Systemic Mastocytosis

Systemic mastocytosis is a rare blood disorder that occurs when abnormal mast cells build up throughout the body, releasing chemicals that cause a continuous allergic response affecting the skin, digestive system, bones, and other organs.

Table of contents

• What is systemic mastocytosis?
• Types of systemic mastocytosis
• Signs and symptoms
• What causes systemic mastocytosis?
• Who gets systemic mastocytosis?
• How is it diagnosed?
• Treatment and management
• Living with systemic mastocytosis
• What to expect

What is systemic mastocytosis?

Systemic mastocytosis is a rare disorder that results in too many mast cells building up in your body^[1]. A mast cell is a type of white blood cell that helps your immune system function properly. Mast cells are found in connective tissues throughout your body and normally help protect you from disease^[1].

When you have systemic mastocytosis, excess mast cells build up in your skin, bone marrow, digestive tract, or other body organs^[1]. In systemic mastocytosis, abnormal mast cells continue to release histamine long after they should. Histamine sets off an allergic response. This chemical overload causes a continuous allergic response that can affect your skin and internal organs^[2].

Systemic mastocytosis is different from cutaneous mastocytosis, where 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 clusters of mast cells are also present in the skin^[3].

The condition is rare, affecting about 13 out of every 100,000 people worldwide^[2]. It is estimated to occur in approximately 32,000 people in the U.S.^[5].

Types of systemic mastocytosis

There are six types of systemic mastocytosis. Each can affect you in different ways. In general, the more abnormal mast cells you have, the greater the chance you’ll have complications^[2].

Indolent systemic mastocytosis is the most common type. Symptoms usually develop over several years. Abnormal mast cells increase and cause symptoms that affect your skin, liver, spleen, and gastrointestinal tract. This form accounts for around 90% of adult systemic mastocytosis cases^[7]. People with indolent systemic mastocytosis generally have a normal or near normal life expectancy^[6].

Smoldering systemic mastocytosis has more significant symptoms and can sometimes lead to organ problems. In this type, abnormal mast cells multiply in your liver and spleen. Eventually, the cells may cause an enlarged spleen or enlarged liver^[2]. Smoldering mastocytosis may progress to advanced disease in approximately 9% of cases^[5].

Systemic mastocytosis with associated hematologic neoplasm involves a situation where an additional blood disorder is present. This type affects about one-fifth of people with systemic mastocytosis^[2].

Aggressive systemic mastocytosis is associated with progressive organ damage. This type can affect your bone marrow and bones. Abnormal mast cells can grow into your bones, making them weak and more likely to break^[2].

Mast cell leukemia is an extremely rare and aggressive form of systemic mastocytosis that affects the bone marrow and blood. Very rarely, systemic mastocytosis becomes mast cell leukemia, which is a form of acute myeloid leukemia^[2].

Mast cell sarcoma is a very rare condition where tumors made of abnormal mast cells attack tissue. Very few people with systemic mastocytosis develop mast cell sarcoma^[2].

Signs and symptoms

Signs and symptoms of systemic mastocytosis depend on the part of the body affected by excessive mast cells. Too many mast cells can build up in the skin, liver, spleen, bone marrow, or intestines. Less commonly, other organs such as the brain, heart, or lungs also may be affected^[1].

Symptoms vary depending on where the abnormal mast cells gather. For example, if you have too many mast cells in your stomach, you might develop ulcers and belly pain. In the same way, abnormal mast cells that build up in your bone marrow may affect blood cell production^[2].

Systemic mastocytosis symptoms may include^[1][2]:

• Flushing, itching, or hives on the skin
• Abdominal pain, diarrhea, nausea, or vomiting
• Anemia (low red blood cell count) or bleeding disorders
• Bone and muscle pain
• Enlarged liver, spleen, or lymph nodes
• Depression, mood changes, or problems concentrating
• Fatigue
• Heart palpitations
• Urticaria pigmentosa (dark, itchy bumps on your skin)

People with systemic mastocytosis may suddenly develop several symptoms all at once. Healthcare providers may refer to this as a mastocytosis attack or flare^[2].

