Urticaria pigmentosa

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Epidemiology

Epidemiologic data on the true prevalence of UP are lacking. It has been estimated that 1 of 1000 to 8000 new patients visiting a dermatology department may have UP [7]. Although UP generally occurs sporadically, rare familial cases have been reported [8]. The gender distribution seems to be approximately equal [9]. Sixty-five percent of patients with cutaneous mastocytosis have been reported to be children [10]. About 80% of lesions in children appear before 1 year of age [10]; congenital

Clinical presentation of urticaria pigmentosa

UP is the presenting feature in 56% to 100% of patients with systemic mastocytosis [12], [13], [14], [15]. The term “urticaria pigmentosa” sometimes has been used to collectively describe any form of cutaneous mastocytosis [16], [17], [18]. The classical single lesion of UP is a hyperpigmented macule or papule and thus, typical UP may also be referred to as maculopapular cutaneous mastocytosis [19], [20]. When mechanically irritated (stroked bluntly with a spatula or pen), this lesion develops

Typical urticaria pigmentosa

Cases of typical UP (maculopapular cutaneous mastocytosis), the most common form of mastocytosis [30], [31], differ between adults and children. In adults, lesions are characterized by red-brown macules or slightly elevated papules (Fig. 1A). In a study of 48 adults, mean and maximum diameters of the lesions were 3 mm and 4 mm, respectively [30]. Lesions occur in a symmetric and random distribution [19]. The sides of the trunk and thighs often tend to have the highest density of lesions [32].

Other forms of urticaria pigmentosa

Lesions of pediatric UP sometimes are large, flat, slightly elevated doughy hyperpigmented plaques rather than macules; these lesions are referred to as the plaque-type of UP (Fig. 2A) [20]. They also have been described as multiple mastocytomas.

Multiple sharply demarcated yellow or cream-colored nodules or papules ranging in diameter from few millimeters to approximately 2 cm have been observed rarely as a nodular variant of UP (Fig. 2B) [24]. They also have been described as

Other cutaneous manifestations of mastocytosis

In addition to UP, mastocytomas and diffuse cutaneous mastocytosis are distinct manifestations of cutaneous mastocytosis [20]. Solitary mastocytomas are common in children and rare in adults [31], [41]. Most of these lesions are present at birth or develop within the first 3 months of life [17]. They typically are flat or mildly elevated, well-demarcated macules, plaques, or nodules that are several centimeters in diameter (Fig. 2D). The lesions usually have a reddish-brown color with a yellow

Mast cell mediator release syndrome

Mast cells are the source of a vast array of biologically active preformed mediators stored in their granules, newly generated membrane-derived lipid mediators, and cytokines (Table 1) [58]. Most symptoms in patients with mastocytosis are believed to be related to the release of mast cell mediators by an increased number of mast cells and may be summarized as a mast cell mediator release syndrome [59]. Symptoms generally seem to be more severe in patients with extensive systemic disease and

Classification of systemic involvement

Systemic mastocytosis rarely is diagnosed in children, but UP in adults more often is associated with internal organ involvement than previously assumed [73], [74]. A revised classification of mastocytosis was proposed after a consensus meeting on mastocytosis and was adopted by the World Health Organization (Box 2) [75].

In about 90% of patients with systemic involvement, the course is indolent, and the prognosis is good (indolent systemic mastocytosis). The bone marrow is the most common site

Prognosis

The prognosis in patients with UP is variable and depends on the classification of disease. Most children and adults have an indolent disease and a good prognosis.

In children, UP often is the only manifestation of mastocytosis, with pruritus as an associated symptom. In only a few children, indolent systemic mastocytosis is diagnosed [30]. More severe disease categories are rare [89], [90]. Children with mastocytomas have not been reported to develop systemic disease, and their lesions exhibit

Pathogenesis

The understanding of the pathogenesis of UP and other forms of mastocytosis has increased substantially over the past decade. Activating mutations in KIT, the receptor for stem cell factor (SCF), seem to be the key events for the excessive, SCF-independent mast cell proliferation leading to mastocytosis. Further research has focused on conditions that influence proliferation and differentiation of mast cells.

