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Systemic Mastocytosis

Mastocytosis is a disorder in which abnormal mast cells are increased in one or more organs. In this condition the growth of mast cells is poorly controlled, sometimes as the result of mutations that produce clones, or identical copies, of cells. The growth and replication of normal mast cells is controlled by a membrane protein named KIT, which can be regulated as a switch ON and OFF. Mutations in KIT that keep the switch ON are the cause of mastocytosis. The most common mutation, called KIT D816V, produces a receptor that is constantly activated resulting in continuous growth and activation of mast cells. When mast cell numbers are increased, the amount of released mediators is increased, producing mast cell mediator related symptoms, which can be systemic and localized in multiple organs.

Mast cells are one of the immune cells that carry the allergic antibody called IgE that binds allergens such as pollen, peanut or penicillin. The binding of IgE to the allergens triggers the release of chemical mediators such as histamine, tryptase, leukotrienes, and prostaglandins. These and other mediators cause an allergic response. In severe cases they can lead to anaphylaxis, which is the most severe of the allergic reactions. Anaphylaxis can lead to cardiovascular collapse and death. Mast cells can also be triggered to release mediators by other non-specific stimuli such as changes in temperature, stress, alcohol and exercise among others. In addition to the increase in mediators as the result of increased numbers, abnormal mast cells in mastocytosis can be prone to release mediators more easily in general.

Mastocytosis is categorized based on where the increased numbers of cells are found, the symptoms and clinical presentation, and findings on pathology. In cutaneous mastocytosis, the increased numbers of mast cells are found only in the skin. In systemic mastocytosis, the increased numbers of mast cells are found in other organs, whether or not the clusters of mast cells are also present in the skin. Mast cell sarcoma is a very rare condition with a single mass of cells, which can occur in any organ. Mastocytosis can occur in both children and adults, with a predominance for cutaneous mastocytosis in children and systemic mastocytosis in adults.

In this article, we focus on systemic mastocytosis.

Most adults with systemic mastocytosis have infiltration of one or more internal organs with abnormal mast cells and can present with or without cutaneous mastocytosis.

Mastocytosis may be suspected when there are persistent symptoms of mast cell mediator release, especially in the absence of known triggers of mast cell mediator release, such as allergy or certain medications. Patients may experience one or more of the symptom groups listed.

Symptoms of Mastocytosis include:
•    Anaphylaxis
•    Itching, flushing, hives, swelling
•    Wheezing or shortness of breath
•    Sinus congestion and pressure
•    Throat swelling
•    Palpitations, changes in blood pressure, dizziness, fainting
•    Nausea, vomiting, abdominal pain, diarrhea
•    Uterus cramps/bleeding
•    Bone or muscle pain, osteopenia, osteoporosis
•    Headache, brain fog, anxiety, short memory span, depression

Potential triggers for mast cell mediator release in mastocytosis include:
•    Heat, cold or sudden temperature changes
•    Stress: emotional, physical, including pain
•    Environmental: weather changes, pollution, odors, perfumes, chemicals
•    Allergens: pollen, pet dander, dust mites
•    Exercise
•    Fatigue
•    Food or beverages, including alcohol
•    Drugs (opioids, NSAIDs, antibiotics and some local anesthetics) and contrast dyes
•    Venoms (bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes, biting insects, such as flies, mosquitos and fleas, etc.)
•    Infections (viral, bacterial or fungal)
•    Mechanical irritation, friction, vibration
•    Vaccines

Mastocytosis is diagnosed by sampling the tissues where there is an abundance by using biopsies, measuring mast cell mediators in blood and urine, blood counts, liver function studies and genetic tests. Most adult patients with cutaneous mastocytosis also have other organs involved (unlike the case in most children). Thus, in adults it is important to look for possible systemic mastocytosis using biopsies of organs in addition to the skin. A bone marrow biopsy is typically used because mast cell precursors originate in the bone marrow before migrating to other organs to mature and are more abundant there. Gastrointestinal biopsies are also a good source to look for increased mast cells.

