Mastocytosis

What is mastocytosis?

Mastocytosis is a diverse group of disorders characterised by the expansion and accumulation of mast cells in one or more organ systems. It can affect the skin, bone marrow, liver, spleen, gastrointestinal tract, or lymph nodes. 

In 2022, the World Health Organisation (WHO) categorised three main types of mastocytosis:

• Cutaneous mastocytosis (affecting the skin alone), most commonly maculopapular cutaneous mastocytosis
• Systemic mastocytosis
• Mast cell sarcomas.

Cutaneous mastocytosis in an infant - yellow-brown macules over the chest and back. The chest lesion has urticated 5 minutes after rubbing (Darier sign)

Extensive diffuse mastocytosis in an infant

Maculopapular cutaneous mastocytosis (urticaria pigmentosa); red-brown maculopapular lesions on the leg

Telangiectasia in maculopapular cutaneous mastocytosis

Dermoscopy showing prominent telangiectasia in telangiectatic maculopapular cutaneous mastocytosis

Solitary mastocytoma on a toddler’s hand

Who gets mastocytosis?

Mastocytosis can occur at any age, although some types are more common in particular age groups. Females have a slightly higher risk of developing mastocytosis than males. In most cases, there is no family history of mastocytosis.

Cutaneous mastocytosis is most commonly diagnosed in childhood. It can be present at birth and around 50% of children develop skin lesions before they are 6 months old. It usually resolves by puberty but in some cases may persist. Urticaria pigmentosa (maculopapular cutaneous mastocytosis) more commonly presents in adulthood and may be persistent and slowly progressive.

Systemic mastocytosis is usually diagnosed in adulthood after the second decade of life. 

What is the cause of mastocytosis?

Mastocytosis is caused by a mutation of the KIT gene on the 4q12 chromosome. This results in too many mast cells being produced.

Mast cells contain chemicals that mediate inflammation (eg, via histamine, leukotriene C4, prostaglandins, tryptase, TNFα, and IL-8). Upon activation, mast cells release these mediators, resulting in localised itching, swelling, redness and sometimes blistering of the skin. This can be a normal reaction; for example, to insect bites. However, in mastocytosis, this process becomes uncontrolled. 

In rare cases, the KIT genetic defect is inherited. In most cases, it is sporadic, with no family history.

What are the clinical features of mastocytosis? 

Cutaneous mastocytosis

There are three main forms of cutaneous mastocytosis:

• Maculopapular cutaneous mastocytosis (urticaria pigmentosa)
• Diffuse cutaneous mastocytosis
• Mastocytoma of the skin.

In all forms, rubbing or scratching an area of skin affected by mastocytosis results in redness, swelling, itching, and occasionally blistering within a few minutes (Darier sign).

Table 1. Cutaneous mastocytosis

Systemic mastocytosis

Patients usually have skin lesions, although these may be smaller than those of childhood-onset cutaneous mastocytosis. Evidence of other organ involvement may include:

• Symptoms of peptic ulcer disease
• Enlarged lymph nodes
• Splenomegaly
• Abnormal blood tests. 

Depending on clinical presentation, systemic mastocytosis can be classified as indolent (slow expansion), smouldering (premalignant), or aggressive. It can be limited to the bone marrow (bone marrow mastocytosis). In rare cases, it may be associated with haematological neoplasia or progress to mast cell leukaemia. 

How do clinical features vary in differing types of skin?

In darker skin tones:

• Urticaria and blistering may appear more purple or violaceous
• Lesions and Darier sign may be less visible but are still positive.

Skin biopsy findings in all Fitzpatrick skin types would demonstrate increased mast cell numbers.

What are the complications of mastocytosis?

• Severe pruritus (itching)
• Sleep disturbance
• Gastrointestinal upset
• Anaphylaxis (especially after stings)
• Splenomegaly
• Hepatomegaly with impaired liver function; rarely ascites and portal hypertension
• Aggressive systemic disease (rare) can also lead to cytopaenias, osteoporosis, bone fractures, malabsorption, and weight loss
• Progression to mast cell leukaemia (rare, poor prognosis)
• Mast cell sarcoma, a solid tumour of malignant mast cells (rare) 

How is mastocytosis diagnosed?

It is important to differentiate between cutaneous and systemic mastocytosis. A full history should be taken, along with skin and abdominal examination and checking for lymphadenopathy.

