CME Article

Submitted: 29.6.2017 DOI: 10.1111/ddg.13418

Accepted: 14.11.2017
Conflict of interest
None.

Mastocytosis – pathogenesis, clinical

manifestation and treatment

Nicola Wagner 1, Summary

Petra Staubach2 The term mastocytosis designates a group of rare disorders characterized by typical skin
(1) Department of Dermatology, lesions, frequently associated episodes of anaphylaxis, and clinical symptoms related
University Medical Center, Erlangen, to the release of various mediators. Dermatologists/allergists are frequently the first to
Germany establish the diagnosis. The condition is based on clonal mast cell proliferation, usually
(2) Department of Dermatology, in the skin or bone marrow and only rarely in the gastrointestinal tract or other tissues.
University Medical Center, Mainz, In general, mastocytosis has a good prognosis in terms of life expectancy. Rare variants
Germany – including mast cell leukemia, aggressive mastocytosis, and the exceedingly rare mast
cell sarcoma – require cytoreductive therapy. In cases associated with hematological
Redaktion neoplasms, the prognosis depends on the underlying hematologic disorder.
Prof. Dr. D. Nashan, Dortmund

Introduction
Mastocytosis is a heterogeneous condition characterized by clonal proliferation
and accumulation of mast cells in various tissues. In particular, these include the
skin and/or bone marrow; involvement of the gastrointestinal tract, liver, spleen,
and lymph nodes is more uncommon [1–3]. The World Health Organization
(WHO) classification divides the clinical manifestations of mastocytosis into cuta-
neous and systemic subtypes as well as mast cell sarcoma (Table 1) [4].
The characteristic skin lesions of cutaneous mastocytosis were fi rst described
by Nettleship and Tay in 1869 [5]. In 1878, Sangster coined the term urticaria
pigmentosa [6 ]. One year later, Paul Ehrlich discovered the mast cell, and in 1887,

Table 1 WHO classification of mastocytosis.

WHO classification of mastocytosis 2016 (4)

Cutaneous mastocytosis (CM)
– Maculopapular CM (MPCM) (formerly urticaria pigmentosa)
– Diffuse CM (DCM)
– Cutaneous mastocytoma
Systemic mastocytosis (SM)
– Indolent SM (ISM)
– Smoldering SM (SSM)
– SM with associated hematologic neoplasm (AHN; syn. SM-AHNMD*)
– Aggressive SM (ASM)
– Mast cell leukemia (MCL)
Mast cell sarcoma (MCS)
*systemic mastocytosis associated with clonal hematologic, non-mast-cell
lineage disease.

42 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
CME Article
Disorders designated as mastocytosis
are characterized by clonal proliferation
of mast cells in various organs. A muta-
tion in the KIT gene (usually D816V),
which codes for the KIT (CD117) recep-
tor of the stem cell factor (SCF), results
in SCF-independent proliferation and
activation of mast cells.
Mast cells are ubiquitous throughout
the body. Via various membrane-bound
receptors, they are involved in inflam-
mation, tumor defense, angiogenesis,
as well as other processes.
Mastocytosis is rare. Approximately
65 % of patients are children; 35 % are
adults. There is no gender predilection.
Almost always is the condition caused
by spontaneous mutations.
© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
Unna described the correlation between urticaria pigmentosa lesions and an in-
creased number of dermal mast cells [7 ].
Mast cells migrate – in the form of immature CD-34-positive precursor cells –
from the bone barrow via the blood stream into various tissues, where they undergo
maturation [8]. Binding of the stem cell factor (SCF) to the SCF receptor KIT (CD117)
regulates mast cell proliferation, differentiation, and survival. In patients with
mastocytosis, a somatic mutation of the KIT gene – usually a point mutation in codon
816 ( = KITD816V) – results in autocrine dysregulation (gain of function mutation) and
clonal proliferation of mast cells [9]. Only very rarely do adult mastocytosis patients
exhibit other mutations. The clinical symptoms associated with mast cell disorders are
attributable to the release of histamine and other mast cell mediators such as prost-
aglandins, leukotrienes, and cytokines. Disease course and prognosis depend on the
clinical manifestation, age of onset, and potentially associated comorbidities [10].
Mast cell function
Mast cells are ubiquitous throughout the body, with increased numbers found
around blood vessels and nerves. Their maturation and function depend on their
respective environment. Mast cell activation can be mediated through various
membrane-bound receptors. Apart from IgE-mediated, allergen-dependent ac-
tivation, mast cells are also involved in the defense against microorganisms via
the latter’s pathogen-associated molecular patterns (PAMPs). Binding of PAMPs
to membrane-bound pattern recognition receptors (PRR) – especially via toll-like
receptors, a PRR subgroup – results in the release of mediators and initiation of an
inflammatory response [11]. Other stimuli that trigger mast cell activation include
neuropeptides, cytokines, toxins, complement, growth factors, immune comple-
xes, certain drugs, and physical stimuli [12]. Mast cells are also involved in repair
mechanisms of tissue and bone, tumor defense, neuroimmunological interactions,
angiogenesis, adaptive immunity, and immune tolerance [11, 13].
Epidemiology
Mastocytosis is rare. While the annual incidence is thought to range between 5 and
10 new cases per 1 million population, the condition is likely more common [14]
as patients with only minimal clinical manifestations frequently go undiagnosed.
There has been a marked uptick in the number of reported cases in the USA and
Europe in the past 20 years because of improved diagnostic methods, greater awa-
reness at national and international conferences, and increased education of the
general public [2]. Roughly 65 % of patients are children; 35 % are adults. There is
no gender predilection [14]. Nearly all cases are caused by a spontaneous mutation;
familial mastocytosis disorders, usually with a dominant inheritance pattern, have
been described very rarely [15].
Clinical manifestations
Pediatric cutaneous mastocytosis
Mastocytoma
In childhood, cutaneous mastocytosis frequently occurs in the form of mastocyto-
ma, which presents as yellowish to red-brown, sharply demarcated plaques or no-
dules; lesions may be solitary or multiple and predominantly arise on the trunk.
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 CME Article

