Cutaneous mastocytosis constitutes 90 percent of cases of mastocytosis that are not associated with a hematologic disorder.7 Urticaria pigmentosa is the most common variety, occurring in about two thirds of patients with cutaneous mastocytosis.8 It may be apparent at birth, it may appear during the first few months of infancy or it may have an onset at any age thereafter. About one third of patients first develop the characteristic lesions in adulthood.9,10
Physical Stimuli and Substances that Can Activate Mast Cells
- Emotional stress
- Physical stimuli (e.g., heat, cold, friction, exercise, sunlight, sexual intercourse)
- Bacterial toxins
- Venoms (bee sting)
- Biologic polypeptides (e.g., lobster, crayfish, jellyfish, ascaris)
- Polymeric eye drops (containing dextran)
- Immunologic stimuli (e.g., IgE)
- Complement-derived anaphylotoxins
- Acetylsalicylic acid (aspirin)
- Amphotericin B (Fungizone)
- Gallium (Ganite)
- Narcotics (e.g., morphine, meperidine [Demerol], codeine)
- Nonsteroidal anti-inflammatory drugs
- Polymyxin B (Aerosporin)
- Radiographic contrast containing iodine
- Scopolomine (Transderm Scop)
NOTE: Not all stimuli are active in individual patients.
Adapted with permission from Longley J, Duffy TP, Kohn S. The mast cell and mast cell disease. J Am Acad Dermatol 1995;32:545-61 [Published erratum in J Am Acad Dermatol 1995;33:52].
The tan to red-brown macules typical of urticaria pigmentosa initially emerge on the trunk and rapidly spread symmetrically and centripetally. The palms, soles, face and scalp are usually spared. The lesions may remain small and freckle-like or may evolve into papules, nodules or plaques. Mucous membranes may also be involved.2 Exposure to physical stimuli such as heat, cold or pressure is typically followed by the onset of localized urticaria (Darier's sign). Local or generalized pruritus is common after exposure to physical stimuli, as is dermatographism, localized erythema and generalized flushing. Vesicles, bullae (rarely with local hemorrhage) and superficial erosions occur only in patients under two years of age.8 Scarring is unusual unless superinfection occurs.
Abdominal pain, nausea, vomiting and diarrhea severe enough to cause malabsorption can occur in patients with a heavy mast cell burden. Headache, hypotension leading to syncope, bleeding diathesis, peptic ulcer disease and psychologic changes such as irritability and difficulty in concentration may also be associated with the disorder.
When urticaria pigmentosa begins in infancy or early childhood, the skin lesions and symptoms eventually abate by adulthood in 50 percent of patients.9 Others show significant improvement, with lesions clearing and symptoms decreasing in frequency and severity. Residual pigmentation can remain after regression of childhood disease. Unlike the childhood disease, adult-onset urticaria pigmentosa usually persists for the patient's lifetime.5
Solitary mastocytomas are more common in infants and children than in adults. They are rare in adults because resolution usually occurs early in life.9 The nodule is usually large (3 to 4 cm), frequently occurs on an extremity and demonstrates Darier's sign. Since the increase in the number of mast cells is small, systemic symptoms are unusual. Second mastocytomas are also uncommon; when they develop, they usually do not occur more than two months after the first lesion.
Diffuse Erythrodermic Mastocytosis
Diffuse erythrodermic mastocytosis is a rare form of cutaneous mastocytosis that primarily occurs in children under three years of age. The infant's skin may appear normal at birth, but the skin rapidly evolves into a generalized thickening, much like peau d'orange. Bullae and blisters are common, and systemic symptoms can be severe. Spontaneous resolution is the rule, although there is a risk of persistence and systemic involvement extending into adulthood.
Telangiectasia Macularis Eruptiva Perstans
Telangiectasia macularis eruptiva perstans is a rare condition found primarily in adults. Its name describes the nonpruritic lesions of this type of mastocytosis. The lesions in this disorder are smaller than those of urticaria pigmentosa.
