Urtikaria Pigmen

Immunol Allergy Clin N Am
24 (2004) 287 – 316
Urticaria pigmentosa
Knut Brockow, MD
Department of Dermatology and Allergy Biederstein, Technical University Munich, Biedersteiner
Strasse, 29 80802 Munich, Germany
In the first report of urticaria pigmentosa (UP) published in 1869, Nettleship

and Tay described a case of chronic urticaria leaving brown stains [1]. The term
‘‘urticaria pigmentosa’’ was introduced 9 years later by Sangster and described a
similar case with ‘‘anomalous mottled rash, accompanied by pruritus, factitious
urticaria, and pigmentation’’ [2]. In 1887, Unna associated clinical features of UP
with increased mast cell numbers [3]. The term ‘‘mastocytosis,’’ however, was
not used until about 50 years later in Sézary’s description of individual lesions
of UP [4]. Systemic involvement of mastocytosis first was reported by Ellis
in 1949 [5]. Mastocytosis now is defined by excessive numbers of mast cells in
characteristic distributions in the skin, bone marrow, gastrointestinal tract, liver,
spleen, or lymph nodes [6]. Mast cell accumulations may be restricted to the skin
(cutaneous mastocytosis, mostly UP) or may be found in extracutaneous organs
(systemic mastocytosis).
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 re-
ported to be children [10]. About 80% of lesions in children appear before 1 year
of age [10]; congenital cases have been described in up to 25% [11]. A second
peak of incidence occurs in the third and fourth decades of life [10].
E-mail address: knut.brockow@lrz.tum.de
0889-8561/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2004.01.002
288 K. Brockow / Immunol Allergy Clin N Am 24 (2004) 287–316
Clinical presentation of urticaria pigmentosa

UP is the presenting feature in 56% to 100% of patients with systemic
mastocytosis [12 – 15]. The term ‘‘urticaria pigmentosa’’ sometimes has been used
to collectively describe any form of cutaneous mastocytosis [16 – 18]. The clas-
sical 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 a wheal-like edematous erythema. This reaction is referred to as
Darier’s sign [21]. UP may have heterogeneous clinical presentations that are
less typical and not recognized easily [6]. In some cases, UP may be telangiec-
tatic and pigmentless [22,23], plaque-like, or nodular [24 –28]. To avoid the term
‘‘urticaria pigmentosa,’’ it has been proposed that cutaneous mastocytosis should
be classified based on different morphologic aspects alone [29]. The term has
historical roots, however, and is used widely in dermatologic textbooks. In this
article, UP and other forms of cutaneous mastocytosis are classified according to
the recent consensus nomenclature (Box 1) [20].
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 pap-
ules (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]. In extensive disease, lesions may form clusters
Box 1. Classification of cutaneous forms of mastocytosis

Urticaria pigmentosa and maculopapular cutaneous
mastocytosis
Subvariants:
Typical UP (maculopapular cutaneous mastocytosis)
Plaque form
Nodular
Telangiectasia macularis eruptiva perstans (TMEP)
Diffuse cutaneous mastocytosis
Mastocytoma of skin
Data from Valent P, Horny HP, Escribano L, et al. Diagnostic cri-

teria and classification of mastocytosis: a consensus proposal.
Leuk Res 2000;25:603– 25.
K. Brockow / Immunol Allergy Clin N Am 24 (2004) 287–316 289
Fig. 1. Typical UP and maculopapular cutaneous mastocytosis in a child and an adult. Typical UP is
the most common form of cutaneous mastocytosis. In adults, lesions are numerous and disseminated
(A) and consist of small red-brown macules and slightly elevated papules. In children, lesions are
larger (B), more hyperpigmented, and well demarcated.
and may become confluent to form mottled skin areas or diffuse patches of in-
volved skin [30]. Palms, soles, face, and scalp are mostly free of lesions [19].
Darier’s sign is positive in most patients who are not taking antihistamines and
may be used as a diagnostic tool. Urticarial dermographism on uninvolved skin,
as seen in factitious urticaria, is rare. Pruritus is typical, but may be lacking in
limited disease [30].
In children, lesions of UP are larger compared with adult lesions (mean di-
ameter, 5 mm; maximum, 15 mm) (Fig. 1B) [33]. The lesions tend to be more
hyperpigmented than erythematous. The trunk is the most heavily affected area.
Involvement of the face and scalp are not untypical. Lesions are demarcated
better than are lesions in adults, and confluating and diffuse lesions are rare. The
total extent of skin lesions does not differ between adults and children [33]. In
the first few years of life, vesicles and blisters may form on lesions of UP
spontaneously or after provocation by mechanical injury (sometimes even after
elicitation of Darier’s sign) [34]. These blisters are tense and may become hem-
orrhagic, but they heal without scarring [35]. Blisters may be the first manifes-
tation of cutaneous mastocytosis [36]. Blistering episodes resolve spontaneously
beyond the third year of life.
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 multi-
ple mastocytomas.
Multiple sharply demarcated yellow or cream-colored nodules or papules
ranging in diameter from few millimeters to approximately 2 cm have been ob-
served rarely as a nodular variant of UP (Fig. 2B) [24]. They also have been
described as pseudoxanthomatous mastocytosis or xanthelasmoideae [26,27,37].
Lesions may be present at birth, but more often develop in the first year of
life [38].
UP lesions may be erythematous and telangiectatic rather than hyperpig-
mented. The most extreme form, TMEP (telangiectatic type of UP), is observed
in less than 1% of all patients with mastocytosis [19]. Most of these patients are
adults, especially obese middle-aged women [22], but TMEP in children has been
reported [39]. TMEP is characterized by matted red telangiectases on erythema-
tous to brown macules (Fig. 2C). Darier’s sign is typically negative, and histo-
logic findings are subtle. Pruritus and blisters are rare. Systemic involvement
seems to be less common as compared with UP, but involvement of the bone
marrow and associated hematologic diseases have been reported [40]. In some
patients, TMEP coexists with typical UP or develops from UP lesions [22].
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 appearance. Mastocytomas occur at any location of the body,
including soles. Darier’s sign is positive. Blisters may be present. Flushing and
anaphylactic reactions may occur in some cases [42,43].
Diffuse cutaneous mastocytosis is a rare condition that is characterized by
diffuse mast cell infiltration of the entire skin. Typical lesions develop in the skin
of newborns shortly after birth [44 – 46]. On examination, the color of the lesions
normally resembles that of UP but may appear normal. Severe edema and
leathery induration of the skin leads to accentuation of the skin folds (pseudo-
lichenified skin) and peau-d’orange-like aspect. Severe involvement may result
Fig. 2. Less typical forms of cutaneous mastocytosis. In children, UP may present with palpable
elevated lesions of the plaque form (A) or with lesions of the nodular variant (B). TMEP (C), the most
extreme form of UP, with telangiectatic lesions lacking hyperpigmentation. Mastocytomas are solitary
elevated plaques (D).
in a prematurely aged or elephant-like appearance [47]. Pedunculated papules,

