The predominant presentation of this mast-cell disorder is development of pruritic lesions—especially after rubbing or exposure to heat.
A 2-year-old girl presented with a history of several brown macules located over her trunk and extremities. Her parents reported that the lesions had been present for two months and that some of them became “red and swollen.” The clinician gently stroked one of the lesions with a cotton-tipped applicator. A few minutes later, the appearance of an urticarial plaque over the lesion indicated a positive Darier’s sign. A diagnosis of urticaria pigmentosa, a form of cutaneous mastocytosis, was made.
The mastocytoses comprise a heterogeneous group of disorders that demonstrate mast-cell proliferation in the skin and/or other tissues. Mast cells arise from pluripotential CD34+ cells in the bone marrow and circulate in the peripheral blood as agranular monocytelike cells. The mast cell’s characteristic intracytoplasmic granules develop later and are the source of a host of mediators; some of these are preformed and others are formed upon stimulation of the mast cells. The preformed mediators includes histamine, heparin, chemotactic agents, tryptase, and chymase. The group of newly formed mediators include prostaglandin D2, leukotriene C4, tumor necrosis factor-α, interleukin (IL)-4, IL-5, IL-6, IL-7, and platelet-activating factor. The release of these mediators induces the local and systemic effects associated with mast cells and mastocytosis.
An uncommon disorder, mastocytosis is seen more frequently in Caucasians than in others and affects adults in a male-to-female ratio of 1.5:1; in the pediatric age group, the sex distribution is equal. Fifteen percent of cases occur in newborns, while 65%-75% of patients with mastocytosis develop it by the age of 15 years. In the remainder of the affected population, the age of onset is usually between 20 and 40 years.
Classification of mastocytosis
Mastocytosis can be classified according to the extent of involvement of the skin and internal organs. The following groups have been recognized: disease restricted to the skin, mastocytosis associated with myeloproliferative or myelodysplastic disorders, aggressive disease, mast-cell leukemia, mast-cell sarcoma, and extracutaneous mastocytomas.
The majority of infants and adolescents develop mastocytosis involving only the skin. The various forms of cutaneous mastocytosis include urticaria pigmentosa, plaque-type mastocytosis, nodular mastocytosis/mastocytoma, diffuse mastocytosis, and telangiectatic mastocytosis. In the pediatric population, the usual presentation is mastocytoma or urticaria pigmentosa and, rarely, diffuse cutaneous mastocytosis. In adults, the lesions are usually urticaria pigmentosa or telangiectatic mastocytosis. Systemic involvement occurs more frequently in adults, while bullous and nodular lesions are more common in children.
The predominant presentation of mastocytosis is a pruritic lesion or lesions, especially after rubbing or exposure to heat. In some cases, flushing, headache, or fatigue can occur. The range of symptoms is related to the extent of the disease, mediators released, and organs involved. GI symptoms, tachycardia, hypotension, bone pain, and organomegaly may be presenting symptoms.
Of the cutaneous lesions, mastocytomas and urticaria pigmentosa have similar morphologic features. The lesions can vary in color, exhibiting different shades of pink, red, tan, and brown. They exhibit the characteristic Darier’s sign, whereby rubbing causes erythema and swelling of the lesion and localized pruritus. Occasionally, bullous lesions may be present.
Mastocytomas are nodules or plaques that usually appear singly, although multiple lesions may be observed. Accounting for 10%-15% of cutaneous lesions, mastocytomas can occur at any site but most often involve the distal extremities. Mastocytomas involute spontaneously.
The lesions of urticaria pigmentosa are multiple macules, papules, or plaques, mostly on the trunk. They account for 70%-90% of mastocytosis in children. The majority of urticaria pigmentosa lesions resolve by adolescence.
In diffuse mastocytosis, a rare form of the disorder, the entirety of the skin becomes thickened and edematous with accentuation of the skin folds. Within the thickened skin are tiny, yellowish papules that impart their color to the skin. Telangiectatic mastocytosis is also rare and is seen mainly in adults as ill-defined, telangiectatic macules, 2-6 mm in diameter, on a tan-to-brown background. These occur mainly on the trunk and usually do not urticate when rubbed.
Diagnosis is generally based on the clinical presentation and histologic findings of increased numbers of mast cells. Cytochemical stains (chloroacetate esterase, toluidine blue, and aminocaproate esterase) and immunohistochemical stains (tryptase and CD117) are helpful in distinguishing mast cells from other cells with cytoplasmic granules.
