3.2.8 Cutaneous Mastocytosis

This disease is caused by an accumulation of mast cells in the skin. It is frequently caused by mutations in the KIT gene (KIT D816V) and is most often sporadic. MRGPRX2 activates mast cells which in turn release tryptase and histamine with local or systemic symptoms. Patients with severe MC mediator-related symptoms are usually diagnosed with MC activation syndrome (MCAS).

The most common form of skin mastocytosis is urticaria pigmentosa (maculopapular mastocytosis) presenting as numerous isolated red-brown, maculopapular lesions. Flushes and pruritus are common.

Diffuse cutaneous mastocytosis is rare and can manifest as diffuse erythema, skin infiltration, blistering, generally occurring in the first month of life.

Localized mastocytosis (mastocytoma) is a single lesion (or sometimes 1-3 lesions), most often found in children.

Telangiectatic mastocytosis is an extremely rare form of cutaneous mastocytosis.

Mastocytosis skin lesions respond with an urticarial reaction spontaneously or after irritation (Darier’s sign: wheal, erythema, itch).

Furthermore, a so-called idiopathic mast cell activation syndrome (MCAS) was recently introduced as an entity within the mast cell disorders. Patients experience repeated episodes of symptoms mimicking anaphylaxis – allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing and severe diarrhea may occur.

Cutaneous mastocytosis (urticaria pigmentosa and diffuse cutaneous mastocytosis) shows a disseminated appearance on the entire body. Mastocytoma is a unique lesion, or multiple (generally 1 to 3) lesions localized anywhere on the skin. MCAS is a mast cell products release disorder without specific localization without diffuse increase of mast cells as in the diffuse type and can be accompanied by angioedema.

The 2022 updated WHO classification of mastocytosis identifies 4 forms of cutaneous mastocytosis:

• Maculopapular cutaneous mastocytosis.

• Urticaria pigmentosa: Monomorphic variant, Polymorphic variant.

• Diffuse cutaneous mastocytosis.

• Cutaneous mastocytoma: Isolated mastocytoma, Multilocalized mastocytomas.

Serum tryptase levels are correlated with the mast cell tumor burden. A complete blood count is useful to screen for hematologic (medullary) involvement followed by bone marrow aspiration. Increases in serum mast cell tryptase and in urine levels of N-methylhistamine, 11B -Prostaglandin F2α (11B-PGF2α) and/or Leukotriene E4 (LTE4) are the only useful tests in diagnosis of MCAS.

The histological image is characterized by dense perivascular infiltrates of mast cells which stain positively with Giemsa or toluidine blue (heterochromasia). Immunohistochemistry (anti-CD117=KIT, anti-tryptase, and anti-CD25 antibodies) can help identify mast cells in skin. The KIT mutation (mostly D816V) can be identified in skin by molecular biology.

Complications are not common. In adults, flushes, diarrhoea, vomiting, headache, depression, breathing problems can occur. Osteoporosis can be detected by osteodensitometry. Visceral involvement should be investigated at diagnosis (abdominal ultrasonography, complete blood count). Anaphylaxis is a rare but severe complication. Worsening of symptoms may be provoked by alcohol and certain foods (histamine provocation) or drugs.

Diagnosis is made based on typical clinical features: hyperpigmented macules and papules with positive Darier’s sign, and confirmed by histopathology. At baseline, no additional workup is required in children. Serum tryptase levels, complete blood count, abdominal ultrasonography and osteodensitometry are performed at baseline in adults. In diffuse type of mastocytosis and KIT anomaly a bone marrow aspiration is indicated.

No therapy is needed for this disease if the symptoms are mild. Treatment possibilities include non- sedating antihistamines; H2 blockers or cromoglycate for gastrointestinal symptoms; PUVA; short- term high-potency topical glucocorticoids. Patients (especially with elevated tryptase levels) should be informed about the risk of anaphylaxis, and given written information about the avoidance of triggers (e.g., certain medications, anesthetics, may trigger histamine release). Patients with a high risk of anaphylaxis (or history of anaphylaxis) should be prescribed an adrenaline syringe and be informed about how to use it in case of anaphylaxis.