nodules, and tumors may be present. Severe dermographism is typical. Bullous
eruptions are frequent, particularly after mechanical trauma [48,49]. Serious com-
plications, including hypotension and gastrointestinal bleeding, may occur
[46,50]. Patients with diffuse cutaneous mastocytosis are at risk for systemic
involvement and persistence of the condition into adulthood [18,51 –57].
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 often are absent in patients with only
cutaneous disease; however, the severity of symptoms cannot always be predicted
by the amount of total mast-cell burden in different patients [30].
Patients with mastocytosis experience symptoms with variable intensity
during discrete attacks caused by the spontaneous or induced release of mast
cell mediators. Patients typically report that the attacks last for approximately
30 minutes. They are often characterized by pruritus, whealing (reddening and
swelling of skin lesions), and flushing (erythematous diffuse rash with feeling of
warmth); palpitations, tachycardia, and lightheadedness may occur [12,60]. Other
symptoms, such as headache, dizziness, or syncope, may develop. Spontaneous
recovery is usual. Attacks are followed by lethargy and fatigue for several hours.
Table 1
Mast cell mediators
Type of mediator Examples
Preformed granule-associated Histamine
mediators Serine proteases
Tryptase, chymase, cathepsin G, carboxypeptidase A
Acid hydrolases
b-hexosaminidase, N-acetyl-b-glucosaminidase, b-glucuronidase
Proteoglycans (heparin, chondroitin sulfate)
Lipid mediators Leukotrienes (LTB4, LTC4)
Prostaglandin D2
Platelet-activating factor
Thromboxane B2
Cytokines Interleukins (IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-16)
SCF
TNF-a
Transforming growth factor b
Granulocyte-macrophage colony-stimulating factor
In patients with extensive mast cell mediator release syndrome, strong stimuli
may lead to severe or protracted hypotension, life-threatening vasodilatory
shock, and vascular collapse [12,13]. Mastocytosis may present as idiopathic ana-
phylaxis before the diagnosis is made [61]. Fatal reactions have been described
[62 – 64]. Pseudoallergic reactions caused by exposure to radiocontrast material,
agents used for general anesthesia, or opiates are common. Although allergic
diseases are not more frequent in patients with mastocytosis [65], reactions can be
more severe in allergic patients with mastocytosis. These patients may develop
severe anaphylaxis after Hymenoptera stings or during the course of insect
venom hyposensitization [66,67].
Gastrointestinal symptoms occur during attacks or may be not associated with
a cutaneous flareup [68]. Diarrhea and abdominal pain are frequent in adults with
systemic mastocytosis [12]. Diarrhea often is described by patients as the daily
occurrence of multiple loose stools or semiformed stools. The author has ob-
served that diarrhea also may constitute a problem in infants with UP, resulting
in a failure to thrive. Diarrhea tends to spontaneously resolve by the age of
2 to 3 years. Upper abdominal pain may be dyspeptic in nature and associated
with some form of dyspeptic gastroduodenal disease [13]. Nondyspeptic pain
may present with upper abdominal discomfort, often triggered by alcohol, food
intake, or stress, or is located in the lower abdomen and then has a crampy and
colicky character. Nausea and vomiting are less frequent. Mild steatorrhea may
be present, but malabsorption is rare and limited to patients with extensive,
aggressive disease.
Pulmonary mastocytosis is rare [69,70]. Chest pain has been described in
patients with systemic mastocytosis but was not associated with any abnormali-
ties on coronary angiography [71]. Respiratory symptoms, such as wheezing,
occasionally are reported [12]. In one patient, bronchial hyperresponsiveness, but
no airway inflammation, was demonstrated [72].
Patients with systemic mastocytosis sometimes experience neuropsychiatric
abnormalities. Altered cognitive functions, such as poor attention, irritability,
impaired memory, personality change and depression, have been seen in as-
sociation with mastocytosis [12].
Constitutional symptoms include fatigue, weight loss, mild fever, and night
sweats [13]. Fatigue often is associated with musculoskeletal (bone) pain, and
these symptoms may become severe and debilitating in patients with systemic
mastocytosis. Weight loss, fever, and sweats are rare and normally are limited to
patients with aggressive disease or mast cell leukemia, in which they may be the
presenting symptoms.
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 consen-
Box 2. Classification of mastocytosis