The diagnosis of systemic mastocytosis is determined by criteria established by the World Health Organization consensus group and requires meeting the major criterion plus one minor criterion or, alternatively, three of the minor criteria.

Major criteria: Multifocal dense infiltrates of mast cells (MCs) (> 15 MCs in aggregate) in tryptase stained biopsy sections of the bone marrow or other extracutaneous organs such as the gastrointestinal tract.

Minor criteria:
1.    More than 25% of MCs in bone marrow or other extracutaneous organ(s) show abnormal morphology (i.e., are atypical MC type 1 or are spindle–shaped MCs) in multifocal lesions in histologic examination
2.    KIT mutation at codon 816 in extracutaneous organ(s) (in most cases bone marrow) or peripheral blood
3.    KIT+ MCs in bone marrow show aberrant expression of CD25 (and/or less specifically CD2)
4.    Serum total tryptase > 20 ng/mL (except in patients with associated hematologic neoplasm (AHN)-type disease.)
In addition to the initial diagnosis, systemic mastocytosis is divided into subtypes determined by findings such as the amount of organ infiltration by mast cells (mast cell burden), presence or absence of other blood malignancies, and organ involvement with mast cell related damage such as enlarged liver, spleen or lymph nodes, or bone damage. There are five systemic mastocytosis subtypes and other rare variants have been described, including well differentiated systemic mastocytosis. Determining the subgroup helps in directing therapy and establishing prognosis. The subgroups are listed here, with indolent systemic mastocytosis being the most frequent, and the other subgroups in order of increasing aggressiveness:

• Indolent systemic mastocytosis
• Smoldering systemic mastocytosis
• Aggressive systemic mastocytosis
• Systemic mastocytosis with an associated hematologic neoplasm
• Mast cell leukemia

Most adult patients fit into the indolent systemic mastocytosis category. While they may be symptomatic, indolent systemic mastocytosis patients generally have low morbidity and normal life expectancy not different from their peers. Smoldering systemic mastocytosis patients have an inferior survival compared to indolent systemic mastocytosis, but the advanced age of those patients account for most of the difference. Indolent systemic mastocytosis patients have a low risk of progression to more severe disease, while the risk of progression to more severe disease is higher for Smoldering systemic mastocytosis patients.

Aggressive systemic mastocytosis patients have more significant symptoms, including enlarged liver and lymph nodes, as well as blood abnormalities such as anemia and low platelets. Patients with systemic mastocytosis with an associated hematologic neoplasm suffer from additional problems caused by the associated blood malignancy. Mast cell leukemia is very rare, but comes with a difficult prognosis and shorter life span.
The objective of treatment is to control the effects of mast cell released mediators by avoidance of triggers, as well as the use of various medications. Most treatment is supportive, but there have been recent successes with targeted therapies.

Topicals, such as emollients, are important to keep skin moisturized and less prone to physical stimuli. Topical corticosteroids are not routinely used. Antihistamines, including both H1 and H2 antihistamines, are commonly used to block the effects of mast cell histamine. Mast cell stabilizers, such as cromolyn sodium and ketotifen, along with leukotriene inhibiting agents, may provide benefit. Epinephrine may be required to treat episodes of anaphylaxis or low blood pressure. It is suggested that mastocytosis patients should carry two epinephrine injectors due to the increased mast cell burden and increased mediator release. More aggressive forms of systemic mastocytosis may require interferon, immune modulators or chemotherapeutic agents. Osteoporosis therapy can ameliorate bone damage. Anemia and low platelet counts are treated by transfusion. Targeted therapies, such as kinase inhibitors, are now proving to be of value in aggressive disease—and more recently to increase the quality of life of patients with indolent systemic mastocytosis.


Find out more about Mast Cell Activation Syndrome (MCAS).


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