Leukemia Research 25 (2001) 519– 528

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Clinical and histopathological aspects of cutaneous mastocytosis

Klaus Wolff *, Michael Komar, Peter Petzelbauer
Department of Dermatology, Di6ision of General Dermatology, Uni6ersity of Vienna, Vienna General Hospital, Waehringer Guertel 18 -20,
1090 Vienna, Austria
Received 15 November 2000; accepted 5 February 2001

Abstract

The organ most frequently involved in mastocytosis is the skin. Cutaneous mastocytosis (CM) is classified according to clinical
presentation and is further defined by onset of disease. CM tends to appear early in life but adult onset CM occurs. CM in
children has a low incidence of systemic involvement whereas systemic mastocytosis occurs in \ 25% of CM in adults. Almost
all patients with CM belong into the indolent category of the consensus revised classification (Valent et al., Diagnostic criteria and
classification of mastocytosis: a consensus proposal. Leukemia Research 2001;25:603– 625.) and thus have a good prognosis. CM
of infancy and childhood frequently involutes spontaneously, CM of adults does not. The prevalence of the disease is unknown
and familiar occurrence is very rare. © 2001 Elsevier Science Ltd. All rights reserved.

Keywords: Mastocytosis; Urticaria pigmentosa; Mastocytoma

1. Introduction ‘urticaria pigmentosa’ (UP) for these lesions [3]. Mast

The skin is the organ most frequently involved in
mastocytosis. Cutaneous mastocytosis (CM) is classified
according to clinical presentation and is further defined
by onset of disease. CM tends to appear early in life but
adult onset occurs. Almost all patient with CM belong
into the indolent category of the consensus revised
classification [1] and thus have a relatively good prog-
nosis. The prevalence of the disease is unknown and
familiar occurrence is very rare. CM is often accompa-
nied by symptoms of mast cell activation and mast
cell-derived mediator release including flushing, pru-
ritus, urtication, abdominal pain, nausea, vomiting,
diarrhea, bone pain, vascular instability, headache and
neuropsychiatric problems. Historically, CM was de-
scribed by Nettleship and Tay in 1869 [2] as a symmet-
rical maculopapular eruption with urtication of lesions
after rubbing. In 1878 Sangster suggested the term
Abbre6iations: CM, cutaneous mastocytosis; SM, systemic mastocy-
tosis; UP, urticaria pigmentosa; TMEP, teleangiectasia macularis
eruptiva perstans.
* Corresponding author. Tel.: + 43-1-4055242; fax: +43-1-
4081928.
E-mail address: klaus.wolff@akh-wien.ac.at (K. Wolff).
cells were recognized as the cellular substrate of skin
lesions by Unna in 1887 [4] and the term mastocytosis
was first used by Sézary et al. in 1936 [5]. It was not
until 1933 that Touraine [6] noted involvement of the
spleen in a patient with UP. Multiple organ involve-
ment in a patient with CM was described by Ellis in an
autopsied case in 1949 [7]. Bony changes in patients
with UP were noted by Sagher in 1957 [8] and a
malignant form of systemic mastocytosis (SM) present-
ing as leukemia was described in 1957 by Efrati et al.
[9].
2. Patients and methods
We reviewed the records of all patients (n= 67) with
a diagnosis of CM consecutively seen from 1995 –2000
in the Department of Dermatology, University of Vi-
enna, for consultation and continuing care. Patients
were evaluated for onset of disease, type of cutaneous
involvement as assessed by clinical description and
reevaluation of clinical photographs (available for all
patients), presence or absence of systemic symptoms
(flushing, syncope, abdominal pain, nausea, vomiting,
diarrhea, bone pain, headaches) and systemic involve-
ment. Criteria for systemic mastocytosis (SM) were

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PII: S0145-2126(01)00044-3
520 K. Wolff et al. / Leukemia Research 25 (2001) 519–528