Cutaneous mastocytosis
Indolent systemic mastocytosis
Subvariants:
Isolated bone marrow mastocytosis
Smouldering systemic mastocytosis
Systemic mastocytosis with AHNMD (SM-AHNMD)
Aggressive systemic mastocytosis
Subvariant:
Lymphadenopathic mastocytosis with eosinophilia
Mast cell leukemia
Mast cell sarkoma
Extracutaneous mastocytoma
Adapted from Valent P, Horny HP, Escribano L, et al. Diagnostic

criteria and classification of mastocytosis: a consensus proposal.
Leuk Res 2000;25:603– 25.
sus 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 of mast cell accumulation in mastocytosis outside of the
dermis. Forty-six percent to 92% of adults with cutaneous mastocytosis have
focal or diffuse accumulations of mast cells in the bone marrow [73,76,77].
Examination of the bone marrow in children is performed only when systemic
involvement is suspected. In one study, subtle nondiagnostic accumulations of
mast cells were found in the bone marrow of 66% of children [78]. Hypercel-
lularity or fibrosis of the bone marrow may lead to hematologic abnormalities,
such as anemia, leukopenia, leukocytosis, thrombocytopenia, or eosinophilia, by
displacement of other cell types [79]. Severe bone involvement in some patients
is associated with osteoporosis, osteopenia, sclerosis, cystic lesions, and patho-
logic fractures [79]. Patients with extensive disease may exhibit hepatomegaly,
splenomegaly, or lymphadenopathy caused by accumulation of mast cells in these
organs. In a prospective study of 41 patients with indolent systemic mastocytosis,
hepatomegaly was present in 24% of patients [80]. The spleen has been reported
to be involved in 40% to 50% of patients, and peripheral lymphadenopathy was
demonstrated in 26% to 56% of patients with systemic mastocytosis (reviewed
in [81]). Organomegalies are typical for patients with smoldering (indolent)
systemic mastocytosis, a provisional subvariant that is characterized by a high
mast cell load, but without associated hematologic abnormalities and apparently
good prognosis.
Approximately 10% of patients with systemic mastocytosis develop systemic

mastocytosis with an associated hematologic non-mast cell lineage disorder
(SM-AHNMD), such as myeloproliferative or myelodysplastic syndromes,
lymphomas, or myeloid leukemias [82]. Only a few patients with aggressive
mastocytosis have been described in the literature, in whom fibrosis, cirrhosis,
ascites, and portal hypertension may develop because of aggressive mast cell
infiltration and can lead to fatal complications [83,84]. A subgroup is described
as having lymphadenopathy, pronounced eosinophilia, and hepatosplenomegaly
[85,86].
Mast cell leukemia is the most aggressive form of mastocytosis [87]. This
distinct entity is characterized by diffuse infiltration of atypical mast cells in
the bone marrow, leading to the presence of atypical mast cells in the peripheral
blood [20]. Rare cases with solitary mast cell tumors or mast cell sarcomas
have been reported in the literature [6,88].
Prognosis
The prognosis in patients with UP is variable and depends on the classifi-
cation 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 resolution during childhood [18]. More than 50% of pediatric
cases have been reported to resolve during puberty, and most of the remainder of
patients experience a reduction of cutaneous symptomatic lesions and dermogra-
phism [91]. Some children with UP have lesions persisting into adult life [92],
however, and in adulthood exhibit a course similar to that of adult-onset disease.
Prospective studies on the frequency of persisting UP are lacking. Children with
diffuse cutaneous mastocytosis have a higher risk for systemic disease than those
with other forms of cutaneous mastocytosis [51 – 54]. In one study, serum tryptase
levels in children with UP were correlated inversely to the duration of disease,
consistent with a slow resolution of the disease [30]. This finding contrasted
findings in adults, in whom a direct correlation between duration of disease and
tryptase levels was found [30].
In adults, indolent disease tends to progress slowly over many years or remain
stable according to the clonal nature of the disease [85,93]. Survival is not af-
fected, and symptoms are generally under control. Evolution from an indolent
form into a more severe form is rare. In a retrospective study of patients who were
followed for more than 10 years, approximately 10% of adults experienced a
regression of cutaneous UP lesions after a median duration of disease of 17 years
[94]. In patients with SM-AHNMD, this regression was associated with disease
progression; in patients with indolent disease, however, regression was paralleled
by an improvement of mast cell – mediated symptoms. Even in these patients,