Skin lesions may or may not accompany systemic mastocytosis. Systemic involvement can precede, but more frequently follows, the development of urticaria pigmentosa, which is a feature in 85 percent of patients with systemic mastocytosis.5 The prevalence of systemic involvement increases with age, and approaches 15 to 30 percent in adults with skin lesions.10,11
|Although not pathognomonic for cutaneous mastocytosis, urticaria that begins following exposure to physical stimuli such as heat, cold or pressure strongly suggests the diagnosis. This response is called Darier's sign.
Patients with systemic disease frequently report intermittent, brief spells of urticaria, flushing, pruritus, palpitations, headache, lightheadedness and syncope, rhinorrhea, nausea, vomiting, diarrhea and crampy or burning abdominal pain in association with the ingestion of hot, cold or spicy foods. Gastritis, esophagitis and peptic ulcer disease are common. A period of lethargy usually follows the attacks.
Asymptomatic hepatosplenomegaly with mast cell infiltration is frequently present. Lymphadenopathy can occur. After the skin, the bone marrow is the second most frequently involved organ, and its infiltration by mast cells can lead to bone pain, anemia and pathologic fractures. Other bony lesions include osteosclerosis and osteoporosis.
Recognition of mastocytosis can be difficult, especially in patients who do not have the characteristic skin lesions and Darier's sign. In addition, many clinicians may be unfamiliar with the disease and thus may fail to consider the diagnosis. Even when mast cell disease is suspected, confirmatory testing can be falsely negative as a result of technical problems.
The three criteria to consider for establishing the diagnosis of mastocytosis are as follows: (1) histopathology of a skin lesion, if available; (2) histologic evidence of systemic involvement with or without an underlying hematologic disorder; and (3) biochemical markers of mast cell activity. The presence of all of these criteria in each patient is not required.
|Symptoms of systemic mastocytosis include flushing, palpitations, nausea, headache, syncope, rhinorrhea and abdominal pain.
When skin lesions are present, a skin biopsy should be obtained to confirm the diagnosis of mastocytosis, since Darier's sign is not pathognomonic. The skin should be anesthetized by injecting a local anesthetic without epinephrine below the biopsy site, not directly into the biopsy site. Direct trauma or epinephrine injection can cause degranulation of the mast cells, making their identification more difficult. Special stains such as toluidine blue, Giemsa or fluorescein isothiocyanate-avidin12 are required because routine histologic staining may not clearly demonstrate the excess number of mast cells. When the specimen is submitted, the pathologist should be informed of the tentative diagnosis.
A liver or bone marrow biopsy in patients with systemic mastocytosis often demonstrates an increase in mast cells. Before a bone marrow sample is obtained, the pathologist must be informed about the possible diagnosis, because a bone marrow sample has special fixation requirements for the diagnosis of mastocytosis.
Laboratory abnormalities associated with systemic mastocytosis include hypocholesterolemia (10 to 20 percent of patients10), which is probably due to an increased heparin level. Thrombocytopenia, eosinophilia (12 to 25 percent of patients5) and elevation of alkaline phosphatase and liver enzymes may also be present in patients with systemic disease. If there are no characteristic pigmented lesions, a bulla should be biopsied if one is present.
Circulating biochemical mediators are often increased, especially when a large number of mast cells are activated during attacks. Although several biochemical tests of the blood and urine have been used to support the diagnosis of mastocytosis, one of the most sensitive, when it is available, is an elevated plasma tryptase level.4,13 Other indicators of mast cell degranulation are the presence of chronically elevated plasma and urinary histamine levels and its metabolite N-methylhistamine, the presence of chronically elevated urinary metabolites of prostaglandin D214 and a prolonged partial thromboplastin time documented in a blood sample obtained immediately after an attack.15 Serum heparin levels are not useful.2 Testing is not necessary in patients with cutaneous disease only.7
Overview of the Diagnostic Work-up
A suggested diagnostic work-up for adults with suspected mastocytosis is summarized in Table 4. Cutaneous mastocytosis in children is a benign disease. Thus, evaluation beyond a skin biopsy is not necessary. If systemic signs are present or if the disease first appears after age five, the diagnostic work-up in a child is the same as that suggested for an adult.
