Mastocytosis refers to a spectrum of entities characterized by increased numbers of mast cells that may involve any organ system (1). The skin is most commonly involved, followed by the bones and the gastrointestinal tract (1, 2). Clinical signs and symptoms are due to mast cell release of preformed mediators (histamine, heparin, and proteases), newly synthesized lipid mediators (prostaglandins [PGD2] and leukotrienes [LTC4, LTD4, and LTE4]), and platelet-activating factor. After mast cell activation, growth factors and inflammatory cytokines are generated. Men and women are affected equally; however, the disease is most common in whites (3). Over 55% of cases occur in patients <2 years of age, and another 10% of cases appear in patients between the ages of 2 and 15 (3).
Cutaneous spectrum of mastocytosis
The 4 types of cutaneous mastocytosis are urticaria pigmentosa, mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans.
Of these, urticaria pigmentosa (Figure 1) is the most common. Characteristically, multiple red-brown macules or papules are scattered over the trunk and extremities in a symmetrical fashion (1). Usually, this condition spares the mouth and other mucous membranes. Especially in younger patients, these lesions may display a wheal and flare reaction after mild trauma or stroking (Darier's sign, demonstrated in Figure 2). Clinically, pruritus and dermatographism are often present. After age 10, the lesions become more numerous and less reactive (4). Patients can have hundreds of lesions, and they may become confluent. Systemic involvement is possible and most commonly involves the bones (osteoporosis or osteosclerosis), liver (hepatomegaly), spleen (splenomegaly), and gastrointestinal tract (rugal thickening, malabsorption, or steatorrhea) (1).
A mastocytoma is a 2- to 5-cm brown or tan raised plaque, occasionally yellowish or pink, found almost exclusively in children (Figure 3). Usually the lesions appear at birth or within the first few weeks of life (3). Solitary lesions are most common, but 3 or 4 lesions may be present—usually on the trunk, neck, and arm (especially near the wrist). Lesions may be annular or linear with a smooth or “peau d'orange” surface and a rubbery consistency on palpation. Darier's sign is often present in these lesions, and bullae may develop. Associated systemic symptoms include flushing (facial or generalized) and colic (3).
Diffuse cutaneous mastocytosis (4) usually presents in patients <3 years of age as a generalized orange-yellow-brown discoloration of the skin, often described as a thickening of the skin, or a “peau d'orange” appearance. In neonates, this variant may present as bullous lesions with no macular, papular, or nodular pigmented lesions present. Bullous lesions in the neonatal period may be associated with systemic mastocytosis and a poorer prognosis. Patients with bullae of later onset have a better prognosis.
Telangiectasia macularis eruptiva perstans, the rarest form of cutaneous mastocytosis, usually presents as multiple telangiectatic, reddish brown macules on the trunk in adults (1).
Rare noncutaneous entities include diffuse mastocytosis, which is characterized by infiltration of the liver, spleen, gastrointestinal tract, and skeleton. This disease is more commonly seen in children and is associated with a poorer prognosis. In addition, a malignant mast cell leukemia exists, which is uniformly fatal.
Systemic symptoms of mastocytosis
Most patients are asymptomatic; however, patients with systemic mastocytosis frequently have skin lesions, bone lesions, hepatosplenomegaly, pruritus, headaches (mild frontal or occipital), flushing, tachycardia, syncope, hypotension, and gastrointestinal complaints (anorexia, nausea, hypermotility, vomiting, diarrhea, peptic ulcers, malabsorption, and steatorrhea).
Flushing, which occurs mainly in infants and children on the face, neck, and upper chest, usually resolves within 20 to 30 minutes. These episodes are characterized by increased urinary histamine excretion. Chronic flushing is occasionally seen in adults.
Hemorrhage and bleeding diathesis are usually related to circulating heparin-like anticoagulants and abnormalities of splenic or hepatic function. Mast cell leukemia is often associated with ecchymoses and bleeding episodes.