Mast cell growth factors

Mast cell progenitors originate in the bone marrow from a pluripotent CD34+, CD13+, CD117 (KIT)+ stem cell population; circulate through the blood; and mature within tissues [96]. CD49β7 (α4β7 integrin) seems to be required for homing of mast cells to the gut [97]. Homing factors for mast cells in other tissues are not yet known .

Normal mast cell development requires the interaction between SCF and KIT, the receptor for SCF on the surface of mast cells. SCF is produced by numerous stromal

KIT and c-kit mutations

The c-kit proto-oncogene codes for KIT, the transmembrane tyrosine kinase receptor for SCF that is expressed on mast cells, melanocytes, hematopoietic stem cells, and germ cell lineages [109]. Activating mutations in c-kit leading to constitutive autophosphorylation of the receptor and uncontrolled cell growth have been described. The HMC-1 cell line, derived from a patient with mast cell leukemia, is known to carry two mutations in c-kit: one results in an amino acid substitution (Val to Gly)

Chromosome abnormalities in mastocytosis

Nonspecific cytogenetic abnormalities have been found in patients with mastocytosis. In one case report, the presence of trisomy 4 in the CD34+ mononuclear cells of a patient with acute myeloid leukemia and mastocytosis has been associated with an Asp816Tyr mutation of KIT [120]. Two large studies in patients with mastocytosis demonstrated an increased number of chromosome abnormalities, which were similar in type and frequency to those found in some malignant hematologic disorders [121], [122]

Establishment of the diagnosis

The diagnosis of UP is based on clinical grounds and is established by skin biopsy (Table 2). Typical maculopapular skin lesions of UP or other forms of cutaneous mastocytosis and a strong Darier's sign may be sufficient for the diagnosis in some cases.

Mast cells within skin biopsies are characterized by a spindle shape and metachromatic granules. They may be identified using traditional toluidine blue, Giemsa, chloroacetate esterase, or avidin stains [123]. Immunohistochemical staining with

Therapy

There is no cure for mastocytosis. Despite advances in the understanding of the pathophysiology, treatment remains symptomatic. Therapy for mastocytosis encompasses avoiding trigger factors; targeting symptoms of mast cell mediator release; and treating skin lesions, aggressive mastocytosis, and associated hematologic diseases, depending on the patient (Table 4). Future therapeutic strategies have been developed to specifically target proliferating mast cells.

Mast cell mediator–induced symptoms

Nonsedating H1 antihistamines are the drugs of choice for pruritus and whealing (reviewed in [166]). For prophylaxis of recurrent episodes, antihistamines should be administered on a daily basis. For some patients, classical sedating H1-blockers, such as hydroxyzine or diphenhydramine, seem to be more effective. The author often prescribes nighttime use of a combination of a nonsedating H1 antihistamine with a sedating one to control severe pruritus. Hydroxizine was reported to be superior to

Antiproliferative therapy of skin lesions

Patients report a diminution or decrease in intensity of skin lesions in the summer and after repeated exposure to natural sunlight [172]. In most patients with UP, oral psoralen plus ultraviolet A (PUVA) radiation and UVA1 radiation are effective in reducing pruritus and whealing after 4 to 8 weeks of therapy [173], [174], [175], [176], [177], [178]. Fading of lesions is associated with a reduction of mast cell numbers and in histamine and leukotriene levels [175]. Relapse occurs several weeks

Therapy for severe forms of mastocytosis

Patients with SM-AHNMD are treated appropriately for the associated hematologic disease. Interferon α (IFN-α) therapy has been reported to reduce organ infiltration of mast cells (bone marrow, hepatomegaly, lymphadenopathy, cutaneous lesions) and other features of systemic disease (anemia, osteoporosis, flushing), although these findings were not consistent [187]. In a multicenter study in 20 patients with systemic mastocytosis, IFN-α therapy lead to a partial or minor response in patients

Future therapeutic approaches

After allogenic bone marrow transplantation, engrafted bone marrow cells are believed to attack neoplastic mast cells, although experience is limited. One patient with mastocytosis and a myeloproliferative disorder experienced complete remission 2 years after bone marrow transplantation [192]. In two other patients with mastocytosis and myelodysplasia, only the myelodysplasia, but not the mastocytosis, improved after transplantation [193], [194].

Another approach may target markers such as CD25

Acknowledgements

I want to acknowledge Dean D. Metcalfe and Cem Akin, who introduced me to the field of mastocytosis.

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