How Is Indolent Systemic Mastocytosis Diagnosed?

Getting to an indolent systemic mastocytosis (ISM) diagnosis often takes a long time. The non-specific nature of ISM symptoms might mean that you have been diagnosed with allergies, anxiety, or a nervous stomach. If you have been misdiagnosed or have gone undiagnosed for months or years, you are not alone, and the difficulty of your experience is not just “all in your head.”

ISM diagnosis is often a complex process. Here is what that process can involve.

Why ISM is so often missed

Systemic mastocytosis is rare, affecting an estimated 1 in 10,000 to 20,000 people worldwide.¹

Its symptoms can also be a “false flag” for far more common conditions. Irritable bowel syndrome, inflammatory bowel disease, and hives are all on the list doctors must work through to eliminate more common causes.²

Symptoms can also flare suddenly, with several occurring at the same time. This may make your symptoms feel more intense. Doctors may refer to this as a mastocytosis attack or a flare.^3,4

Symptom history and testing

To evaluate you for systemic mastocytosis, your doctor begins with a physical exam and a review of your symptoms and medical history. Once this is complete, they will start testing for raised mast cell numbers or the chemicals mast cells release.^2,4

Doctors look for these markers using a few different tests, including:^2,4

• Blood or urine tests
• Skin biopsy – removing a small sample of skin for laboratory testing
• Bone marrow biopsy – removing a small sample of bone marrow for laboratory testing
• Imaging tests – might include X-rays, ultrasound, bone density scans, or CT scans
• Organ biopsy – removing a small sample of tissue from organs such as the liver
• Genetic testing

What doctors are looking for is a pattern rather than 1 standout symptom. Flushing, digestive trouble, and strong reactions to heat, insect stings, or certain drugs can make up a larger picture that helps determine a cause.^2,3,5

Testing tryptase levels

Tryptase is one of the chemicals that mast cells release.^3,6

A blood test can measure your baseline tryptase level, which is the amount of tryptase in your blood when you are not in the middle of a reaction.^3,6

A repeated increase in tryptase above 20 ng/mL or an increase of more than 20 percent above your baseline level might mean you have systemic mastocytosis. On its own, though, this test result does not confirm that you have ISM.⁶

A normal tryptase test result also does not rule out ISM. If your tryptase levels are normal, but you have other ISM symptoms, it may be worth talking to your doctor about a skin or bone marrow biopsy.^2,6

Genetic testing for the KIT gene change

ISM is usually caused by a change in a gene called KIT D816V. The presence of this gene variant is one of the criteria that will help your doctor diagnose ISM. Research has shown that over 80 percent of people with systemic mastocytosis have this gene variant.^6,7

This change almost always happens on its own during your life rather than being inherited. It is generally not passed down to children.^2,5

The bone marrow biopsy

This is usually the test that confirms systemic mastocytosis. A doctor uses a needle to take a small sample of bone marrow, which is then examined in a lab.^5,7

In ISM, the overall amount of mast cell buildup in the bone marrow is typically low, usually under 5 to 10 percent. But even with a low buildup of mast cells in your bone marrow, you can still have symptoms. Other areas of the body that can be impacted include the skin and the digestive tract.^3,6,7

What your skin can show

Many people with mastocytosis have brownish patches on the skin called urticaria pigmentosa. Rubbing or scratching can make these patches itch and swell, which doctors refer to as a positive Darier’s sign.^3,6,8

Visible skin findings matter, but as with other symptoms, they do not confirm an ISM diagnosis on their own. A skin biopsy showing extra mast cells could help point to systemic mastocytosis.^2,6

How your doctor puts the pieces together

Doctors use a checklist from the World Health Organization (WHO). A diagnosis needs either the 1 major finding plus 1 minor finding, or 3 minor findings.^6,7

The major finding is those dense clusters of mast cells in bone marrow or another tissue outside the skin. The minor findings are:^6,7

• Abnormal shape – Greater than 25 percent of the mast cells are atypical or spindle-shaped.
• A KIT change – An activating change at codon 816 or another key part of the gene.
• Surface markers – Mast cells carrying CD2, CD25, or CD30.
• Tryptase – A baseline blood level above 20 ng/mL.

In addition, a bone density scan is recommended at diagnosis and again during follow-up, and your care team will track your blood and urine over time.^3,4

Talk to your doctor

If you have been struggling to get a diagnosis that makes sense of a complex symptom experience, it is reasonable to ask your doctor whether a mast cell disorder should be ruled out.

Once you have a diagnosis, ask which type of systemic mastocytosis you have and what comes next. Those answers will help shape your treatment journey.