mast cell lesions in the bone marrow remained.
Patients with associated hematologic disease, aggressive mastocytosis, or mast
cell leukemia have a less favorable prognosis and may experience a rapid prog-
ression [13]. Factors determining the clinical course are the nature of the as-
sociated hematologic abnormality and the rapidity of the increase in mast cell
numbers [95]. Patients with associated hematologic disorders have significantly
reduced 5-year survival rates [13]. Mast cell leukemia is the rarest form and has
the most fulminant behavior, with a survival duration of about 6 months [87].
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]. CD49b7 (a4b7 integrin) seems to be required for
homing of mast cells to the gut [97]. Homing factors for mast cells in other tis-
sues 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 cells, such as fibroblasts, endothelial cells, and mast cells, in membrane-
bound and soluble forms [98]. IL-3, IL-4, IL-6, IL-9, and IL-10 may influence
mast cell proliferation and differentiation [99]. Vascular endothelial growth factor
(VEGF)-transfected mice exhibit increased numbers of dermal mast cells [100].
Theoretically, local or systemic overproduction of these growth factors could be
responsible for the mast cell proliferation seen in mastocytosis. Earlier studies
have reported increased immunohistochemical staining for SCF between kerati-
nocytes in cutaneous mast cell lesions [101] and have suggested that patients with
mastocytosis express an abnormal soluble form of SCF in the epidermis. More
recent studies were not able to confirm these findings [102]. Intradermal injection
of recombinant SCF resulted in mast cell hyperplasia and hyperpigmentation of
the skin [103,104].
In another study, however, levels of SCF, IL-3, IL-4, and VEGF were not
elevated in the skin blister fluid or in the plasma of adults with systemic
mastocytosis, as compared with levels in controls [105]. Levels of IL-6 were
elevated in the plasma of patients with systemic mastocytosis and correlated with
plasma tryptase levels and numbers of dermal mast cells. This observation is
of potential importance, because some of the pathologic features of systemic
mastocytosis, such as fever, fatigue, and osteoporosis, are possible consequences
of the overproduction of IL-6 [106]. It is unclear, however, if elevation of IL-6
levels is a primary event or a secondary consequence. IL-6 in the presence of SCF
prevents mast cell apoptosis in vitro [107]. Mast cell apoptosis has been reported
to be reduced in patients with mastocytosis and associated with an overexpression
of the anti-apoptotic proteins BCL-2 and BCL-xL in the skin and bone marrow;
however, the influence of IL-6 has not been studied [108].
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) in codon 560, and the other results in Asp to Val
substitution in codon 816 (Asp816Val, A816D) [110]. The Asp816Val mutation
first was identified in peripheral blood mononuclear cells of adult patients with
mastocytosis and associated hematologic diseases [93]. Subsequent studies in
patients with mastocytosis confirmed the presence of the Asp816Val mutation in
the lesional skin of most adult patients with indolent systemic mastocytosis,
aggressive mastocytosis, or mast cell leukemia [111 – 113]. Higher levels of KIT
mRNA and of soluble KIT protein have been reported in patients with aggressive
mastocytosis or mastocytosis with an associated hematologic disorder, when
compared with levels in patients with indolent mastocytosis [114].
In patients with mastocytosis, c-kit mutations could be identified in peripheral
blood cells of different hematopoietic lineages, such as CD19+ B cells, CD3+
T cells, CD14+ monocytes, and CD15+ myeloid cells of patients with mastocy-
tosis [115]. In B cells, the immunoglobulin repertoire was polyclonal, indicating
that the mutation occurred before recombination [116]. In two patients with mas-
tocytosis, the Asp816Val mutation was shown in the skin and spleen [117]. In a
study of microsected bone marrow cells from a patient with systemic mastocy-
tosis and an associated chronic myelomonocytic leukemia, the presence of the
Asp816Val mutation was demonstrated in the mast cell infiltrate and myelomo-
nocytic infiltrate [113]. These findings support the clonal nature of the disease,
which is consistent with a neoplastic process involving an early pluripotential
hematopoietic stem cell.
The Asp816Val mutation has been described in biopsies of some atypical
pediatric cases [111,113]. Additional polymorphisms in codons 560, 816, 820,
and 839 have been detected in selected children and adults, but their clinical
relevance is less clear [111,112,118,119]. Overall, mutations in c-kit seem to be

uncommon in lesional biopsies of children with typical UP [112]. These findings
suggest the possibility that mastocytosis in many children has a different basis,
and this finding could provide an explanation for the generally more benign
course of most cases of childhood UP.
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+ mono-
nuclear 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]. Comparison of the results at two
different time points showed a change of chromosome pattern in most patients,
consistent with a genetic instability of the hematopoietic cells in mastocyto-
sis [122].
Diagnosis
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 stain-
ing with tryptase is the most accurate stain for the detection of mast cells in mas-
tocytosis in all tissues [124,125].
A 10- to 20-fold increase in mast cell numbers has been reported in lesions of
UP [126], but another study found that the increase may be less pronounced
[105]. Even in the uninvolved skin of patients with UP, mast cells numbers are
elevated twofold as compared with healthy controls (K. Brockow, MD, unpub-
lished data, 2002); however, a two- to fourfold increase has been observed in
several other inflammatory disorders (eg, urticaria, eczema, psoriasis, parasitic
infestations) and neoplastic disorders (eg, neurofibromas, basal cell carcinomas)
and is not diagnostic [127,128]. Absence of other inflammatory cells in the
dermal infiltrate is a characteristic feature in mastocytosis, with the exception of
some eosinophils in a few cases [19]. Mast cell accumulations are located in the
papillary dermis, particularly around blood vessels and skin appendages. In more
Table 2
Diagnostic principles
Principle Explanation
Establishment of the diagnosis History and clinical examination
Inspection of cutaneous lesions, Darier’s sign,
dermographism test
Skin biopsy
In nondiagnostic patients (eg, patients with symptoms of
mediator release but no skin involvement): mutational
analysis from bone marrow aspirate or skin biopsy, flow
cytometric determination of CD2, CD25 in bone marrow
aspirate or biopsy
Surrogate markers for Determination of extent and density of skin involvement, serum
disease severity tryptase levels
In selected cases: plasma sCD25, plasma sCD117, or serum
IL-6 levels
Staging procedures All patients: blood count and differential, blood chemistry,
coagulation parameters, abdominal ultrasound, bone
densitometry
In patients with suspected systemic involvement: bone marrow
biopsy, bone marrow aspirate (if possible: flow cytometric
determination of CD2, CD25),
In case of symptoms indicating specific organ involvement,
for example, endoscopy, abdominal CT, bone scans
infiltrated lesions, such as in mastocytomas, nodular variants, or diffuse cutane-

