(See also Overview of Allergic and Atopic Disorders.)
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, nonsteroidal anti-inflammatory drugs (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
Cutaneous mastocytosis 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. Nodular lesions and plaques can also develop. 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.
Cutaneous forms rarely progress to systemic disease in children but may do so in adults.
Lesions consist of reddish brown, irregular plaques that urticate when rubbed (Darier sign).
The infant shown here has profuse papulonodular and plaque lesions of urticaria pigmentosa.
This photo shows reddish brown macules on the back of a school-aged child.
Systemic mastocytosis can cause yellowish tan to reddish brown macules and papules, which, when stroked, may produce a linear hive.
Urticaria pigmentosa may manifest as reddish plaque-like lesions on the skin.
Systemic mastocytosis
Systemic mastocytosis 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 gastrointestinal (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 in mastocytosis—whether a single mastocytoma or more diffuse disease. The following may worsen itching:
Stroking or rubbing skin lesions causes urticaria and erythema around the lesion (Darier 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
Diagnosis of mastocytosis 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); these tests include the following:
-
Serum gastrin level to rule out Zollinger-Ellison syndrome in patients with ulcer symptoms
-
Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) to rule out carcinoid syndrome in patients with flushing
-
Measurement of plasma free metanephrines or urinary metanephrines to help rule out pheochromocytoma
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
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 or twice a day.
Mastocytoma usually involutes spontaneously and requires no treatment.
Systemic mastocytosis
All patients should be treated with H1 and H2 blockers and should carry a prefilled, self-injecting epinephrine syringe.
Aspirin controls flushing but may enhance leukotriene production, thereby contributing to other mast cell–related symptoms; it should not be given to children because Reye syndrome is a risk.
Cromolyn 200 mg orally 4 times a day (100 mg 4 times a day for children 2 to 12 years; not to exceed 40 mg/kg/day) may help by preventing mast cell degranulation. Ketotifen 2 to 4 mg orally twice a day is inconsistently effective. No treatment can reduce the number of tissue mast cells.
In patients with an aggressive form, interferon alfa-2b 4 million units subcutaneously once a week to a maximum of 3 million units a day induces regression of bone lesions. Corticosteroids (eg, prednisone 40 to 60 mg orally once a day for 2 to 3 weeks) may be required. Some limited evidence suggests that splenectomy may improve survival in patients with aggressive disease.
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 when treating adults with aggressive systemic mastocytosis but is ineffective in patients with the D816V c-kit mutation. Midostaurin (a 2nd-generation tyrosine kinase receptor inhibitor) can be used to treat adults with aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic disorders, or mast cell leukemia.
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, self-injecting epinephrine syringe.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
mercaptopurine |
PURINETHOL |
Midostaurin |
Midostaurin |
epinephrine |
ADRENALIN |
prednisone |
RAYOS |
etoposide |
ETOPOPHOS |
Ketotifen |
ALAWAY, ZADITOR |
cromolyn |
CROLOM |
Imatinib |
GLEEVEC |
heparin |
PANHEPRIN |
Aspirin |
No US brand name |
