Mast Cell Disorders

Mast cell disorders (MCDs) are a diverse group of conditions characterized by inappropriate mast cell activation and/or the proliferation and accumulation of abnormal mast cells 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 mast cell mediators (eg, tryptase and histamine) and/or end organ damage.  The diagnostic approach depends on the type of MCD. Laboratory testing involves serum tryptase measurement and 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 (CM) 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 (MCD)  and is the most specific marker of mast cell activation available. KIT mutational analysis, preferably performed by digital droplet (dd) or allele-specific oligonucleotide (ASO) quantitative polymerase chain reaction (qPCR) testing 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 to provide 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 who present 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, as described in the following table.

Mast Cell Disordersa
Clonal Disorder Description
CM Typically a skin-only disease that affects young children <2 yrs of age and spontaneously resolves during childhood
SM Chronic and systemic disease that predominantly affects adults and frequently involves the bone marrow and can involve virtually any other organ (eg, skin, spleen, liver, gastrointestinal tract)
Indolent SM Most common form in adults with SM
Smoldering SM Less aggressive than advanced SM
SM with an associated hematologic neoplasm Aggressive clinical course and poor prognosis; as a group, SM with an associated hematologic neoplasm, aggressive SM, and mast cell leukemia are referred to as advanced SM
Aggressive SM Aggressive clinical course and poor prognosis; as a group, SM with an associated hematologic neoplasm, aggressive SM, and mast cell leukemia are referred to as advanced SM
Mast cell leukemia Aggressive clinical course and poor prognosis; as a group, SM with an associated hematologic neoplasm, aggressive SM, and mast cell leukemia are referred to as advanced SM
MMAS Recurrent anaphylaxis, without skin lesions, and evidence of mast cell clonality that does not meet criteria for SM
Nonclonal Disorder Description
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 MCDs may also involve 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 MCAS

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

aTotal serum tryptase is the recommended marker of choice; 24-hr urine histamine metabolites and 11-beta-prostaglandin F2 are less specific.

Source: Valent, 2019 

WHO 2017 Diagnostic Criteria for SM
Major Criteriona Minor Criteria
Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)

>25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle shaped in mast cell infiltrates detected on histologic sections of visceral organs

KIT point mutation present 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.

Source: Swerdlow, 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, 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 MCDs by Body System
Body System Clinical Presentation
General Anaphylaxisa (especially after 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 

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 ultrasensitive quantitative polymerase chain reaction (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 for 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 (ng/mL) Interpretation
<11.4 Considered normal by most laboratories
11.4-20.0

Suggestive of NC-MCAS; consider retesting during or after future symptomatic episode

May also be seen in hereditary alpha tryptasemia,  renal failure, asthma, and other conditions

>20.0 Minor criterion for diagnosis of SM; if elevated on 2 separate occasions, evaluation for SM should be pursued
Sources: Hamilton, 2018 ; Lyons, 2018 
Other Mast Cell Mediators

Although serum tryptase is the only mast cell mediator included in consensus criteria, other laboratory tests that can 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 MCD evaluation. 

Bone Marrow Examination

When bone marrow is examined for MCD, 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)
  • Fluorescence 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 MCD, 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 the KIT D816V mutation 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 having 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 allele-specific oligonucleotide (ASO) or digital droplet (dd)-qPCRs can be used to 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, a 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. 

Additional Genetic Testing

Tryptase copy number determination is helpful in establishing a diagnosis of hereditary alpha tryptasemia (elevated copy number of the alpha tryptase-encoding gene, TPSAB1). Hereditary alpha tryptasemia is associated with an increase in the basal serum tryptase level and a risk of mast cell activation; this can be present in patients with or without SM.

Monitoring

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

Serial measurements of the KIT D816V allele burden by ultrasensitive qPCR techniques appear useful to monitor 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 who are 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

Use to diagnose MCDs

Use to monitor and determine prognosis of SM

Useful in diagnosis and monitoring of MCAS

May assist in diagnosis and monitoring of MCAS

Used mainly for research purposes

KIT Mutational Analysis

Aids in diagnosis of mastocytosis​

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

Additional Mutational Analysis and Genetic Testing

Useful in all patients with SM because 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

References

Resources from the ARUP Institute for Clinical and Experimental Pathology®