ous mastocytosis, dense mast cell infiltrates may extend into the entire dermis and
sometimes into the subcutaneous tissue. Findings in TMEP are subtle and usually
show dilated capillaries surrounded by few scattered mast cells.
The demonstration of elevated serum levels of mast cell mediators, such as an
elevated total tryptase level [129], and of surface markers on neoplastic mast cells
may support the diagnosis (discussed later in article) [130]. In questionable cases,
detection of point mutations in c-kit in lesional tissue, such as skin or bone
marrow, may be warranted [131].
Surrogate markers for disease severity

An examination of the extent and density of cutaneous lesions in adults helps
to identify patients with extensive indolent systemic mastocytosis. Patients with
UP with a high extent (50% body surface area) and density of skin lesions in
the most affected region (10% of skin is lesional) exhibit organomegalies, high
serum tryptase levels, and severe bone marrow pathology. Such patients should
be evaluated, treated, and followed up thoroughly. Patients with SM-AHNMD,
aggressive mastocytosis, or mast cell leukemia typically do not exhibit severe
skin involvement and may lack skin lesions. Absence of UP has been reported to
be a poor prognostic feature in patients with systemic mastocytosis [13]. More
than 90% of patients with indolent systemic mastocytosis exhibit UP, whereas
only 50% of patients with an associated hematologic disorder or aggressive

mastocytosis have UP. In mast cell leukemia, skin involvement is rare [85,95].
Tryptase is used widely as a surrogate marker for systemic mastocytosis
[132]. The currently available immunoassay measures the sum of a-tryptase and
b-tryptase [133]. Whereas b-tryptase levels are elevated after mast cell degranu-
lation, such as after anaphylaxis [134], baseline total tryptase levels are primarily
a reflection of a-tryptase [129], which is believed to be released constantly from
mast cells. Total tryptase levels in the serum correlated with levels in the suction
skin blister fluid and with dermal mast cell numbers [135] and are interpreted as a
measure for the body mast cell burden [136]. Mean baseline tryptase levels of
more than 20 ng/mL are suggestive of systemic mastocytosis, whereas normal
subjects and patients with only cutaneous mastocytosis have levels below 14 ng/
mL [129].
Biochemical demonstration of elevated levels of histamine in the plasma, or
elevation in levels of urinary histamine metabolites, also supports the diagnosis
of mastocytosis [137 –139]. These tests are not more sensitive or specific than
determination of tryptase [132].
CD25 and CD117 (KIT) are expressed on the surface of neoplastic mast cell
and are shed from the membrane to produce soluble CD25 (sCD25) and soluble
CD117 (sCD117). In one study, sCD117 and sCD25 levels in serum correlated
better than tryptase levels with associated hematologic disorders and with aggres-
sive disease [140]. Another new surrogate marker under investigation for more
severe disease categories is IL-6 [141,142].
Staging procedures
In patients with UP, those with internal organ involvement and those with
aggressive forms of disease should be identified. Criteria for the diagnosis of
systemic mastocytosis have been defined (Table 3) [75,95]. Physical examination
or abdominal ultrasound should be performed to reveal hepatomegaly, spleno-
Table 3
Criteria for systemic mastocytosis
Type of criteria Explanation
Major Multifocal dense infiltrates of mast cells in bone marrow or other
extracutaneous organs
Minor More than 25% of the mast cells in the bone marrow smears or tissue
biopsy sections are spindle shaped or display atypical morphology
Detection of a codon 816 c-kit point mutation in blood, bone marrow,
or lesional tissue
Mast cells in the bone marrow, blood, or other lesional tissue expressing
CD25 or CD2
Baseline of total tryptase level of greater than 20 ng/mL
Major and one minor or three minor criteria needed for a diagnosis of systemic mastocytosis.
Data from Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of masto-
cytosis: a consensus proposal. Leuk Res 2000;25:603 – 25.
megaly, or lymphadenopathy in patients with extensive disease. Hepatic and