evidence of focal infiltrates of mast cells in bone marrow
specimens and/or evidence of other organ involvement
and/or \20 mg/ml serum tryptase levels. Bone marrow
and serum tryptase level examinations were performed
by Department of Medicine I, Division of Hematology
and Hemostaseology, University of Vienna. Histological
slides were available from 45 patients and were analyzed
in a blinded fashion. Histological infiltration patterns
were correlated with clinical manifestations. In addition,
records, clinical photographs and histological slides of
patients with rare forms of CM, not contained in this
series of 67 patients, were retrieved from the hospital files
and evaluated along the same criteria. These were three
cases with diffuse CM and four patients with teleangiec-
tasia macularis eruptiva perstans (TMEP).
3. Results and discussion
3.1. Clinical manifestations
CM manifests as nodular CM with solitary or multiple
lesions, as maculopapular CM with lesions occurring in
generalized and random distribution and as diffuse CM
with diffuse involvement of almost the entire skin.
Bullous lesions can occur in all forms of CM, most
frequently in nodular and diffuse CM, and are related to
the lesional mast cell load in CM. Bullous skin therefore
does not represent a specific subset of the CM pheno-
type.
3.2. Nodular cutaneous mastocytosis
Nodular CM may be present at birth but most lesions
appear within the first 3 months of life [10,11]. These
lesions, also called mastocytomas, are either solitary or
very few in number and present as plaques or nodules,
larger than 1 cm in diameter (Fig. 1a, b). Multiple
nodular lesions are very rare [12]. They are usually
located on the extremities, but may also occur in the
face, scalp and trunk but not on the palms and soles.
They have a brownish or orange– yellow color (Fig. 1a),
are usually sharply defined and when rubbed show the
Darier’s sign consisting of urtication and an axon flare
(Fig. 1b). Nodular CM may become bullous, either
spontaneously or after rubbing (Fig. 1f). They have not
been reported to be associated with systemic involve-
ment and in none of our patients systemic symptoms of
mast cell mediator release occurred. However, flushing
associated with nodular CM has been described [13].
Nodular CM are a rare manifestation of CM; in our
series of 67 consecutive patients with CM seen over the
past 5 years we found nodular CM in nine patients
(13.43%; Fig. 2). All were infants; solitary lesions were
present in six patients, up to three lesions were seen in
three patients. Nodular CM usually involutes sponta-
neously before puberty, but persistence of lesions has
been described [11,12].
3.3. Maculopapular cutaneous mastocytosis
This form of cutaneous involvement is the most
common manifestation of CM. In our series, maculo-
papular CM was present in 86.5% (Fig. 2). It presents as
a generalized eruption of macules, papules and plaques
that occur in random distribution but may also form
clusters, usually on the trunk. All regions of the body
including scalp and mucous membranes may be in-
volved, but the palms and soles are often spared. Pru-
ritus, dermographism and Darier’s sign are additional
features of these eruptions. Darier’s sign is pathog-
nomonic for CM, when it occurs in lesions of CM.
Clinically three subsets are recognized:
1. The papular/plaque variant of CM consists of slightly
tan or orange to yellowish papules and plaques up to
1 cm in diameter (Fig. 1c, d). Clustered lesions
coalesce and form larger plaques (Fig. 1d) and may
have a cobblestone-like surface. This type of CM,
originally described as xanthelasmoidea by Tilbury
Fox in 1875 [14], usually occurs in infancy, often
within 1 or 2 months after birth. It has a 50% tendency
for spontaneous involution before puberty [10,15].
Such lesions rarely occur in adults [16]. Lesions
involve the trunk (Fig. 1c, d), extremities but also the
face and scalp and are characterized by a brisk
Darier’s sign with erythema, urtication and blister
formation with subsequent crusting. In the case of
only a few large plaques, a sharp line of distinction
from multiple mastocytomas cannot be drawn.
2. Urticaria pigmentosa (UP) consists of small macules
and papules of a deep-brown color (Fig. 3b, d). UP
lesions usually appear in large numbers, disseminated
over the entire body (Fig. 3a, c) but spare the face and
scalp, palms and soles. UP is a misnomer as it neither
represents urticaria nor is a pigmentary disorder and
it remains to be clarified why UP features heavy

Fig. 1. Clinical presentations of CM (I): (a) Nodular mastocytosis. A solitary, flat nodule, irregularly but sharply defined of tan color and
cobblestone-like surface in a 6 months old infant. This is a classical mastocytoma. When traumatized or rubbed it showed urtication and even
blister formation; (b) Three flat, yellowish to tan nodules on the scalp, neck and back of a 3-months-old infant. Note Darier’s sign (urtication
and axon flare) on the lesion on the back; (c) Papular plaque type CM. Multiple, coalescing yellowish to tan plaques involving the entire trunk;
(d) Larger magnification of papular/plaque type lesions that are very irregular but sharply defined. Note difference of clinical presentation to UP
lesions shown in Fig. 3b; (e) Diffuse CM. The skin of this infant is thickened and fiery red. Note blanching where skin is being stretched; (f)
Bullous reaction in two adjacent mastocytomas that have been vigorously rubbed. When punctured the little blisters will drain a serous fluid and
there will be crusting.
K. Wolff et al. / Leukemia Research 25 (2001) 519–528 521

