Mastocytosis

What is mastocytosis?

Mastocytosis is the term for a diverse group of conditions where a single (or clonal) population of mast cells accumulate in one or more tissues, for example, skin, bone marrow, liver, spleen, gastrointestinal tract and lymph nodes.

The severity of symptoms depends on the number of mast cells in the tissues. A high load of mast cells leads to more severe symptoms. Cutaneous mastocytosis causes itching, swelling and blistering of the affected skin, particularly when it is rubbed or scratched.

What is the cause of mastocytosis?

Most forms of mastocytosis are caused by a mutation of the KIT gene on the 4q12 chromosome – a mutation that increases cellular reproduction. The c-KIT gene mutation creates an overgrowth of one cell line of mast cells. This clonal expansion of mast cells leads to areas of abnormal skin that easily reddens, swells and itches. The c-KIT mutation can also lead to the proliferation of mast cells within the bone marrow, resulting in systemic mastocytosis.

In some cases, the genetic disorder is inherited, but in most cases, it is spontaneous, and there is no family history of mastocytosis.

What are mast cells?

Mast cells are healthy cells in the body, usually found in the skin and other tissues. Mast cells have a role in the early steps of the body’s coordination of healing responses to an injury. Granules within the mast cells contain histamine and other chemicals.

• histamine
• leukotriene C4
• prostaglandin D2
• carboxypeptidase
• heparin
• cathepsin G-like protease
• tryptase
• tumour necrosis factor-A
• chymase
• interleukin-8
• others 

When a mast cell is activated, these chemicals are released into the surrounding skin. Mast cell chemicals are mediators of inflammation, and cause the blood vessels to leak, resulting in localised itching, swelling, redness and sometimes blistering. This reaction is normal in insect bites and is thought to be a protective mechanism. For example, a mosquito injects saliva when it bites. The saliva triggers mast cell activation to a varying degree, depending on the individual's hypersensitivity to the saliva. The unpleasant itch soon persuades the person to try to avoid getting bitten again.

Rubbing an area of skin affected by mastocytosis may also activate the mast cells. The rubbed skin becomes reddened, swollen and itchy within a few minutes (Darier sign). In young children, the rubbed area may later blister.

Urticaria pigmentosa

Urticaria pigmentosa: Darier sign

Maculopapular mastocytosis Urticaria pigmentosa

How is mastocytosis diagnosed?

Cutaneous mastocytosis is usually diagnosed by its clinical appearance and positive Darier sign. However, a skin biopsy may be helpful for confirmation (see maculopapular cutaneous mastocytosis pathology).

Mast cells may be difficult to see on standard histology with haematoxylin and eosin staining (H&E). They can be identified with special stains, such as Giemsa, toluidine blue, Astra blue or immuno-histochemical stains like tryptase and CD117 (this stains for c-KIT membrane receptor on the surface of mast cells).

A blood test showing high levels of tryptase suggests systemic involvement.

What are the different types of mastocytosis?

Mastocytosis can be broadly characterised into two groups:

• Localised mastocytosis (localised to a single tissue)
• Systemic mastocytosis (involving one or more tissues)

The World Health Organisation (WHO) classifies mastocytosis (2016) as:

• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with associated haematological disease
• Aggressive systemic mastocytosis
• Smouldering systemic mastocytosis
• Mast cell leukaemia
• Mast cell sarcoma
• Extracutaneous mastocytoma.

Cutaneous mastocytosis

A positive Darier sign characterises all forms of cutaneous mastocytosis.

Approximately two-thirds of cases of cutaneous mastocytosis occur in children.

Cutaneous mastocytosis is classified as follows:

• Solitary mastocytoma
• Maculopapular cutaneous mastocytosis
• Diffuse cutaneous mastocytosis
• Telangiectatic cutaneous mastocytosis (telangiectasia macularis eruptiva perstans)
• Plaque-type mastocytoma
• Solitary and multiple nodular mastocytomas

Solitary mastocytoma and maculopapular mastocytoma are the most common forms of mastocytosis in children.

Solitary mastocytoma

A solitary mastocytoma present in infancy as an itchy area of a reddish or yellowish-brown thickened patch of skin. Mastocytomas generally entirely or mostly resolve in time.