other organ involvement should be looked for in liver function tests (especially
alkaline phosphatase), blood chemistry, and coagulation tests (prothrombin time
[PT], partial thromboplastin time [PTT]). A blood count with differential, bone
densitometry, and detection of serum mast cell tryptase is obtained as part of the
routine evaluation of all patients.
A bone marrow biopsy, particularly in adults, is warranted in patients with
extensive cutaneous disease, severe symptoms, or other detected abnormalities,
which suggest systemic disease. Bone marrow involvement of mastocytosis is
characterized by focal or diffuse mast cells in paratrabecular or perivascular areas
[143]. Fibrosis or infiltrates of lymphocytes and eosinophils surrounding focal
mast cell lesions may be associated features. In patients with an associated
hematologic disorder, mast cells may become dysplastic, and their granules more
coarse, or are even absent. Such dysplastic mast cells may resemble hyper-
granulated monocytes [95]. In those cases, identification of mast cells in the bone
marrow may be difficult.
A focal increase of mast cells in the bone marrow may be missed by a single
biopsy or aspirate. Flow cytometric analysis of activation markers for neoplastic
mast cells in the bone marrow aspirate may have a better sensitivity for detection
of bone marrow involvement. CD2 and CD25 are expressed on the surface of
mast cells in patients with systemic mastocytosis but not in normal individuals
[144]. Other markers, such as CD56 and CD69, are overexpressed on the bone
marrow mast cells of patients with systemic mastocytosis [145].
Other investigations of organ involvement, such as gastrointestinal endoscopy;
examination of tissue specimens obtained from the liver, spleen, gastrointestinal
tract, or lymph nodes; abdominal CT; and bone scans, may be considered de-
pending on the condition and symptoms of the patient.
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 hema-
tologic diseases, depending on the patient (Table 4). Future therapeutic strategies
have been developed to specifically target proliferating mast cells.
Avoidance of trigger factors

All patients with mastocytosis should be informed about the disease, including
its prognosis and complications. Specific information on trigger factors and signs
for mast cell degranulation, potentially leading to anaphylactoid reactions, has to
be provided. A list of trigger factors known to induce symptoms in patients is
given (Box 3).
Table 4
Therapeutic principles
Patient subgroup Treatment
All patients Avoidance of known trigger factors
Patients at risk for Emergency kit
anaphylactoid reactions Epinephrine (eg, Epi-Pen Im)
H1 antihistamines (eg, diphendydramine)
Glucocorticoids (eg, prednisolone)
Skin lesions of cutaneous Encourage sunlight exposure in asymptomatic cases;
mastocytosis UVA1 or PUVA in selected cases
Topical glucocorticoids in highly symptomatic
mastocytomas
Surgical excision in highly symptomatic
mastocytomas
Bullous lesions of cutaneous Local care
pediatric mastocytosis Prevention of infection
Glucocorticoids topically, intralesionally or orally as
a bolus
Mast cell mediator release H1 antihistamines
syndrome associated with H2 antihistamines
cutaneous mastocytosis Cromolyn sodium
UVA1 or PUVA for recalcitrant disease
Flushing and hypotensive Trial with aspirin or other NSAID (beware of
episodes intolerant patients, side effects of high doses)
Gastrointestinal disease
Peptic ulcer disease H2 antihistamines, omeprazole
Abdominal cramping H2 antihistamines, cromolyn sodium, leukotriene
antagonistsa
Diarrhea Cromolyn sodium, omeprazole, anticholinergics,
leukotriene antagonistsa
Malabsorption Cromolyn sodium, glucocorticoids
Osteoporosis Calcium supplementation, vitamin D
Biphosphonates
Estrogen for postmenopausal women
Testosterone for men with low testosterone levels
IFN-a2b for severe osteoporosis (eg, bone fractures)
Mastocytosis with SM-AHNMD Treatment of SM-AHNMD
IFN-a2b
Bone marrow transplantation with appropriate
HLA match
Aggressive mastocytosis, mast cell leukemia, IFN-a2b
mast cell sarcoma Splenectomy (when hypersplenism is present)
Bone marrow transplantation with appropriate
HLA match
Polychemotherapy
Future research treatments (eg, imatinib in patients
with Asp816Val mutations)
a
Leukotrienes do not have a proven efficacy but may be used for short-term trials on theoreti-
cal grounds.
Box 3. Triggers for mast cell mediator release

Mechanical irritation of the skin (rubbing, scratching, friction)
Heat (eg, host shower), cold, sudden change of temperature
(jump in cold water)
Physical exercise
Insect stings (bee and wasp stings; possibly mosquito stings,
ant stings, snake bites)
Drugs (radiocontrast media, codeine, drugs used in general
anesthesia, morphine, dextrometorphan, aspirin, meperidin
and other analgesics)
Infections
Alcohol
Food intake (often not associated to specific foods)
Stress
Allergic and pseudo-allergic reactions, when present in patients with masto-