Fig. 1.
522 K. Wolff et al. / Leukemia Research 25 (2001) 519–528
Fig. 2. Incidence of different clinical subtypes of CM in the present series. Among 67 consecutive cases seen in a 5 year period nodular CM
(mastocytomas) were seen in 13.43% of cases whereas the majority (86.57%) had maculopapular CM.
pigmentation of lesions (Fig. 3b, d) and the papular/
plaque variety does not (Fig. 1c, d). UP occurs later
in childhood and is the classical manifestation of
CM after puberty and in adulthood [12]. Whereas
the papular/plaque type shows a 50% tendency for
spontaneous involution before puberty, UP usually
persists into adulthood but lesions tend to become
more macular, and smaller as patients get older.
Adult onset maculopapular CM is practically
always of the UP type [12] and may manifest
either as a discrete or dense generalized eruption
consisting of small (2– 4 mm) macules and papules
of dark-brownish color (Fig. 3c, d), again in-
volving mostly the trunk and the extremities. A
Darier’s sign is not as easily elicited as in the
papular plaque variety of maculopapular CM, but
systemic symptoms such as flushing, diarrhea,
wheezing or syncopes occurred in 25% of our series.
Adult onset maculopapular CM has a high associa-
tion with systemic involvement (see below) and
there is no tendency for spontaneous resolution [12].
3. Macular teleangiectatic subset. This has been de-
scribed as teleangiectasia macularis eruptiva per-
stans (TMEP) [17] and is a very rare form of
maculopapular CM occurring exclusively in adults.
In our series of 67 consecutive patients none had
TMEP. The rash consists of generalized red to
brown teleangiectatic macules, 2– 4 mm in diameter
and are irregularly defined (Fig. 3e, f). Usually
non-pruritic, the lesions exhibit a Darier’s sign only
when vigorously rubbed and blistering does not
occur. The coexistence with lesions of UP type
maculopapular CM has been described [18]. In our
opinion TMEP is nothing but a macular form of
maculopapular CM. Although TMEP was consid-
ered to be a purely cutaneous form of mastocytosis,
one of us (KW) has observed four cases of TMEP
over a time span of more than three decades and all
had systemic involvement (bone marrow infiltration,
abnormal skeletal radiographs, splenomegaly and
gastrointestinal involvement).
3.4. Diffuse cutaneous mastocytosis
This is an extremely rare form of CM that usually
presents as erythroderma involving almost the entire
skin [19,20] (Fig. 1e). Diffuse CM was not present in
our series of 67 consecutive patients presented here.
One of us (KW) has observed only three patients with
this condition over a time span of more than three
decades. The skin may be just red (Fig. 1e) or have a
red to yellow color. One observes diffuse edema and
thickening with a doughy consistency. Darier’s sign is
pronounced and often associated with hemorrhage and
blister formation. Blisters may be widespread [20]
present at birth and may be the first presentation in an
infant who develops diffuse CM later [21]. Diffuse CM
exclusively presents in infancy and usually resolves
spontaneously before the third and fifth year. Due to
the widespread and heavy mast cell load in the skin
these children have flushing, hypotension, shock and
may have diarrhea and gastrointestinal bleeding. Little
is known about the incidence of systemic involvement
and none was present in the three patients observed by
one of us (KW). In one patient followed over a period
of 22 years no involvement of internal organs was
noted [22].
3.5. Course and relationship of cutaneous mastocytosis
to systemic mastocytosis
The onset of CM occurs between birth and 2 years of
age in roughly 50% of patients, in another 10% of
patients until the age of 15 [23]. In the series presented
here all cases with CM of infancy (6%) and CM of
childhood (48%) (Fig. 4) had an onset before the age of
 K. Wolff et al. / Leukemia Research 25 (2001) 519–528 523

Fig. 3. Clinical presentation of CM (II): (a) Maculopapular CM, urticaria pigmentosa (UP) type of childhood. Generalized discrete, brown
papules involving mainly the trunk. Note difference of clinical appearance as compared to papular/plaque type of CM shown in Fig. 1c); (b)
Larger magnification of UP lesions revealing the dark-brown color. One lesion appears slightly more elevated thatn the others and is surrounded
by an erythematous halo (axon flare) after having been rubbed (Darier’s sign); (c – d) Maculopapular CM, UP type of adulthood. Note that lesions
are smaller, flatter and more closely set than in infantile UP (shown in a and b); (e) Teleangiectasia macularis eruptiva perstans type of
maculopapular CM. Lesions are strictly macular (i.e. not elevated), reddish-brown and as shown in the higher magnification; (f) Are ill-defined
and exhibit fine teleangiectasias.
524 K. Wolff et al. / Leukemia Research 25 (2001) 519–528

