings that are the result of the abnormal growth and accumulation of neoplastic mast cells in various organs (eg, urticaria pigmentosa, progressive cytopenia, ascites, malabsorption).    

Clinical Presentation of Mast Cell Disorders by Body System
Body System Clinical Presentation
General Anaphylaxisa (especially following hymenoptera venom exposure)
Skin Maculopapular (urticaria pigmentosa-like) lesions

Dermatographism

Darier’s sign

Flushing (especially face and chest)

Itching

Sweating

Rashesb

Angioedemab

Respiratory Rhinitis

Throat itching, swelling

Dyspnea

Wheezing

Digestive Abdominal pain, tenderness

Bloating

Reflux

Loose stools, diarrhea

Nausea

Vomiting

Muscular/skeletal Bone, musculoskeletal pain

Osteopenia, osteoporosis (with or without bone fractures)

Nervous Headache

Cognitive issues

Memory and concentration difficulties

Anxiety

Depression

Circulatory Chest pain

Palpitations

Tachycardia

Lightheadednessa

Syncopea

Blood pressure changes

aSignificantly increased in clonal disorders

bSignificantly increased in nonclonal disorders

Sources:Hamilton, 2018 ; Jennings, 2018 

Common Triggers in Individuals with a Mast Cell Disorder
Heat, cold, sudden temperature change

Emotional, physical, environmental stress

Fatigue

Exercise, friction, vibration, surgery

Food and beverages (including alcohol)

Medicationsa (anesthetics, antibiotics, nonsteroidal anti-inflammatory drugs, opioids), contrast dyes

Hymenoptera venom

Strong odors (perfumes, smoke, cleaning agents)

Infections

aSignificantly increased in nonclonal disorders

Sources: Hamilton, 2018 ; Jennings, 2018 

Laboratory Testing

Diagnosis

The European Competence Network on Mastocytosis (ECNM) and the National Comprehensive Cancer Network (NCCN) recommend that initial testing for a suspected MCD include measuring serum tryptase levels and evaluating a peripheral blood sample for the KIT D816V mutation via an allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR) assay. Depending on results, additional testing, including bone marrow aspiration and core biopsy, may also be indicated. 

Mast Cell Mediators

Serum Tryptase

Serum tryptase is an important initial test in the evaluation of patients with a suspected MCD  and is the most specific marker of mast cell activation available. Mast cells in the tissue produce and constitutively release the alpha form of tryptase, which can be detected by a commercial fluoroimmune enzyme assay. When evaluating patients for nonclonal MCAS (NC-MCAS), a baseline level should be obtained, and tryptase should be measured again shortly (within 4 hours) after a symptomatic episode; if increased, mast cell involvement is suggested.   Alternatively, if a clonal process is suspected (eg, SM), serum tryptase can be tested at any time.

A serum tryptase level >20 ng/mL is a minor diagnostic criterion of SM.  The expert panel for the diagnostic criteria of NC-MCAS agreed that a 20% + 2 ng/mL increase from the baseline level constitutes mast cell activation.   

Tryptase can be consistently elevated in other hematologic malignancies, including myelodysplastic syndromes and acute leukemia; therefore, follow-up of elevated tryptase should include bone marrow aspiration and biopsy.

Interpretation of Serum Tryptase Results
Tryptase Result Interpretation
<11.4 ng/mL Considered normal by most laboratories
11.4-20.0 ng/mL Suggestive of NC-MCAS; consider retesting during or after future symptomatic episode
>20.0 ng/mL Minor criterion for diagnosis of SM; if elevated on 2 separate occasions, evaluation for SM should be pursued
Source: Hamilton, 2018 
Other Mast Cell Mediators

While serum tryptase is the only mast cell mediator included in consensus criteria, other laboratory tests that may be considered include 24-hour urine tests for metabolites of histamine, N-methylhistamine, leukotrine E4, 2,3-Dinor-11beta-prostaglandin F2 alpha, and prostaglandin D2. These markers are most commonly used for the evaluation of MCAS and have been studied in research settings, but lack sensitivity and/or specificity for use in mast cell disorder evaluation. 