There is no definitive treatment or cure for mastocytosis. Therapy for cutaneous mastocytosis is mainly symptomatic, the goal being to reduce the symptoms that result from mast-cell release of the various mediators (Table 1). One of the most important steps is avoidance of factors that initiate mediator release, such as friction, temperature change, physical exertion, emotional stress, general anesthetics, alcohol intake, and use of nonsteroidal anti-inflammatory medications and narcotic analgesics. Other drugs that may trigger the release of mediators include polymyxin B, dextran, and radiologic contrast media.
The mainstay of symptomatic treatment is antihistamines, H1 with or without H2, to reduce pruritus, flushing, and wheal formation. In general, nonsedating antihistamines may be tried first. Of the sedating antihistamines, hydroxyzine (10-25 mg) is given in one to four daily doses, depending on the severity of symptoms. Cyproheptadine has also been used effectively. Doxepin has the added advantages of being an H2-antagonist, more active than H1-antagonists, and is soporific. Ketotifen is a membrane stabilizer and H1-receptor antagonist; it does not seem to have advantages over hydroxyzine, however.
Of the H2-antagonists, cimetidine, either alone or with an H1-antagonist, is indicated. H2-antihistamines and/or disodium cromoglycate (400-800 mg/day) are useful for abdominal pain and GI symptoms. Disodium cromoglycate, a membrane stabilizer, is also useful for relieving headache and musculoskeletal pain. Flushing may be alleviated by the use of antihistamines and careful use of aspirin, which is an inhibitor of prostaglandin D2 synthesis. Aspirin should not be used by patients who are sensitive to it.
Other modalities of treatment include corticosteroids, phototherapy, interferon-α, and cyclosporine. Potent corticosteroids used topically with occlusion may help in controlling pruritus and decreasing the number of mast cells. One should caution against such use of corticosteroids for urticaria pigmentosa, however, because of the resultant local atrophy and possible systemic effects, especially as the numbers of mast cells tend to increase after treatment. Lasers, including the neodymium:yttrium-aluminum-garnet and the 585-nm flashlamp-pumped pulsed dye lasers, have produced temporary improvement in the appearance of urticaria pigmentosa and telangiectatic mastocytosis, respectively, although the lasers do not destroy mast cells. Systemic steroids are of help in aggressive mastocytosis and for patients with malabsorption.
Neither chemotherapy nor splenectomy is effective in cutaneous mastocytosis. An isolated mastocytoma that has not involuted spontaneously may be treated with surgical excision. Phototherapy utilizing UVA plus psoralen (PUVA) or UVA1 has been shown to be effective in reducing mast cells and some symptoms. In adults with mastocytosis, however, lesions can recur after cessation of phototherapy. Oral PUVA may be superior to, or as effective as, UVA1, although bath PUVA appears to be ineffective.
Patients with mastocytosis are especially sensitive to insect venoms. There are reported cases of death due to anaphylactic shock following yellow-jacket stings. Those with a history of anaphylactoid reactions to Hymenoptera stings may benefit from venom immunotherapy. Even so, susceptible patients should continue to exercise caution, as anaphylaxis can occur despite immunotherapy. Patients with mastocytosis and parents of children with mastocytosis, especially those with bullous lesions, should be educated as to the disease and the hazards of mediator release that can lead to anaphylaxis.
Individuals at risk of developing anaphylaxis must carry emergency medicines (such as epinephrine, corticosteroids, and antihistamines), and they should be educated on administering these in the event of an emergency. Extensive bullous disease in children may require management in burn units, with the added concern for possible bleeding in the skin and GI tract. Prophylactic H1– and H2-antihistamine treatment is also worth considering.
On the horizon
Although some mastocytosis has been linked to a mutation in the c-kit gene, recent work has shown that the available c-kit inhibitors are ineffective. Future study, however, may identify other c-kit inhibitors that can be helpful in these patients.
There are conflicting reports with regard to the effectiveness of interferon-α. Cyclosporine used in combination with methylprednisolone has been successful in the treatment of aggressive mastocytosis.
Leukotrienes are known mediators in the pathogenesis of several allergic disorders and inflammatory skin reactions. Antileukotriene drugs have been newly introduced as therapeutic agents to counteract the cysteinyl leukotrienes that are produced by mast cells and contribute to the manifestations of mastocytosis.