2 and this is in accord with the data from the National
Institutes of Health [24]. Infantile CM has a high
tendency for spontaneous involution and the general
rule of thumb indicates that the earlier onset the greater
is the chance of spontaneous resolution [13]. Most
nodular CM have regressed by the time of puberty and
this was also the case for most cases of diffuse CM who
thus have an excellent prognosis [10]. With diffuse CM
this holds true only if there is no catastrophic episode
of systemic vascular reaction such as hypotension,
shock or gastrointestinal hemorrhage [25]. Maculo-
papular CM of infancy and childhood has a 50%
chance of spontaneous involution [24] and this particu-
larly applies to the papular/plaque subset. Fifty percent
go on to evolve into the UP type of maculopapular
CM. Adult onset maculopapular CM practically never
resolves completely.
SM is not found (and also not looked for) in most
cases of CM of infancy and childhood [12]. It has been
reported, however, that infants with diffuse CM and
bullae as the initial symptom may have systemic disease
[26]. None of our infants and children with bullous
lesions had systemic disease. In adults, the percentages
of CM with systemic involvement vary considerably
between different series [10,27]. It should be noted,
however, that in the older literature assessments of
systemic involvement were less subtle than is possible
today and this definitely requires scrutiny in prospective
studies. In our own series of 31 consecutively observed
adults with CM (100% UP type) SM was found in 29%

Fig. 4. Age distribution in the present series. Age is defined as age at diagnosis, not age of onset. Slightly over 50% were infants or children.

Fig. 5. Systemic mastocytosis (SM) in adults ( B 16 years) with CM in the present series. Roughly 30% had SM, in 45% SM was excluded but
25% were not assessed for SM either because there was absence of systemic symptoms or patients did not consent to a systemic work-up. All
patients ( = 100%) had CM of the UP type.
 K. Wolff et al. / Leukemia Research 25 (2001) 519–528
Fig. 6. Systemic mastocytosis (SM) in all ages of the present series. Lumping of CM of infancy and childhood with CM of adulthood reveals a
low incidence of SM (13.43%), mainly because systemic work-up was not considered necessary or was refused in 53.73% of patients.
and excluded in 45% (Fig. 5). However, 26% of patients
were not assessed for SM for various reasons. Lumping
childhood and adulthood CM we found systemic in-
volvement in only 13.5% (Fig. 6), but due to the high
proportion of children in this series about 50% of
patients were not assessed for SM.
Cutaneous lesions are present in practically all cases
of indolent SM [28]. They may also be seen in a
majority of cases with smouldering SM but are found
only in a minority of those with aggressive mastocytosis
and almost invariably are absent in mast cell leukemia.
All patients in our series with SM had cutaneous lesions
of the UP type. This corresponds with the data of
Horan and Austen [28] who observed 17 patients with
UP among 21 patients with SM.
3.6. Histopathology of cutaneous mastocytosis
The histopathological substrate of all lesions of CM
is an infiltrate by mast cells that can be recognized by
the experienced dermatopathologist in H&E sections
but is better visualized by the use of basic dyes such as
Giemsa, toluidin blue, Astra blue (Fig. 7a) or by histo-
chemical techniques to reveal chloroacetate esterase or
immunocytochemical stains revealing tryptase and chy-
mase (Fig. 7b). By electron microscopy cutaneous mast
cells usually exhibit scroll-poor granules [29] and this is
also true for mast cells in CM [30]. Mast cells in CM
are spindle shaped or spherical and are both tryptase-
and chymase-positive [31] (Fig. 7b). Four patterns of
dermal mast cell infiltrates can be recognized: (1)
perivascular in the papillary body and upper dermis
(Fig. 7a, c); (2) sheet-like within the papillary body and
upper reticular dermis (Fig. 7d); (3) interstitial (Fig. 7e);
(4) nodular (Fig. 7f).
There is only a partial correlation of histological
patterns (Fig. 7c– f) and the clinical appearance of
525
lesions [32]. Differences between the clinical manifesta-
tions of CM are thus mainly quantitative (density of
mast cell infiltrate) in nature. The perivascular pattern
(Fig. 7a, c) is found in small, flat, macular forms of
maculopapular CM, and has been present in one pa-
tient with diffuse CM of our series. A perivascular
pattern may also be found in the TMEP variety of CM,
however, it should be noted that the increase in num-
bers of mast cells may be very subtle in these patients.
In two patients seen in our clinic the preeminent histo-
pathologic finding consisted in a proliferation of blood
vessels within the papillary dermis with very few mast
cells intermingled with eosinophils in a perivascular and
interstitial position. The sheet-like distribution pattern
(Fig. 7d) can be found in all forms of maculopapular
CM (even in flat lesions) and in our series in one case
of diffuse CM. The interstitial pattern (Fig. 7e) is found
in maculopapular CM, whereby the clinical picture of
maculopapular CM does not provide a clue whether a
particular patient will have the ‘sheet’ or ‘interstitial’ or
‘nodular’ type of infiltration. The nodular infiltration
pattern (Fig. 7f) is found nodular CM, in larger lesions
of the papular/plaque or of the UP type of maculo-
papular CM. Examination of skin biopsies thus only
permits a diagnosis of CM and not of individual clini-
cal patterns. It also does not help to predict the risk of
systemic involvement [33] but it has been shown by
morphometric techniques and electronmicroscopy that
lesional mast cells from adults with SM had a larger
mean cytoplasmic area, nuclear size and granular di-
ameter than mast cells from normal individuals [30].
Mast cells have been found to be increased in numbers
in normal skin between the lesions of maculopapular
CM [34]. In one study, lesional skin specimens of UP
contained roughly 6009 280 mast cells per square mil-
limeter as compared to 409 4 in normal skin [34]. With
regard to patients with a low mast cell load within
526 K. Wolff et al. / Leukemia Research 25 (2001) 519–528

