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.
MCDs are categorized as clonal and nonclonal disorders:
Clonal Mast Cell Disordersa
||Typically a skin-only disease that affects young children <2 years of age and spontaneously resolves during childhood
||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)
||Most adults with SM have the indolent form of the disease
||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
|Mast cell leukemia
||Recurrent anaphylaxis, without skin lesions, and evidence of mast cell clonality not meeting criteria for SM
||MCAS is secondary to another disorder, such as collagen vascular disease
||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
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
- Multifocal dense infiltrates of MCs (≥15 MCs in aggregates) in BM biopsies and/or in sections of other extracutaneous organ(s)
- >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 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
||Anaphylaxisa (especially following 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
Sources:Hamilton, 2018 ; Jennings, 2018
Common Triggers in Individuals with a Mast Cell Disorder
|Heat, cold, sudden temperature change
Emotional, physical, environmental stress
Exercise, friction, vibration, surgery
Food and beverages (including alcohol)
Medicationsa (anesthetics, antibiotics, nonsteroidal anti-inflammatory drugs, opioids), contrast dyes
Strong odors (perfumes, smoke, cleaning agents)
|aSignificantly increased in nonclonal disorders
Sources: Hamilton, 2018 ; Jennings, 2018
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 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
||Considered normal by most laboratories
||Suggestive of NC-MCAS; consider retesting during or after future symptomatic episode
||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 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.
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.