Many people with systemic mastocytosis develop a skin condition called urticaria pigmentosa, which is characterized by raised patches of brownish skin that sting or itch with contact or changes in temperature^[6].

Nearly half of individuals with systemic mastocytosis will experience severe allergic reactions (anaphylaxis). People with systemic mastocytosis have a higher risk of anaphylaxis, a severe, life-threatening allergic reaction^[2][6].

Common triggers

When triggered, mast cells release substances that can cause signs and symptoms similar to those of an allergic reaction. People have different triggers, but the most common ones include^[1]:

• Alcohol
• Spicy foods
• Insect stings
• Certain medications
• Skin irritation
• Exercise

Mast cells can also be triggered to release mediators by other non-specific stimuli such as changes in temperature, stress, heat, cytokines, venoms, and hormones^[4].

What causes systemic mastocytosis?

Systemic mastocytosis occurs when white blood cells called mast cells, which are produced in bone marrow, abnormally accumulate in one or more tissues^[6]. In most cases of systemic mastocytosis, the accumulated mast cells have a mutation in a gene called KIT. The KIT gene provides instructions for making a protein that plays an important role in development and activity of mast cells^[6].

The most common mutation, called KIT D816V, produces a receptor that is constantly activated, resulting in continuous growth and activation of mast cells^[3]. In approximately 95% of cases, systemic mastocytosis occurs due to this genetic mutation^[5].

The growth and replication of normal mast cells is controlled by a membrane protein named KIT, which can be regulated like a switch ON and OFF. Mutations in KIT that keep the switch ON are the cause of mastocytosis^[3].

In systemic mastocytosis, KIT gene mutations are somatic, which means they are acquired during a person’s lifetime rather than inherited. These mutations result in a KIT protein that is always turned on (activated). As a result, signaling pathways are overactive, leading to increased production and accumulation of mast cells^[6].

The cause or causes of mastocytosis are not fully known, but there’s thought to be an association with the KIT mutation. In very few cases of mastocytosis it appears the KIT mutation is passed down through families. However, in most cases the mutation happens for no apparent reason^[7].

Who gets systemic mastocytosis?

Systemic mastocytosis is a rare disorder. It affects males and females equally^[4]. Individuals with the condition can develop signs and symptoms at any age, but it usually appears after adolescence^[6].

Most of the cases of mastocytosis are limited to the skin, and 80 percent of them appear during childhood. By adolescence, the majority of them improve or resolve completely. Systemic mastocytosis accounts for more than 95 percent of adult cases and usually persists for a longer time^[4].

How is it diagnosed?

To diagnose systemic mastocytosis, your doctor will likely start by reviewing your symptoms and discussing your medical history, including medications you’ve taken^[9].

A physical examination of the skin is the first stage in diagnosing cutaneous mastocytosis. Your doctor or skin specialist may rub the affected areas of skin to see if they become red, inflamed, and itchy. This is known as Darier’s sign^[7].

Tests used for diagnosis

The following tests are commonly used to diagnose systemic mastocytosis^[7][9]:

• Blood or urine tests to look for high levels of mast cells or the substances they release
• Blood tests including a full blood count and measuring blood tryptase levels. Tryptase is almost always secreted by mast cells and therefore it is used as an important diagnostic factor^[4]
• Bone marrow biopsy – where a local anesthetic is used and a long needle is inserted through the skin into the bone underneath, usually in the pelvis. A diagnosis of systemic mastocytosis is usually made by finding typical changes on a bone marrow biopsy^[7]
• Skin biopsy – a small skin sample is taken and checked for mast cells^[7]
• An ultrasound scan to look for enlargement of the liver and spleen if it seems likely
• A DEXA scan to measure bone density
• Biopsy of organs affected by the disease, such as the liver
• Genetic testing to look for the KIT D816V mutation

Treatment and management

There’s no cure for mastocytosis, so the aim of treatment is to try to relieve the symptoms. Healthcare providers can’t cure the condition, but treatment can ease your symptoms^[2][7].

Treatment options will depend on the type of mastocytosis and the severity of the symptoms. Therapy for systemic mastocytosis is primarily symptomatic^[13].