Mastocytoma

Mastocytoma: Darier sign

Mastocytoma after rubbing: Darier sign

Mastocytoma after rubbing: Darier sign

Maculopapular cutaneous mastocytosis

Maculopapular cutaneous mastocytosis was previously called urticaria pigmentosa. It is the most common form of mastocytosis in adults and children.

Maculopapular mastocytosis in adults is unlikely to resolve with time. It is associated with systemic involvement, where the mastocytosis spreads to more than one tissue (see below). 

Maculopapular mastocytosis Urticaria pigmentosa

Maculopapular mastocytosis Urticaria pigmentosa

Maculopapular mastocytosis Urticaria pigmentosa

Diffuse cutaneous mastocytosis

Diffuse cutaneous mastocytosis presenting in infancy usually presents as diffuse redness of the skin (erythroderma), sometimes with widespread blistering of the skin. Adults and adolescents with diffuse cutaneous mastocytosis often have a generalised thickening leathery appearance and texture to most or all of their skin, with a positive Darier sign.

Diffuse cutaneous mastocytosis

Diffuse cutaneous mastocytosis

Diffuse cutaneous mastocytosis

Telangiectatic cutaneous mastocytosis

Telangiectatic cutaneous mastocytosis is also known as telangiectasia macularis eruptiva perstans (TMEP). Telangiectatic cutaneous mastocytosis is very persistent and may sometimes lead to systemic involvement. The name relates to extensive telangiectases.

Telangiectatic cutaneous mastocytosis

Telangiectatic cutaneous mastocytosis

Dermatoscopy view

Systemic mastocytosis

This includes:

• Indolent systemic mastocytosis
• Systemic mastocytosis with associated clonal haematological non-mast cell lineage disease (SM-AHNMD)
• Smouldering systemic mastocytosis
• Aggressive systemic mastocytosis

Systemic mastocytosis is diagnosed by the presence of a certain number of features: 1 major criterion and 1 or more minor criteria or the presence of 3 minor criteria. Diagnosis requires tissue biopsy and the use of special stains.

Major criteria

• Multiple areas of dense infiltrate of mast cells in the bone marrow or other extracutaneous organs, confirmed by special stains on histology, such as mast cell tryptase (> 15 mast cell aggregating)

Minor criteria

• In mast cell infiltrates in the bone marrow or other extracutaneous organs, >25% of mast cells are spindle-shaped or otherwise atypical OR in bone marrow smears > 25% of mast cells are spindle-shaped or otherwise atypical
• Activating point mutation of the stem cell factor, c-KIT in codon 816 is present in extracutaneous organs
• Mast cells in extracutaneous organs found using CD117 co-express either CD2 or CD25, or both, as determined by flow cytometry
• Serum tryptase is persistently > 20ng/ml (this is not relevant in patients that have SM-AHNMD)

Systemic mastocytosis occurs more commonly in adults than children (it is extremely rare in children).

Indolent systemic mastocytosis

Indolent systemic mastocytosis is the most common and least serious presentation of systemic mastocytosis in adults – it is characterised by a low mast cell burden (<30%), the presence of mediator-related symptoms such as flushing and diarrhoea, and skin involvement (usually maculopapular cutaneous mastocytosis, see above).

Rarer subsets of indolent systemic mastocytosis

• Isolated bone marrow mastocytosis
• Well-differentiated systemic mastocytosis (round cells; compact, multifocal mast cell infiltrates without expression of CD25; KIT mutation outside of codon 816)
• Smouldering systemic mastocytosis (borderline or benign hypercellular marrow; dysplasia; marrow mast-cell infiltrates >30%; serum tryptase >200 ng/ml; and enlarged spleen, liver, lymph nodes without organ impairment

Systemic mastocytosis with associated clonal haematological non-mast cell lineage disease

SM-AHNMD accounts for one-third of all systemic mastocytosis cases. It is associated with concurrent myeloproliferative neoplasms (in which there is increased bone marrow production of blood cells) and myelodysplasia (in which the bone marrow produces too few blood cells).

Aggressive systemic mastocytosis

Aggressive systemic mastocytosis is due to uncontrolled neoplastic cell proliferation and leads to impaired organ function. It results in flushing, itching, low blood pressure, anaphylaxis, diarrhoea and bleeding from the gastrointestinal tract. These patients may have high serum tryptase levels.

