Mastocytosis is mast cell infiltration of skin or other tissues and organs. Symptoms result mainly from mediator release and include pruritus, flushing, and dyspepsia due to gastric hypersecretion. Diagnosis is by skin or bone marrow biopsy or both. Treatment is with antihistamines and control of any underlying disorder.

Mastocytosis is a group of disorders characterized by proliferation of mast cells and infiltration of the skin, other organs, or both. Pathology results mainly from release of mast cell mediators, including histamine, heparin, leukotrienes, and various inflammatory cytokines. Histamine causes many symptoms, including gastric symptoms, but other mediators also contribute. Significant organ infiltration may cause organ dysfunction. Mediator release may be triggered by physical touch, exercise, alcohol, NSAIDs, opioids, insect stings, or foods.

Etiology in many patients involves an activating mutation (D816V) in the gene coding for the stem cell factor receptor c-kit, which is present on mast cells. The result is autophosphorylation of the receptor, which causes uncontrolled mast cell proliferation.

Classification

Mastocytosis may be cutaneous or systemic.

Cutaneous mastocytosis

This type typically occurs in children. Most patients present with urticaria pigmentosa, a local or diffusely distributed salmon or brown maculopapular rash caused by multiple small mast cell collections. Less common are diffuse cutaneous mastocytosis, which is skin infiltration without discrete lesions, and mastocytoma, which is a large (1 to 5 cm) solitary collection of mast cells.

Urticaria Pigmentosa

Systemic mastocytosis

This type most commonly occurs in adults and is characterized by multifocal bone marrow lesions; it often involves other organs, most commonly skin, lymph nodes, liver, spleen, or GI tract. Systemic mastocytosis is classified as

• Indolent mastocytosis, with no organ dysfunction and a good prognosis
• Mastocytosis associated with other hematologic disorders (eg, myeloproliferative disorders, myelodysplasia, lymphoma)
• Aggressive mastocytosis, characterized by impaired organ function
• Mast cell leukemia, with > 20% mast cells in bone marrow, no skin lesions, multiorgan failure, and a poor prognosis

Symptoms and Signs

Skin involvement is often pruritic. Changes in temperature, contact with clothing or other materials, or use of some drugs (including NSAIDs) may worsen itching, as may consuming hot beverages, spicy foods, or alcohol or exercising. Stroking or rubbing skin lesions causes urticaria and erythema around the lesion (Darier's sign); this reaction differs from dermatographism, which involves normal skin.

Systemic symptoms can occur with any form. The most common is flushing; the most dramatic are anaphylactoid and anaphylactic reactions with syncope and shock. Other symptoms include epigastric pain due to peptic ulcer disease, nausea, vomiting, chronic diarrhea, arthralgias, bone pain, and neuropsychiatric changes (eg, irritability, depression, mood lability). Hepatic and splenic infiltration may cause portal hypertension with resultant ascites.

Diagnosis

• Clinical evaluation
• Skin lesion biopsy and sometimes bone marrow biopsy

Diagnosis is suggested by clinical presentation. Diagnosis is confirmed by biopsy of skin lesions and sometimes of bone marrow. Multifocal, dense infiltrates of mast cells are present.

Tests may be done to rule out disorders that cause similar symptoms (eg, anaphylaxis, pheochromocytoma, carcinoid syndrome, Zollinger-Ellison syndrome). Serum gastrin level is useful to rule out Zollinger-Ellison syndrome in patients with ulcer symptoms; urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) is measured to rule out carcinoid syndrome in patients with flushing. Measuring plasma-free metanephrines or urinary metanephrines can help rule out pheochromocytoma.

Pearls & Pitfalls Rule out disorders that cause symptoms similar to those of mastocytosis (eg, anaphylaxis, carcinoid syndrome, pheochromocytoma, Zollinger-Ellison syndrome).

If the diagnosis is uncertain, levels of mast cell mediators and their metabolites (eg, urinary N-methylhistamine, N-methylimidazole acetic acid) may be measured in plasma and urine; elevated levels support the diagnosis of mastocytosis. The level of tryptase (a marker of mast cell degranulation) is elevated in systemic mastocytosis but is typically normal in cutaneous mastocytosis. A bone scan, GI workup, and identification of the D816V c-kit mutation can also be helpful in cases where the diagnosis requires confirmation.

Treatment

• For cutaneous mastocytosis, H₁ blockers and possibly psoralen plus ultraviolet light or topical corticosteroids
• For systemic mastocytosis, H₁ and H₂ blockers and sometimes cromolyn
• For aggressive forms, interferon alfa-2b, corticosteroids, or splenectomy

Cutaneous mastocytosis

H₁ blockers are effective for symptoms. Children with cutaneous forms require no additional treatment because most cases resolve spontaneously. Adults with cutaneous forms may be treated with psoralen plus ultraviolet light or with topical corticosteroids once/day or bid. Mastocytoma usually involutes spontaneously and requires no treatment. Cutaneous forms rarely progress to systemic disease in children but may do so in adults.

Systemic mastocytosis

All patients should be treated with H₁ and H₂ blockers and should carry a prefilled epinephrine syringe. Aspirin controls flushing but may enhance leukotriene production, thereby contributing to mast cell–related symptoms; it should not be given to children because Reye's syndrome is a risk. Cromolyn 200 mg po qid (100 mg qid for children 2 to 12 yr; not to exceed 40 mg/kg/day) may help by preventing mast cell degranulation. No treatment can reduce the number of tissue mast cells. Ketotifen 2 to 4 mg po bid is inconsistently effective.

In patients with an aggressive form, interferon alfa-2b 4 million units sc once/wk to a maximum of 3 million units/day induces regression of bone lesions. Corticosteroids (eg, prednisone 40 to 60 mg po once/day for 2 to 3 wk) may be required. Splenectomy may improve survival.

Cytotoxic drugs (eg, daunomycin, etoposide, 6-mercaptopurine) may be indicated for treatment of mast cell leukemia, but efficacy is unproved. Imatinib (a tyrosine kinase receptor inhibitor) may be useful in some patients but is ineffective in patients with the D816V c-kit mutation. Midostaurin (a 2nd-generation tyrosine kinase receptor inhibitor) is under study in such patients.

Key Points

• Patients with cutaneous mastocytosis, usually children, typically present with a diffuse salmon or brown, often pruritic maculopapular rash.
• Systemic mastocytosis causes multifocal bone marrow lesions, usually in adults, but often affects other organs.
• All types can cause systemic symptoms (most commonly, flushing but sometimes anaphylactoid reactions).
• For cutaneous mastocytosis, use H₁ blockers to relieve symptoms, and in adults, consider treatment with psoralen plus ultraviolet light or topical corticosteroids.
• For systemic mastocytosis, use H₁ and H₂ blockers and sometimes cromolyn, and for aggressive mastocytosis, consider interferon alfa-2b, systemic corticosteroids, or splenectomy.
• Make sure all patients with mastocytosis carry a prefilled epinephrine syringe.

Last full review/revision July 2012 by Peter J. Delves, PhD