When cutaneous mastocytosis begins in adulthood, a bone marrow biopsy is recommended to exclude the presence of an associated hematologic disease, especially in an elderly patient with systemic symptoms, lymphadenopathy or hepatosplenomegaly. A technetium bone scintiscan can establish a baseline to avoid confusion with other bone diseases.2 Bone densitometry should be performed to determine whether osteoporosis is present. Osteoporosis in patients with mastocytosis is believed to be secondary to elevated prostaglandin D2 and heparin levels.
Endoscopy is warranted in patients who have upper gastrointestinal symptoms unresponsive to treatment. Bone marrow biopsy and biochemical tests are required for the diagnosis of systemic mastocytosis in patients without skin involvement. The risk of associated malignant disease in adults with mastocytosis ranges from 2 percent in those with only urticaria pigmentosa9 to 70 percent in elderly symptomatic patients with systemic mastocytosis and no skin lesions.12 The role of periodic surveillance is uncertain, but it may be useful to obtain a complete blood count regularly.
Patients with symptomatic mastocytosis should identify and avoid triggering factors. Extremes of temperature, alcohol and certain drugs (Table 3) should be avoided completely or used with caution.
Pharmacologic treatment of mastocytosis involves stabilizing mast cell membranes to decrease the severity of the attacks while blocking the action of inflammatory mediators. Other approaches include surgical removal of isolated mastocytomas, topical corticosteroid therapy and therapy with psoralen plus ultraviolet A (PUVA) to fade multiple pigmented lesions. There is no specific cure for the disease, although improvement can be expected in children.
Suggested Diagnostic Evaluation of Adults with Suspected Mastocytosis
- For patients with cutaneous mastocytosis, the following studies are recommended:
- Skin biopsy
- Complete blood count and differential
- Bone marrow biospy
- If systemic involvement is suspected, consider obtaining the following studies, depending on the symptoms:
- Urine collection for biochemical testing
- Bone scan
- Gastrointestinal endoscopy
- Neuropsychiatric examination
- Liver biopsy
- Computed tomography of the abdomen
Histamine H1 antagonists are used to treat the pruritus, flushing, bullae and urticaria. Hydroxyzine (Atarax), doxepin (Sinequan) and chlorpheniramine may help relieve the symptoms. Nonsedating antihistamines may also be used. The dosage is titrated to obtain the most effective regimen. The nonulcer dyspepsia that sometimes occurs with mastocytosis frequently responds to use of H1 blockers.16
Histamine H2 blockers can be used to decrease the gastric hyperacidity that often accompanies concomitant ulcer disease in patients with systemic mastocytosis. Not all mast cells have H1 receptors, and H2 blockers may also decrease cutaneous symptoms.
Orally administered cromolyn sodium (Gastrocrom) can relieve diarrhea and abdominal pain. Although intestinal absorption of cromolyn is limited, this agent has been reported to decrease bone pain and headaches17 while improving cognitive abilities and skin symptoms.8 The dosage is 200 mg four times a day. Several weeks of therapy may be required before benefits are noted. Anticholinergic agents may help alleviate abdominal cramping.
Both H1 and H2 blockers should be used to treat anaphylaxis.18 Patients with mastocytosis should also wear a medical alert bracelet and carry an adrenaline-filled syringe. The emergency treatment of shock in association with mastocytosis is the same as that of anaphylaxsis. Fluids, adrenaline, antihistamines and pressor agents are often required.3
Aspirin has been used to treat the flushing that is associated with elevated prostaglandin levels during attacks. Caution is required, however, because of the potential for aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) to cause degranulation. Treatment with aspirin is reserved for use in patients with vascular collapse that is not prevented by H1 and H2 blocker prophylaxis.19 Treatment is initiated in the hospital, and should begin at a low dosage. The patient should receive antihistamines before intervention with aspirin is undertaken.20
PUVA therapy may provide cosmetic skin changes and temporary relief from symptoms.7,18 High-potency topical or intralesional injection of corticosteroids affords only transient improvement. Topical or intralesional corticosteroid therapy is, however, useful in the treatment of solitary mastocytoma. Systemic steroids may be necessary to control the severe skin disease, malabsorption or ascites of systemic mastocytosis.18,21
The authors thank Linda Hamlin, of the MaineDartmouth Family Practice Residency, for technical assistance, and Eileen Ringel, M.D., in Waterville, Me., for reviewing the manuscript and providing the photographs.