Managing symptoms and preventing reactions

Antihistamines can be used to treat symptoms such as itchiness and skin redness. H1 and H2 receptor blockers are used to control anaphylactic symptoms. H1 antagonists are used to treat pruritus and flushing. Nonsedating antihistamines may be recommended for daytime use, and sedating ones for nighttime use^[13].

H2 receptor blockers have been used to treat gastric hypersecretion and peptic ulcer disease associated with systemic mastocytosis. Proton pump inhibitors are also useful for this^[13].

Cromolyn sodium has proved useful for relieving abdominal pain and diarrhea, pruritus, whealing, and flushing, and impaired cognition^[13].

Leukotriene antagonists, such as zafirlukast and montelukast, have also been used in the treatment of systemic mastocytosis^[13].

Corticosteroids have been used to control malabsorption, ascites, abdominal pain refractory to cromolyn, bone pain, and diffuse cutaneous disease refractory to topical therapy, and to prevent anaphylaxis^[13].

Bisphosphonates and calcium supplements may be given if you have weakened bones (osteoporosis) resulting from abnormal mast cell activity in your bones^[11].

Mild to moderate cases of cutaneous mastocytosis can be treated with a very strong steroid cream (topical corticosteroids) for a limited length of time^[11].

Emergency treatment

Epinephrine is used in acute anaphylaxis. Patients should be prescribed self-injectable epinephrine and trained to treat recurrent cardiovascular symptoms or anaphylaxis^[15]. In children, the dose is 0.01 mL/kg (up to 0.3 mL) administered every 10-15 minutes as needed^[13].

Advanced treatments

For patients with advanced systemic mastocytosis, treatment options include tyrosine-kinase inhibitors and cladribine, with variable duration and extent of response^[15].

Imatinib mesylate was the first drug approved for systemic mastocytosis lacking the KIT D816V mutation. Midostaurin is active on both wild-type and mutant KIT D816V, while Avapritinib is a selective KIT D816V inhibitor: they are approved for the treatment of advanced systemic mastocytosis^[15].

Cladribine is a purine analog with significant activity that has been used in treatment^[15].

Allogeneic stem cell transplantation is usually performed in younger selected patients^[15].

In patients with anaphylaxis that is recurrent or refractory to conventional therapies, omalizumab (anti-immunoglobulin E), a humanized monoclonal antibody that inhibits the binding of IgE to mast cells, reduced the frequency of anaphylaxis in some patients with systemic mastocytosis^[13]. Omalizumab is effective on all vasomotor symptoms, including anaphylaxis, but not on respiratory, musculoskeletal, and neuropsychiatric symptoms^[15].

Living with systemic mastocytosis

A healthy lifestyle is especially important when you have systemic mastocytosis. Following basic recommendations on a balanced, healthy diet and regular physical activity is incredibly important for this disease. Maintaining your health and wellness may make you eligible for more treatment options^[16].

Identifying and avoiding triggers

Identifying and avoiding triggers may not be easy. People with systemic mastocytosis may avoid certain food or medication triggers and may use treatments to help address some of their symptoms. Some people with systemic mastocytosis have found that certain over-the-counter medications helped with their symptoms. As always, you should talk to your doctor before starting any new medications to manage symptoms^[17].

Communication and support

Communication is one of the most important elements when it comes to managing systemic mastocytosis. Being open and honest with those around you may help create a support network that can aid in your journey^[17].

Your innermost circle can be your strongest supporters. Sharing how your symptoms affect your life may help others understand you. If you’re with a larger group, make sure at least one person there knows about your condition and how to help if you experience symptoms. Make sure the people you’re closest with know the signs and protocols, such as how to administer an EpiPen if needed or get you immediately to the emergency room if necessary^[17].

What to expect

The prognosis for systemic mastocytosis varies greatly depending on the type. Individuals with the milder forms of the condition generally have a normal or near normal life expectancy, while those with the more severe forms typically survive months or a few years after diagnosis^[6].

Indolent systemic mastocytosis may progress to smoldering systemic mastocytosis or advanced systemic mastocytosis in approximately 5% of cases. Smoldering systemic mastocytosis may progress to advanced systemic mastocytosis in approximately 9% of cases^[5].

The severe types include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. These types are associated with a reduced life span, which varies among the types and affected individuals^[6].