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ISM Diagnosis

CE / CME

Diagnosis of Indolent Systemic Mastocytosis: What You Need to Know

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Nurses: 0.25 Nursing contact hour

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

Pharmacists: 0.25 contact hour (0.025 CEUs)

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Released: November 13, 2023

Expiration: November 12, 2024

Tracy George
Tracy George, MD
CME/CE Information

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Key Takeaways
  • The most common KIT mutations associated with mast cell disease are resistant to imatinib.
  • The mean time from symptom onset to diagnosis for patients with mast cell disease is 6.5 years.
  • Accurate and timely diagnosis of systemic mastocytosis using the 2022 WHO 5th Edition Classification of Tumours of Haematopoietic and Lymphoid Tissues criteria is very important.

Mastocytosis Pathogenesis
Mastocytosis pathogenesis is caused by a somatic mutation in KIT, most commonly the KIT D816V mutation. This results in increased mast cell proliferation and motility and organ infiltration by neoplastic mast cells, most commonly seen in bone marrow, spleen, and liver, but it also can be seen in skin and other organs. There is a large gap in time between symptom onset and diagnosis of systemic mastocytosis (SM), with a mean of 6.5 years from symptom onset to diagnosis for patients with mast cell disease.

KIT mutations of mast cell disease are important because they have implications for tyrosine kinase inhibitors, such that most KIT mutations, like the KIT D816V mutation, are resistant to imatinib. Only rare juxtamembrane mutations such as those found in exon 11 are sensitive to imatinib.

Symptoms
Mast cells release many different mediators, affecting the symptoms that patients have. Mast cells are activated by numerous allergens, bacteria, cytokines, drugs, fungi, peptides, toxins, and viruses. Then they release several mediators, including corticotropin-releasing hormone, histamine, interleukin-6, and tumor necrosis factor, which can give rise to systemic symptoms, such as fatigue, malaise, and weight loss. Mast cells also release mediators that give rise to respiratory symptoms, including congestion, pruritus, shortness of breath, wheezing, and throat swelling. These also can give rise to neurologic symptoms like anxiety, depression, brain fog, migraines, and insomnia; musculoskeletal symptoms like bone pain, aches, osteopenia, and osteoporosis; digestive symptoms, including cramps, diarrhea, reflux, nausea, and vomiting; cutaneous symptoms such as flushing, pruritus, urticaria, and angioedema; and cardiovascular symptoms, including hypotension, syncope, lightheadedness, and tachycardia. These numerous symptoms make it very difficult to diagnose this disease.

Diagnostic Criteria From the 2022 WHO 5th Edition Classification of Tumours of Haematopoietic and Lymphoid Tissues
The 2022 WHO 5th Edition Classification of Tumours of Haematopoietic and Lymphoid Tissues states the diagnostic criteria for SM. The major criterion includes multifocal dense aggregates of mast cells. The minor criteria include ≥25% mast cells with atypical morphology; the KIT D816V mutation or other activating KIT mutation; expression of CD2, CD25, and/or CD30 expression on mast cells; and an elevated serum total tryptase of >20 μg/mL. Now, this last criterion of an elevated serum total tryptase level does not apply if there is an associated myeloid neoplasm. It is suggested that this must be adjusted for the presence of hereditary α tryptasemia per the WHO diagnostic criteria as described below. To make the diagnosis of SM, the patient must have at least 1 major and 1 minor criteria, or at least 3 minor criteria.

With the elevated basal serum tryptase level, the average serum tryptase levels in healthy individuals are <5 μg/mL, but elevated serum tryptase levels can be seen in those patients with hereditary α tryptasemia. Therefore, testing for hereditary α tryptasemia is needed to address the serum tryptase level. This can be adjusted by dividing the serum total tryptase level by 1 plus the number of extra genes that encode for hereditary α tryptasemia. It is important to note that this is not valid in the presence of an associated myeloid neoplasm.

The classification of mastocytosis includes cutaneous disease and systemic disease. When I think about systemic disease, there is the more indolent type of disease, such as indolent SM (ISM), smoldering SM, and advanced disease. With advanced SM, this includes patients with SM having an associated hematologic neoplasm, aggressive SM, or mast cell leukemia.

Standard of Care
The mastocytosis pathology testing standard of care includes laboratory findings, morphologic findings, genetic findings, as well as phenotypic findings. It is very important to do high-sensitivity polymerase chain reaction testing for KIT D816V to avoid false-negative results. Most adults will fit into the subtype of ISM, which has a low morbidity and low risk of disease progression. The standard of care is mainly supportive, but recent advances with targeted therapies have been successful. There is an exciting, novel therapy that my colleague, Dr Mariana Castells will discuss in the ClinicalThought “The Treatment of ISM: An Expert’s Review.”

Your Thoughts?
What are your biggest challenges when it comes to the diagnosis of ISM? Answer the polling question and join the discussion by posting a comment.

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Are you using the 2022 WHO 5th edition diagnostic criteria for ISM?

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