lesions, there exists no reliable numerical cut off point within the limits of normal skin or whether it is in-
that allows a decision whether a mast cell count is creased. Difficulties therefore arise in purely macular

Fig. 7.
 K. Wolff et al. / Leukemia Research 25 (2001) 519–528 527

forms of maculopapular CM, in particular in the
TMEP variety, where mast cell numbers may be rela-
tively low and comparable to those found in other
inflammatory diseases such as urticaria or atopic der-
matitis. The decisive criterion in such cases that may
help in diagnosis is the fact that in non-CM inflamma-
tory conditions there are also lymphocytes and a host
of other inflammatory cells that are usually absent in
CM lesions. Eosinophils, however, may be increased in
number in CM lesions.
4. Comment
Several attempts have been made to predict the
course of the cutaneous disease and the occurrence of
systemic involvement. We have shown that the age of
onset of lesions and the clinical appearance gives some
clues to allow a limited estimation of the of patient’s
prognosis. The histological pattern of mast cell infiltra-
tion does not allow to predict the course of the disease.
Measurements of tryptase levels or of soluble stem cell
factor receptor (c-kit, CD117) and IL-2 receptor alpha
chain (CD25) levels in the plasma of patients with
mastocytosis give some clue to a relationship between
disease severity and bone marrow pathology [35,36],
but larger patient series have to be analyzed to deter-
mine the true value of these serologic markers. So far
this holds also true for somatic mutations found in
CM, particularly in the proto oncogen c-Kit. c-Kit is a
type III transmembrane tyrosine receptor with an extra-
cellular domain that binds to the mast cell growth
factor (also known as steel factor or stem cell growth
factor), which is responsible for growth, function and
survival of mast cells. It has thus been suggested that
c-Kit mutations may be important for CM. Indeed, in
some but not all CM patients somatic c-Kit mutations
have been identified [37,38]. C-Kit mutations may cause
constitutive activation of the receptor resulting in con-
stitutive signaling, but also in mutations causing a
dominant loss of function. Systemic involvement could
yet not be definitely correlated with a distinct c-Kit
mutation [37– 39]. It should be noted, however, that
SM so far has not been diagnosed as often as it should
because of lack of careful systemic work-up and bone
marrow examination. In this context we currently be-
lieved that c-Kit mutation will probably only be found
in SM and not in pure CM. Consequently the mutation
probably defines SM and if noted in CM (such as UP)
it probably indicates that the disease is not restricted to
the skin alone. Larger patient groups are required to
properly address this question.
Acknowledgements
This work was in part supported by a grant from the
Austrian Science Foundation P12240-MED. All au-
thors contributed equally to this effort and gave final
approval for the article.
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Fig. 7. Histopathology of CM: (a) Perivascular pattern. Mast cells are revealed by Astra blue stain and are seen to surround subepidermal
postcapillary venules (cuffing); (b) Immunocytochemical demonstration of tryptase in mast cells cuffing subepidermal vessels. (Courtesy of Dr
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