Acute attacks last 1 to 2 hours and manifest as fullness in the face and head associated with bright red flushing of the face with or without conjunctival injection and a pounding headache (frontal first). Other associations include tachycardia, nausea/ vomiting, syncope, and hypotension.
The diagnosis of mastocytosis can usually be made based on history and physical examination. A skin biopsy is the most common confirmatory test because mast cells can easily be identified with special stains (Giemsa, toluidine blue, or methylene blue). Extensive cutaneous involvement should prompt a baseline radiologic survey and bone scan to identify asymptomatic bony lesions early (2
). If systemic disease is suspected, urinary histamine and N
-methyl histamine (including 1,4-methylimidazoleacetic acid) should be measured (5
). Urinary levels of histamine are more reliable indicators than blood levels, which fluctuate rapidly. In addition, urinary excretion of histamine is not altered by medications.
Hyperpigmented macules of urticaria pigmentosa can easily be confused with nevi or ephelides. Papular and nodular lesions may mimic xanthomas, nevoxanthoendotheliomas, or drug eruptions. Bullous lesions may be indistinguishable from bullous insect bites, bullous urticaria, and bullous erythema multiforme. Recurrent acute attacks of mastocytosis with prominent flushing must be differentiated from carcinoid syndrome (associated with an elevated urinary 5-hydroxyindoleacetic acid level) and vasoactive peptide-secreting endocrine tumors (i.e., islet cell tumors and medullary carcinoma of the thyroid) (6
Patients should be advised to avoid factors that precipitate mast cell degranulation. Common precipitating factors include physical stimuli (heat, cold, and friction), biologic peptides (jellyfish, lobster, and crayfish), venoms, food (cheese, alcohol, and spicy foods), drugs (aspirin, codeine, morphine, atropine, and amphotericin B), and iodine-containing contrast media (1
). Patients with mastocytosis and a history of anaphylaxis should wear medical alert bracelets. Additionally, they should carry adrenaline-filled syringes and be prepared to self-medicate (7
Treatment and prognosis
There is no cure for mastocytosis—treatment is largely symptomatic. Antihistamines have remained the medications of choice for symptomatic relief in all forms of mastocytosis (7
). Antihistamines primarily directed against H1
receptors (diphenhydramine, hydroxyzine, cetirizine, fexofenadine, and loratadine) help with dermatographism, pruritus, and flushing (1
). For gastrointestinal symptoms, antihistamines directed against H2
receptors (cimetidine and ranitidine) are beneficial (2
). One drug, doxepin, blocks both H1
receptors and is particularly effective if taken at night because it is sedating. Newer agents like cromolyn sodium, which inhibits degranulation and amine release by tissue mast cells, help with chronic gastrointestinal symptoms, headaches, and bone pain (7
). Systemic steroids are reserved for severe cases of mastocytosis (7
). Aspirin and nonsteroidal antiinflammatory drugs, known mast cell degranulators, may be used cautiously in patients who are unresponsive to antihistamines or cromolyn (2
In addition to antihistamines, isolated mastocytomas are usually treated conservatively with steroids under occlusion (3). The majority of these lesions regress during childhood. If these lesions are associated with recurrent episodes of flushing or colic, they may be excised (4). Urticaria pigmentosa is commonly treated with systemic antihistamines, topical or intralesional steroids, or photochemotherapy with psoralen plus ultraviolet A (4, 7, 9, 10). In approximately 50% of child-onset cases, urticaria pigmentosa regresses by puberty. On the other hand, adult-onset cases are usually chronic and persistent, and 20% are associated with systemic disease (3).
Patients with systemic mastocytosis have a poor prognosis, especially if the disease is associated with a hematologic malignancy. In these patients, antihistamines, corticosteroids, antimitotics, and irradiation are seldom effective, and death usually results from bleeding caused by severe thrombocytopenia.