Bone Marrow Examination

When a bone marrow is examined for mast cell disease, good practice recommends examining a blood smear, bone marrow aspirate smear, and a core biopsy. The following ancillary tests are highly useful in this situation :

  • Flow cytometry of bone marrow aspirate for mast cells and other abnormalities
  • Cytogenetic karyotype on bone marrow aspirate (typically abnormal when an associated hematologic neoplasm is present)
  • Fluorescent in situ hybridization (FISH) for eosinophilia (when eosinophilia is present) on blood or aspirate
  • KIT D816V testing on aspirate 
  • Myeloid mutation panel (eg, containing SRSF2, ASXL1, RUNX1)  on aspirate
  • Immunohistochemistry on bone marrow biopsy
    • Tryptase: most specific marker for mast cells; can be dim in advanced SM or with certain therapies (eg, in gastrointestinal biopsies with mast cell disease, this is often dim to negative)
    • CD117: uniformly bright marker for mast cells; will also stain early erythroid and myeloid cells
    • CD25: present on abnormal mast cells and associated with the KIT D816V mutation; can be dim with certain therapies and is typically negative in patients with a KIT mutation other than D816V
    • CD34: negative in mast cells, but positive in CD34-positive blasts
    • CD30: brightly expressed in well differentiated SM (which typically lacks KIT D816V and lacks CD25 expression) and variably expressed in other types of SM

Tests for other markers are performed based on pathology findings.

KIT Mutational Analysis

All individuals suspected of SM should undergo KIT mutational analysis.  In adult patients, an activating KIT D816V mutation is found in >80% of all cases.  Individuals with SM and KIT D816V are resistant to certain therapies (eg, imatinib).

KIT testing can be performed on bone marrow or peripheral blood. Traditionally, KIT mutational testing was performed only on bone marrow because bone marrow lesional tissue has a higher concentration of mast cells; however, highly specific ASO-qPCRs can detect the mutation in peripheral blood in nearly all adult patients with typical SM and is the preferred methodology.  If a KIT D186V mutation is detected in peripheral blood, bone marrow biopsy should be performed to evaluate for SM, including the subtype of disease, and the presence of an associated hematologic neoplasm (found in ~30% of all patients with SM). Bone marrow biopsy should also be performed in cases with a high suspicion of SM even when no KIT mutation is detectable in the peripheral blood.  In a small number of cases, patients could have mutations in locations other than KIT D816V and sequencing of the entire KIT gene by next generation sequencing (NGS) or a similar sensitive methodology might be considered to inform treatment and target therapies. 

Monitoring

Yearly monitoring for SM and CM with no complications is appropriate, unless symptoms worsen. Laboratory tests that may be used for assessment include serum tryptase measurements of mast cell burden, CBC, and chemistry panels. 

Serial measurements of the KIT D816V allele burden by ASO-qPCR techniques appear useful for monitoring of residual disease in aggressive subtypes during or after cytoreductive therapy or allogeneic stem cell transplantation.  The frequency of measurement of the allele burden should be adapted to the individual situation in each patient. Thus, in patients who have idiopathic SM with low mast cell burden and stable clinical course, the KIT D816V allele burden should be measured at diagnosis, but should not necessarily be repeated unless signs of disease progression occur. In patients with more aggressive forms enrolled in clinical trials with cytoreductive therapies, the KIT D816V allele burden should be measured repeatedly before and during therapy.  When symptoms worsen, a bone marrow aspiration and biopsy should be considered.

ARUP Lab Tests

Mast Cell Mediators and Metabolites

Diagnosis of MCDs

Monitoring of SM

Useful in prognosis of SM

Useful in diagnosis and monitoring of MCAS

May assist when diagnosing and monitoring MCAS

Used mainly for research purposes

KIT Mutational Analysis

Aid in diagnosis of mastocytosis​

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

Additional Mutational Analysis and Genetic Testing

Useful in all patients with SM, as certain mutations (eg, SRSF2, ASXL1, RUNX1) are associated with a worse prognosis

Useful for detection of an associated hematologic neoplasm (eg, myelodysplastic syndrome, chronic myelomonocytic leukemia, myeloproliferative neoplasm, and other myeloid disorders)

Use to exclude myeloid and lymphoid neoplasms with eosinophilia when peripheral eosinophilia is present

Medical Experts

Author

George

Tracy I. George, MD
Professor of Clinical Pathology, University of Utah
Executive Director, Clinical Trials and PharmaDx; Medical Director, Hematopathology, ARUP Laboratories
Author

March

Jordon K. March, MD
Jordon K. March, MD
Anatomic and Clinical Pathology Resident, University of Utah/ARUP Laboratories
Associate Medical Director, ARUP Consult

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