Measuring from 1–10 cm in diameter, they are already present at birth or usually
develop in the fi rst weeks of life. Initially, blistering is common, usually triggered
by mechanical stimuli or drugs such as codeine-containing anti-cough medications.
In general, pediatric mastocytoma lesions resolve by the time patients reach adole-
scence; they are not associated with systemic mast cell infi ltration (Figure 1) [16].

Maculopapular cutaneous mastocytosis

Other typical manifestations include red-brown macules. In children, maculopa-

pular cutaneous mastocytosis is divided into a monomorphic variant with small
macules and a polymorphic variant with large patches (> 1.5 cm) [17–19]. The
latter spreads across the entire body, frequently involves the head, and usually
manifests itself during the fi rst six months of life. Blistering may also occur in this
variant, usually in the fi rst three years of life. Likewise associated with a favorable
prognosis, this subtype very rarely shows systemic involvement. Regression prior
to adulthood is common (Figure 2).

Diffuse cutaneous mastocytosis

A rare variant characterized by distinct generalized yellowish-red thickening of

the skin, diffuse cutaneous mastocytosis develops in the fi rst weeks of life. Because

Figure 1 Solitary bullous mastocytoma of the abdominal wall.

44 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
CME Article
In childhood, cutaneous mastocytosis
usually presents as mastocytoma or a
maculopapular rash. The latter is di-
vided into a monomorphic form with
small macules and a polymorphic vari-
ant with large patches.
Prior to adolescence, pediatric
mastocytosis shows a high spontaneous
mutation rate.
In adulthood, patients usually exhibit
red-brown macules (5–10 mm in dia-
meter) that initially frequently develop
on the thighs. Darier's sign – pruritic
erythema and edema – can be elicited
by mechanical irritation.
© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
Figure 2 Polymorphic variant of maculopapular mastocytosis (large patches).
of the massive dermal mast cell infi ltration, the skin has a doughy and leathery
appearance (peau de chagrin) and is fi rm to palpation. Pronounced urticarial der-
mographism may be induced by mechanical stimulation; widespread blistering is
common. Apart from a few cases showing systemic involvement, this variant too is
marked by spontaneous resolution prior to adulthood.
Studies on the course of pediatric cutaneous mastocytosis show complete re-
mission in approximately 70 % of cases; substantial remission, in 20 %; and par-
tial remission in 10 % [20–22].
The incidence of bone marrow involvement in childhood can only be esti-
mated, given that invasive procedures are rarely employed and/or recommended.
In children, too, measurement of serum tryptase is used to assess total mast cell
burden. Elevated tryptase levels indicate extensive disease [19, 20]. Based on flow
cytometric detection of CD25 on mast cells, it is estimated that bone marrow in-
volvement occurs in up to 30 % of pediatric cases [20]. There are currently no
blood markers to predict the clinical course of mastocytosis in children.
Adult-onset cutaneous mastocytosis
In adulthood, 80 % of cutaneous mastocytosis patients typically exhibit small red-
brown maculopapular lesions, measuring 0.5–1 cm in diameter (formerly referred
to as urticaria pigmentosa). Frequently, these lesions initially develop on the thighs
and subsequently spread to the trunk and the proximal aspects of the extremities
(Figures 3, 4). There is also an “occult form” clinically marked by minimal skin
involvement with only isolated or barely visible macules. Whether the very rare
variant designated as telangiectasia macularis eruptiva perstans is a distinct entity
has been subject to controversy.
Adults with cutaneous mastocytosis usually experience bone marrow invol-
vement and/or infi ltration of other organs [23]. Adult-onset mastocytosis generally
does not resolve spontaneously.
Diagnostic sign
Darier’s sign (localized pruritic urticarial swelling) is a characteristic diagnostic
criterion in cutaneous mastocytosis elicited by mechanical irritation of the skin
lesions (Figure 5).
45
 CME Article

