Laboratory Studies
In many patients, urticaria pigmentosa (UP) can be diagnosed when history and physical examination findings reveal the characteristic lesions that demonstrate the Darier sign. Usually, a skin biopsy is a necessary confirmatory test, typically through a 3- or 4-mm punch biopsy. It may be helpful to complete two biopsies, one of the suspected lesion and the other of unaffected skin, in order to compare the presence of mast cells. For aid in the diagnosis, the following stains are recommended to be completed with biopsy: hematoxylin, eosin, toluidine blue, Giemsa, and monoclonal antibodies to tryptase, CD117 and KIT. [22]
Consider the following laboratory tests:
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CBC count: In systemic mastocytosis, CBC counts may reveal anemia, thrombocytopenia, thrombocytosis, leukocytosis, and eosinophilia.
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Plasma or urinary histamine level: Patients with extensive cutaneous lesions may have 24-hour urine histamine excretion at 2-3 times the normal level.
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Total tryptase level: Tryptase is a marker of mast cell degranulation released in parallel with histamine. Total tryptase levels in plasma correlate with the density of mast cells in urticaria pigmentosa lesions in adults with systemic mastocytosis. Patients with only cutaneous mastocytosis typically have normal levels of total tryptase. Total tryptase values are recommended by the WHO as a minor criterion for use in the diagnostic evaluation of systemic mastocytosis. [1, 2, 37] The total tryptase level in serum or plasma seems to be a more discriminating biomarker than urinary methylhistamine for the diagnosis of systemic mastocytosis. [37] Most patients with systemic anaphylaxis of sufficient severity to result in hypotension have elevated serum or plasma beta-tryptase levels. During insect sting–induced anaphylactic hypotension, beta-tryptase levels in the circulation are maximal 15-120 minutes after the sting. [37]
WHO major criteria for the diagnosis of systemic mast cell disease include the following [30] :
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Multifocal dense infiltrates of mast cells (>15 close to each other) observed in bone marrow biopsy specimens and/or mast cells stained for tryptase in biopsy specimens from other extracutaneous organs.
WHO minor major criteria for the diagnosis of systemic mast cell disease include the following [30] :
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Mast cells in bone marrow, or other extracutaneous organs show abnormal (spindling) morphology (>25%) or the presence of greater than 25% atypical mast cells in bone marrow aspirates
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Demonstration of c-kit point mutation on codon 816 in bone marrow, blood, or other extracutaneous organs
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CD117 (c-kit receptor)–positive cells, also positive for CD2 and/or CD25
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Serum tryptase values greater than 20 ng/mL [2]
Imaging Studies
Bone scan and radiologic survey
Obtain a bone scan and radiologic survey in nonpediatric patients or if the CBC count is abnormal in a young child. If a patient has skeletal system symptoms, perform a bone scan and radiologic survey to identify lytic bone lesions, osteoporosis, or osteosclerosis.
GI workup (upper GI series, small bowel radiography, CT scanning, endoscopy)
If a patient has GI symptoms, order a GI workup to identify peptic ulcers, abnormal mucosal patterns, or motility disturbances.
Other Tests
If a diagnosis of mastocytosis is uncertain, tests for elevated mast cell mediators and degradation products may help establish the diagnosis.
Serum tryptase level
Tryptase levels are elevated in patients with mastocytosis. Tryptase levels may be more useful than histamine levels, because histamine can be elevated in hypereosinophilic states.
Urinary N-methylhistamine (NMH) and N-methylimidazoleacetic acid levels
Urinary NMH and N-methylimidazoleacetic acid levels [38, 39] may be more specific and sensitive than urinary histamine levels. NMH levels correlate directly with the extent of skin lesions. NMH levels decrease with age; therefore, consider the patient's age when interpreting results.
Urinary prostaglandin D2 metabolite level
Even during asymptomatic periods, urinary prostaglandin D2 metabolites levels may range from 1.5-150 times higher than normal levels. This test is not widely available.
Procedures
Bone marrow biopsy and aspirate
Perform bone marrow biopsy and aspirate in patients with urticaria pigmentosa if they have peripheral blood test abnormalities, hepatomegaly, splenomegaly, or lymphadenopathy to determine if they have an associated hematologic disorder.
Biopsy
Inject an anesthetic agent without epinephrine adjacent to, not directly into, the lesion chosen as the biopsy specimen to avoid mast cell degranulation, which makes histologic examination difficult.
Histologic Findings
Examination reveals dermal mast cell infiltrates, especially in the papillary dermis around blood vessels (see image below).
Diagnosis of urticaria pigmentosa may require demonstration of mast cell granules using Giemsa stain (see image below) or toluidine blue stain. The Leder stain is not dependent on intact mast cell granules.
Mast cell nuclei are round with surrounding ample cytoplasm producing a “fried egg” appearance. The typical presentation of mast cells is a single nuclei, yet there have also been atypical histological findings reported in four patients with uriticaria pigmentosa that showed mast cells with bilobed and multilobed morphology. [40] In telangiectasia macularis eruptiva perstans (TMEP), mast cells are brick shaped or spindle shaped. In nodular urticaria pigmentosa, mast cells are observed in dense aggregates and may extend through the entire dermis and into subcutaneous tissue. If the lesion from which the biopsy specimen was taken was traumatized during harvest, edema and eosinophil infiltrates may be present. The hyperpigmentation of cutaneous mastocytosis is secondary to increased melanin in the basal cell layer and melanophages in the upper dermis.
Planar xanthoma has been described in association with mastocytomas.
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Urticaria pigmentosa lesions on the face of a child. Courtesy of Lee H. Grafton, MD.
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Urticaria pigmentosa lesions on the back of a child. Courtesy of Lee H. Grafton, MD.
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Lesion on the scalp of an infant.
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Lesion on the arm. Courtesy of Lee H. Grafton, MD.
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Blistering lesion.
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Hematoxylin and eosin stain revealing mast cells in the papillary dermis.
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Giemsa stain revealing mast cells.
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Positive Darier sign on a child's back.
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Urticaria pigmentosa on a child.