Complications may include:

• Marked cytopaenia
• Osteolysis or osteoporosis leading to bone fractures
• Malabsorption
• Weight loss
• Enlarged overactive spleen (which can destroy circulating blood cells)
• Enlarged liver with impaired liver function
• Ascites 
• Portal hypertension.

Other forms of mast cell proliferation

Mast cell leukaemia

Mast cell leukaemia is a rare disease of circulating malignant mast cells with a very poor prognosis.

Mast cell sarcoma

Mast cell sarcoma is a solid tumour of malignant mast cells.

Extracutaneous mastocytoma

Extracutaneous mastocytoma is a benign mast cell tumour where a localised area of mast cell proliferation is not in the skin.

How is mastocytosis investigated?

Patients with solitary mastocytoma generally require no work up. However, a full history should be taken, and skin, lymph nodes, liver and spleen should be examined to check for diffuse or systemic mastocytosis.

In these cases the following investigations may be undertaken:

• Skin biopsy
• Full blood count
• Serum biochemistry
• Liver function tests
• Serum tryptase level: tryptase is a mast cell enzyme. Systemic mastocytosis is unlikely with a tryptase level < 20 ug/L.
• Abdominal ultrasound
• Bone density scan
• Bone marrow trephine
• Blood and marrow smears
• Flow cytometry (to measure CD2 and CD25)
• Genetic examination (looking for c-KIT mutation D816V in bone marrow mast cells)

How is mastocytosis treated?

Most localised forms of cutaneous mastocytosis without symptoms require no treatment.

General measures

Treatment for symptomatic patients with mastocytosis includes general measures to avoid triggers for histamine release. Special care should be taken with patients with systemic mastocytosis or diffuse cutaneous mastocytosis, especially if they have elevated serum tryptase, when under anaesthetic or having imaging requiring radio-contrast.

Triggering agents in mastocytosis are physical agents, emotional factors, drugs, venoms, infections, and others.

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 (narcotics)
• Cough medications
• Alcohol
• Local anaesthetics
• Beta-blockers
• Anticholinergic medications (eg scopolamine)
• Vancomycin
• Amphotericin B
• Thiamine (Vitamin B1)

Venoms

• Hymenoptera
• Snakes

Infectious diseases with fever

• Viral and bacterial

Others

• Dental and endoscopic procedures
• Vaccines
• Surgery
• Contrast media (particularly those containing iodine)

Specific treatments

Non-sedating antihistamines such as cetirizine may also be helpful for control/suppression of histamine-related symptoms in mastocytosis. H2 blockers (cimetidine and ranitidine are some examples), leukotriene antagonists, sodium cromoglycate, and omalizumab (off label) are sometimes useful.

Phototherapy (usually narrowband UVB or PUVA) has been used for localised cutaneous mastocytosis in some cases.

Patients with gastrointestinal symptoms from systemic mastocytosis may be treated with H2 histamine antagonists, proton pump inhibitors (eg, omeprazole, lansoprazole, pantoprazole), or oral sodium cromoglycate.

Subcutaneous adrenaline/epinephrine (eg, EpiPen®) may be used for anaphylactic reactions.

Oral steroids may be used in some cases of systemic mastocytosis. They act as mast cell stabilisers.

Osteoporosis should be treated in patients with this complication of mastocytosis.

In severe cases of systemic mastocytosis or aggressive forms of mastocytosis, the following treatments alone or in combination have been used:

• Miltefosine has been used to inhibit mediator release and mast cell-driven inflammation
• KIT inhibitors midostaurin and dasatinib have been shown to inhibit D816V (one of the specific KIT mutations found in mastocytosis) and mediate KIT activation. Imatinib, masitinib, and bafetinib are unable to block D816V and are ineffective in mastocytosis
• Targeted antibodies against mast cells and mast-cell tryptase (under development)
• Interferon alpha
• Chemotherapy such as cladribine, cytarabine, fludarabine, and hydroxyurea
• Rapidly progressing aggressive systemic mastocytosis, mast cell leukaemia and mast cell sarcoma may be treated with polychemotherapy and bone marrow stem cell transplantation.