Diagnosing SM

I am KIT D816V—the hidden mutation causing systemic mastocytosis (SM). I can evade low-sensitivity testing, and delay diagnosis from symptom onset.1-3,12,19

Accurate detection of the KIT D816V mutation is key to not missing systemic mastocytosis7

Each specialist in a patient’s diagnostic journey has the opportunity to identify and confirm the presence of KIT D816V. The key is to look out for the various symptoms of systemic mastocytosis and pursue an accurate mutational assay.12,19

Once systemic mastocytosis is suspected, the following tests will help you confirm a diagnosis.

Measure serum tryptase

When patients present with systemic mastocytosis symptoms in the areas of skin, gastrointestinal, respiratory, systemic, cardiovascular, neuropsychiatric, or musculoskeletal systems, be sure to run a tryptase test. The level will help direct you to the appropriate next steps.5,34

The measurement of serum tryptase is a diagnostic approach that can be used as a diagnostic marker in systemic mastocytosis, and help distinguish between categories of the disease.35 When serum total tryptase persistently exceeds 20 ng/mL (a WHO minor criterion), results should be interpreted alongside full clinical and lab findings.5,35,a

Mastocytosis unlikely, but cannot be ruled out5,36

Systemic mastocytosis possible– screen for KIT D816V in peripheral blood with high-sensitivity assay5

Bone marrow biopsy and screen for KIT D816V mutation5

  • Unless there is an associated myeloid neoplasm, in which case this parameter is not valid.

Screen for KIT D816V in peripheral blood with high-sensitivity assay

For ~95% of systemic mastocytosis patients, the KIT D816V mutation drives their mastocytosis.1 Low-sensitivity assays may fail to detect the mutation and potentially prolong the search for a diagnosis.12

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend34:

  • Using a highly sensitive assay, such as ASO-qPCR, on the peripheral blood to detect KIT D816V
  • Performing KIT mutational analysis on the bone marrow aspirate following a positive test on the peripheral blood
  • When applied to the bone marrow of patients with systemic mastocytosis, these assays can detect the KIT D816V mutation in >80% of patients
  • In patients with low mast cell burden indolent systemic mastocytosis, if no mutation is found, evaluation for KIT D816V mutation in the skin or from an extracutaneous organ could be considered
  • In patients with high mast cell burden and negative KIT D816V screen, results should be confirmed with the most sensitive test, ASO‑qPCR
  • If test is still negative, evaluation of KIT for alternative codon 816 mutations should be performed
  • If no mutation found at codon 816, sequencing of the whole KIT coding sequence by NGS may be undertaken
  • In patients with low mast cell burden indolent systemic mastocytosis and a stable, clinical course, evaluation of KIT D816V should be considered at diagnosis, but not repeated unless signs of disease progression occur

Complete a bone marrow biopsy and screen for KIT D816V mutation

Bone marrow is the most common site of extracutaneous accumulation of mast cells in patients with systemic mastocytosis.35

The presence of certain clinical/laboratory features support bone marrow investigation when systemic mastocytosis is suspected in adult patients.37

Bone marrow evaluation should look out for multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) as a marker in systemic mastocytosis. Aberrant mast cells in bone marrow express CD25, with or without CD2, in addition to normal mast cell markers apparent in systemic mastocytosis. Specialty pathologist expertise may be required.5,34,38

High-sensitivity peripheral blood KIT D816V testing may aid in identifying patients who should have a bone marrow investigation when systemic mastocytosis is suspected in adult patients.5,37


Diagnosis of systemic mastocytosis per WHO diagnostic criteria requires presence of the major criterion and at least one minor criterion, or when ≥3 minor criteria are present

Major criterion
Multifocal aggregates of ≥15 mast cells in bone marrow sections and/or other extracutaneous organ(s).
Minor criteria
  1. In biopsy sections of bone marrow or other extracutaneous organs, >25% of mast cells in the infiltrate are spindle-shaped or have atypical morphology; or >25% of all mast cells in bone marrow aspirate smears are immature or have atypical features
  2. Presence of activating point mutation at codon 816 of KIT in bone marrow, blood, or other extracutaneous organ
  3. Mast cells in bone marrow, blood, or other extracutaneous organs express CD25, with or without CD2, in addition to normal mast cell markers
  4. Serum total tryptase persistently >20 ng/mL (if patient has an associated myeloid neoplasm, this parameter is not valid)
Screen suspected patients with high-sensitivity KIT D816V diagnostic assays

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