Systemic mastocytosis

Systemic mastocytosis is a type of blood disease in which a specific type of white blood cell, called a mast cell, grows in an abnormal and uncontrolled way. Normally, mast cells are part of the body’s immune system and help fight infections, but in systemic mastocytosis, these abnormal mast cells accumulate and build up in organs throughout the body. The bone marrow (the soft, blood-forming tissue inside bones) is almost always involved, but other organs such as the liver, spleen, lymph nodes, and skin may also be affected. Depending on how many organs are involved and how severely they are affected, systemic mastocytosis can range from mild to very serious.

What are the symptoms of systemic mastocytosis?

The symptoms of systemic mastocytosis vary significantly from one person to another.

Common symptoms can include:

Skin changes, such as reddish-brown spots or patches.
Itching, flushing, or hives.
Stomach pain, nausea, vomiting, diarrhea.
Bone pain or fractures.
Headaches and fatigue.
Low blood pressure, dizziness, or fainting.

In more advanced forms, the disease may cause severe problems such as liver enlargement, low blood counts, significant weight loss, or damage to multiple organs.

What causes systemic mastocytosis?

Systemic mastocytosis is typically caused by mutations (changes) in a gene called KIT. This gene normally helps regulate the growth and multiplication of mast cells. When mutated, mast cells can become overactive, grow excessively, and accumulate in the body. The most common mutation is called KIT p.D816V, found in over 90% of cases. Although these mutations are acquired during a person’s life, the exact reason why they occur in most people remains unknown.

How is this diagnosis made?

The diagnosis of systemic mastocytosis is usually made through examination of a bone marrow biopsy by a pathologist. The pathologist examines the bone marrow tissue under a microscope, looking for aggregates (groups) of abnormal mast cells. These abnormal mast cells typically appear in clusters, with at least 15 mast cells grouped closely together.

The pathologist will also carefully examine the appearance of these mast cells. Abnormal mast cells often have unusual shapes—such as spindle-shaped or immature forms—and may appear less granular than normal mast cells. Special staining techniques are used to identify and confirm the presence of these abnormal mast cells in the sample.

What additional tests may be performed to confirm the diagnosis?

Several additional tests may be performed to help confirm the diagnosis and characterize systemic mastocytosis.

Immunohistochemistry (IHC)

Immunohistochemistry is a specialized laboratory test used by pathologists to detect specific proteins on the surface of cells. In systemic mastocytosis, mast cells typically express proteins called CD25 and sometimes CD2 or CD30, which normal mast cells generally do not. The presence of these proteins helps pathologists confirm that the mast cells are abnormal.

Next-generation sequencing (NGS)

Next-generation sequencing is a powerful genetic testing method used to look for mutations in genes. In systemic mastocytosis, next-generation sequencing (NGS) is commonly used to identify mutations in the KIT gene, particularly the KIT p.D816V mutation. Confirming this genetic mutation supports the diagnosis and may guide treatment decisions.

Additional molecular tests

In some cases, molecular tests may be performed to identify clonality, which means that the abnormal mast cells originate from the same genetic source. These tests can detect whether mast cells or other associated blood cells share genetic changes, helping to confirm that the abnormal cells are part of a single, abnormal clone.

What criteria do pathologists use to make this diagnosis?

Pathologists use specific criteria to diagnose systemic mastocytosis. The diagnosis requires either one major criterion plus one minor criterion, or at least three minor criteria.

Major criterion:

Dense clusters (aggregates) of at least 15 abnormal mast cells in the bone marrow or other organs.

Minor criteria (at least one required if the major criterion is met; or three if major criterion is not met):

More than 25% of mast cells have an abnormal shape or appearance under the microscope.
Mast cells abnormally express proteins like CD2, CD25, or CD30.
Detection of the KIT mutation (typically KIT p.D816V).
A high level of serum tryptase (over 20 ng/mL) in the blood, without other causes.

What is the prognosis for someone diagnosed with systemic mastocytosis?

The prognosis of systemic mastocytosis depends mainly on the type of disease a person has. Many people with indolent systemic mastocytosis (the mildest form) live a normal lifespan, and the condition may remain stable for many years. However, a small number of cases can progress to more severe disease.

People with aggressive systemic mastocytosis, mast cell leukemia, or systemic mastocytosis associated with another blood cancer typically have a more serious outlook, with shorter survival and higher risk of complications. The specific prognosis also depends on factors such as the presence of additional genetic mutations, the extent of organ involvement, and the response to treatments.

Newer therapies targeting the KIT mutation have shown promising results in improving outcomes for patients, even in advanced cases, offering hope for better control and potentially longer survival.

Questions to ask your doctor

What type of systemic mastocytosis do I have, and what does that mean for my health?