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
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.
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.
Ultrasensitive methods such as digital droplet polymerase chain reaction (ddPCR) are the preferred first-line methods for KIT mutational analysis to diagnose mast cell disorders, given that these methods are highly sensitive, specific, and can be performed on peripheral blood. This ensures that invasive blood marrow biopsies are only performed in patients who need them.
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.
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.
MCDs are categorized as clonal and nonclonal disorders, as described in the following table.
|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|
|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
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.
|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.
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).
|Body System||Clinical Presentation|
|General||Anaphylaxisa (especially after hymenoptera venom exposure)|
Maculopapular (urticaria pigmentosa-like) lesions
Flushing (especially face and chest)
Throat itching, swelling
Abdominal pain, tenderness
Loose stools, diarrhea
Bone, musculoskeletal pain
Osteopenia, osteoporosis (with or without bone fractures)
Memory and concentration difficulties
Blood pressure changes
aSignificantly increased in clonal disorders.
bSignificantly increased in nonclonal disorders.
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 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.
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.
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 Laboratory Tests
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
Aids in diagnosis of mastocytosis
Provides prognostic and predictive information for tyrosine kinase inhibitor (TKI) therapy planning and monitoring
Droplet Digital Polymerase Chain Reaction
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)
Massively Parallel Sequencing
Use to exclude myeloid and lymphoid neoplasms with eosinophilia when peripheral eosinophilia is present
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