Diagnosis of cutaneous mastocytosis

Cutaneous mastocytosis is usually diagnosed by its clinical appearance and positive Darier sign, in the absence of systemic symptoms and signs. 

Patients with a solitary mastocytoma generally require no further workup.

Skin biopsy and histology can be helpful for confirmation of cutaneous mastocytosis. This may show aggregates of mast cells with positive staining for CD117 filling the papillary dermis, and may have positive staining for tryptase. See also: Maculopapular cutaneous mastocytosis pathology. 

Diagnosis of systemic mastocytosis

Systemic mastocytosis is diagnosed when a patient has a positive bone marrow biopsy or other extracutaneous biopsy. Specific laboratory and genetic tests may also support the diagnosis.

Relevant tests include:

• Full blood count
• Serum biochemistry
• Liver function tests
• Serum tryptase level (systemic mastocytosis less likely with tryptase level <20 ug/L)
• Abdominal ultrasound
• Bone density scan
• Bone marrow trephine
• Blood and marrow smears
• Flow cytometry (to measure CD2, CD25, and CD30)
• Genetic testing (KIT mutations in bone marrow mast cells).

Table 2. Diagnostic criteria for systemic mastocytosis (≥1 major + 1 minor; OR ≥3 minor criteria)*

*Updated by WHO, 2022

What is the differential diagnosis for mastocytosis?

• Bullous impetigo
• Urticaria
• Juvenile xanthogranuloma
• Arthropod bites and stings
• Autoimmune bullous diseases
• Other haematological diseases

What is the treatment for mastocytosis?

General measures

Many forms of cutaneous mastocytosis without symptoms require no treatment.

Avoidance of triggers for histamine release/ mast cell degranulation is important in patients with symptomatic mastocytosis. 

Special care should be taken with patients with diffuse cutaneous or systemic mastocytosis, especially if they have elevated serum tryptase, prior to receiving anaesthetic or having imaging that requires radio-contrast. 

Potential triggering agents for anaphylaxis in mastocytosis

Physical agents:

• Heat and cold
• Sunlight
• Sudden changes in temperature
• Rubbing of/pressure on skin lesions. 

Emotional factors:

• Stress/anxiety
• Sleep deprivation.

Drugs:

• Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs)
• Morphine, codeine, and derivatives (opioids)
• Muscle relaxants used in general anaesthesia
• Cough medications
• Alcohol
• Local anaesthetics — (lignocaine, bupivacaine, and prilocaine appear safe)
• Beta-blockers
• Anticholinergic medications (eg, scopolamine)
• Vancomycin
• Amphotericin B
• Thiamine (Vitamin B1).

Venoms:

• Hymenoptera order insects (eg, sawflies, wasps, bees, and ants)
• Snakes.

Others:

• Infectious diseases causing fever
• Dental and endoscopic procedures
• Vaccines
• Surgery
• Contrast media (particularly those containing iodine).

An adrenaline (epinephrine) autoinjector (eg, EpiPen®) is recommended in patients with previous anaphylaxis, high tryptase, or significant cutaneous disease.

Specific measures

Specific treatments for patients with cutaneous mastocytosis may include:

• Non-sedating H1 antihistamines
• H2 antihistamines (eg, cimetidine, ranitidine) or proton pump inhibitors (eg, omeprazole, lansoprazole, or pantoprazole) for gastrointestinal symptoms such as diarrhoea and reflux
• Topical steroids
• Montelukast
• Phototherapy eg, narrowband UVB phototherapy or PUVA (photochemotherapy).

Systemic mastocytosis treatments include:

• Imatinib and other tyrosine inhibitors (midostaurin)
• Cytoreductive treatment in systemic mastocytosis can result in disappearance of skin lesions in these patients
• Rapidly progressive systemic mastocytosis, mast cell leukaemia, and mast cell sarcoma may be treated with chemotherapy and bone marrow stem cell transplantation. 

How do you prevent mastocytosis?

There is no known way to prevent mastocytosis. 

What is the outcome for mastocytosis?

Cutaneous mastocytosis is usually self-limiting and benign. If symptomatic, the main aims of management are symptom control and trigger avoidance to prevent anaphylaxis. 

In adults with systemic disease, treatment is more complex and prognosis varies. A multidisciplinary team of haematologists, dermatologists, immunologists, and specialist nurses are often involved, as well as the patient’s general practitioner or primary care physician.