cytosis, may be more severe because of an enlarged effector cell population.
Severe anaphylactoid reactions to aspirin have been reported and may occur in
patients with nonsteroidal anti-inflammatory drug (NSAID) idiosyncrasy
[12,146,147].
The most prominent trigger of systemic reactions is Hymenoptera venom
[148,149]. Severe and fatal reactions are described in patients with mastocytosis
[64,150,151]. In some patients with UP and Hymenoptera venom anaphylaxis, no
sensitization can be detected by means of skin tests and determination of specific
IgE antibodies [152]. Venom immunotherapy has been reported to be beneficial
in such patients [152]. Immunotherapy is associated with a risk for severe adverse
effects in patients with mastocytosis [67,148].
Patients with mastocytosis are considered to be at risk when they are admin-
istered iodinated contrast media, because of the mast cell degranulating properties
of these substances in vitro [153,154].
Severe anaphylactoid reactions and coagulopathy have been reported in patients
with mastocytosis while undergoing general anesthesia [155] or following upper
gastrointestinal endoscopy [156,157]. Treatment is similar to that for systemic
anaphylaxis in other patients and includes H1-antihistamines, glucocorticosteroids
(such as prednisolone), and epinephrine. Protocols aiming at the prevention of
these reactions employ premedication with H1- and H2-antihistamines (eg, diphen-
hydramine, cimetidine) and availability of means of resuscitation [158].
Other drugs reported to induce symptoms of mast cell release include opioids,
such as morphine and codeine [43]; dextromethorphan [159]; and polymyxin B
(through intramuscular injection) [43]. Other substances, such as dextran,
gelatine, and adrenergic and cholinergic receptor antagonists, induce mast cell
mediator release in vitro, although the clinical significance for patients with
mastocytosis is less clear.
It generally is accepted that patients with mastocytosis are at a risk for ana-
phylactoid reactions. The frequency of these reactions in patients with mastocy-
tosis is unknown. Adults with systemic involvement and children with extensive
bullous reactions seem to be at risk [160]; however, anaphylactoid reactions
may occur without systemic involvement [161]. Attacks after flu-like illnesses
and in the absence of identified trigger factors have been described [62,63,160,
162 – 164]. The author recommends that all adults and pediatric patients with
bullous lesions and with more severe involvement, especially patients with pre-
vious reactions, carry an emergency kit for self-medication that consists of an
antihistamine (eg, diphenhydramine), a corticosteroid (eg, prednisolone), and epi-
nephrine (eg, Epipen).
Several patients reported flushing and abdominal pain after intake of ethanol
[12,165]. Despite many patients with mastocytosis complain about gastrointes-
tinal symptoms after food intake [12]; in only a few cases, a food hypersensitivity
can be proved (K. Brockow, MD, unpublished data, 2002).
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, antihis-
tamines 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 non-
sedating H1 antihistamine with a sedating one to control severe pruritus. Hy-
droxizine was reported to be superior to ketotifen in controlling symptoms of
pediatric mastocytosis in a double-blinded, crossover study [78]. Tricyclic
antihistamines, such as doxepin, may be another option. An H2-receptor
antagonist (eg, cimetidine) may be added [167,168].
Gastric acid hypersecretion, peptic ulcer disease, and reflux esophagitis are
managed with H2-receptor blockers (eg, cimetidine) and proton-pump inhibitors
(eg, omeprazole). Cromolyn sodium is effective in some patients for controlling
diarrhea, abdominal pain, nausea, and vomiting [165,169,170]. Although the ab-
sorption of chromolyn is low, reduction of symptoms of cutaneous mastocytosis,
such as pruritus and whealing, has been reported in some studies [165,170]. High
dosages of up to 400 mg/d for children and 800 mg/d for adults should be given.
Anticholinergics are another option for controlling diarrhea, and leukotriene
inhibitors (eg, montelukast) may be tried. Systemic corticosteroids are used in
severe cases of malabsorption or ascites [166].
Acetylsalicylic acid and other NSAIDs decrease prostaglandin D2 production
and have been reported to be effective in a patient with systemic mastocytosis
and flushing episodes with hypotension that was not controlled by antihista-
mines and cromolyn sodium [163]. In another case report, the alleviation of
vomiting and dysphagia was described [171]. Caution must be taken to not
administer these drugs to patients with aspirin idiosyncrasy [171]. To decrease
prostaglandin synthesis, high serum salicylate levels, which may cause gastric
irritation, are needed [163].
Osteoporosis, if present in patients with mastocytosis, may be managed by
calcium and vitamin D supplementation and by use of biphosphonates [166].
Estrogen replacement may be considered in postmenopausal women, and testos-
terone supplementation may be used in men with low serum testosterone levels.
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 –178]. Fading of lesions is associated with a reduction of mast cell numbers
and in histamine and leukotriene levels [175]. Relapse occurs several weeks to
months after therapy is discontinued. Oral PUVA treatment has been beneficial in
patients with bullous diffuse cutaneous mastocytosis [179,180]. Topical PUVA
treatment has been reported to be less effectve than oral PUVA therapy [176,181]
but may be considered in patients with bullous mastocytomas. In patients with
TMEP, PUVA therapy was not effective [166]. In one study, a 585-nm flashlamp
pumped dye laser therapy reduced telangiectasias temporarily, although a
reduction in mast cell numbers was not achieved, and 70% of lesions reoccurred
after 14 months [182]. High-dose UVA1 therapy has been reported to relieve
pruritus and whealing in four patients with UP, paralleled by a decrease in urinary
histamine levels [173]. The benefits of ultraviolet therapy have to be weighed
against the potential of inducing cutaneous malignancies associated with long-
term ultraviolet radiation.
Application of topical steroids, such as intralesional injection of lesions with
triamcinolone acetate [183] or use of 0.05% betamethasone dipropionate under
occlusive dressing for 8 hr/d over an 8- to 12-week period, has been effective in
fading the lesions of UP [183,184] and in reducing the induration of a mas-
tocytoma [185]. Mast cell numbers decrease parallel to the resolution of skin
lesions [183]. After discontinuation of therapy, lesions recur. Cutaneous atrophy
and adrenal suppression are adverse effects of this approach. The author uses
topical steroids only in localized lesions, such as in bullous mastocytomas as
an alternative to topical PUVA therapy [186]. A short bolus therapy with oral
corticosteroids may be given to stop bullous eruptions of UP.
Therapy for severe forms of mastocytosis

Patients with SM-AHNMD are treated appropriately for the associated
hematologic disease. Interferon a (IFN-a) 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-a therapy lead to a partial or
minor response in patients treated over a period of more than 6 months, whereas
bone marrow infiltration remained unchanged [188]. IFN-a therapy should be
considered only in patients with aggressive mastocytosis, severe osteoporosis (eg,
vertebaral collapse), or recalcitrant symptoms of disease associated with high
mast-cell load.
Different chemotherapeutic regimens have been used to treat aggressive
mastocytosis and SM-AHNMD, as reviewed elsewhere [166]. Chemotherapy
has not been shown to produce long-lasting remission, or to prolong survival in
patients with mast cell leukemia. Chemotherapy is not indicated in indolent
mastocytosis, as it may lead to bone marrow suppression without improving the
symptoms of mastocytosis. Promising results on the use of the purine nucleoside
analog cladribine (2-chlorodeoxyadenosine) have been published: Chemotherapy
with cladribine in a patient with systemic mastocytosis lead to a complete
resolution of UP and symptoms of the disease and to a marked reduction of mast
cell infiltration in the bone marrow [189]. In another case with SM-AHNMD,
cladribine use induced clinical remission of the associated lymphoplasmacytic
lymphoma and was associated with normalization of immunophenotypical
changes in bone marrow mast cells [190]. In a pilot study in 10 patients with
systemic mastocytosis treated with cladribine, all patients responded with reduced
signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine
metabolite excretion), though none achieved a complete remission [191].
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 expressed by neoplastic
mast cells on their surface. Humanized anti –IL-2 receptor (CD25) antibodies
daclizumab have been administered successfully for the prevention of graft
rejection and in patients with inflammatory diseases [195], but experience in
mastocytosis is lacking.
Promising strategies may arise from an increased understanding about the
cause of mastocytosis and the signaling pathways initiated by kit activation.
Low-molecular-weight inhibitors of thyroxine kinase activity have become
available. The tyrosine kinase inhibitor Imatinib mesylate (STI571) inhibits the
bcr-abl oncogene product and KIT [196]. Imatinib mesylate is also effective in a
subset of patients with eosinophilic disorders and systemic mastocytosis carrying
a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 and
platelet-derived growth factor receptor a (PDGFRa) genes [197]. The author
analyzed the effect of this substance on the proliferation of neoplastic mast cells
[33,198]. A neoplastic mast cell line and mast cells from patients with systemic
mastocytosis with a mutation at codon 816 (the activation loop of KIT) were
relatively resistant to this substance and were not inhibited preferentially among
bone marrow cells, whereas proliferation of wild-type mast cells and prolifera-
tion of mast cells with a Val560Gly mutation in KIT were reduced by 100% and
73%, respectively [33]. Resistance patterns were similar to those observed in
chronic myeloic leukemia cells that carried a point mutation in the activation
loop of bcr-abl [199]. This field of research is ripe for new substances that pos-
sibly target cells expressing mutated KIT [200,201].
Acknowledgment
I want to acknowledge Dean D. Metcalfe and Cem Akin, who introduced me
to the field of mastocytosis.
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Urtikaria Pigmen

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Immunol Allergy Clin N Am

24 (2004) 287 – 316

In the first report of urticaria pigmentosa (UP) published in 1869, Nettleship

E-mail address: knut.brockow@lrz.tum.de

Clinical presentation of urticaria pigmentosa

Typical urticaria pigmentosa

Box 1. Classification of cutaneous forms of mastocytosis

Data from Valent P, Horny HP, Escribano L, et al. Diagnostic cri-

Other forms of urticaria pigmentosa

Other cutaneous manifestations of mastocytosis

in a prematurely aged or elephant-like appearance [47]. Pedunculated papules,

Mast cell mediator release syndrome

Classification of systemic involvement

Box 2. Classification of mastocytosis

Adapted from Valent P, Horny HP, Escribano L, et al. Diagnostic

Approximately 10% of patients with systemic mastocytosis develop systemic

by an improvement of mast cell – mediated symptoms. Even in these patients,

Mast cell growth factors

KIT and c-kit mutations

relevance is less clear [111,112,118,119]. Overall, mutations in c-kit seem to be

Chromosome abnormalities in mastocytosis

Establishment of the diagnosis

infiltrated lesions, such as in mastocytomas, nodular variants, or diffuse cutane-

Surrogate markers for disease severity

only 50% of patients with an associated hematologic disorder or aggressive

megaly, or lymphadenopathy in patients with extensive disease. Hepatic and

Avoidance of trigger factors

Box 3. Triggers for mast cell mediator release

Allergic and pseudo-allergic reactions, when present in patients with masto-

Mast cell mediator – induced symptoms

Antiproliferative therapy of skin lesions

Therapy for severe forms of mastocytosis

cutaneous lesions) and other features of systemic disease (anemia, osteoporosis,

Future therapeutic approaches

nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J

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