Figure 3 Red-brown macules in adult-onset mastocytosis.

Figure 4 Slightly brownish macules in a patient with cutaneous mastocytosis.

Systemic mastocytosis
The diagnosis of systemic mastocytosis requires the major criterion (multifocal
dense aggregates of 15 or more mast cells in bone marrow and/or one or more

46 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
CME Article
Criteria for systemic mastocytosis: 1) ag-
gregates of ≥ 15 mast cells in bone mar-
row and/or ≥ 1 other extracutaneous
organ(s) (major criterion), 2) 25 % of
mast cells in the infiltrate/blood exhibit
atypical/spindle-shaped morphology,
3) KIT mutation D816V in bone mar-
row, blood, or another extracutaneous
organ, 4) persistently elevated serum
tryptase levels > 20 ng/mL.
© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
Figure 5 Positive Darier’s sign on the right shoulder.
other extracutaneous organs) and at least one minor criterion to be fulfi lled. Al-
ternatively, if the major criterion is not met, three of the four minor criteria are
required: 1) 25 % of mast cells in the infi ltrate in extracutaneous organs or in
the blood exhibit atypical or spindle-shaped morphology, 2) evidence of a KIT
mutation in codon 816 in bone marrow, blood, or another extracutaneous tissue,
3) expression of CD2 and/or CD25 on mast cells in bone marrow, blood, or
another extracutaneous organ, and 4) persistently elevated serum tryptase levels
> 20 ng/mL (Table 2). According to the WHO classification, systemic mastocy-
tosis is divided into indolent systemic mastocytosis (ISM), smoldering systemic
mastocytosis, systemic mastocytosis with an associated hematologic neoplasm
(SM-AHN), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL),
and mast cell sarcoma (Table 1) [4]. Only 20–40 % of pediatric cases are associa-
ted with the typical KIT mutation [24].
Table 2 Criteria for systemic mastocytosis.
Major criteria
– Multifocal dense aggregates of 15 or more mast cells in bone marrow and/or
one or more other extracutaneous organs, confirmed by tryptase immunohis-
tochemistry or other special stains
Minor criteria
– 25 % of mast cells in the infiltrate in extracutaneous organs or in the blood
exhibit atypical or spindle-shaped morphology
– Evidence of a KIT mutation in codon 816 in bone marrow, blood, or another
extracutaneous tissue
– Co-expression of CD2 and/or CD25 on mast cells in bone marrow, blood, or
another extracutaneous organ
– Persistently elevated serum tryptase levels > 20 ng/mL (except in clonal mye-
loid disease)
The diagnosis of systemic mastocytosis requires 1) one major criterion and at least
one minor criterion or 2) 3 minor criteria.
47
 CME Article

By defi nition, individuals with indolent systemic mastocytosis experience no

Mast cell leukemia and aggressive syste-
mic mastocytosis require cytoreductive
therapy.
organ dysfunction as a result of the mast cell infiltration. More than 90 % of
systemic mastocytosis patients have this prognostically favorable variant, with no
impact on life expectancy [10, 23]. Indolent systemic mastocytosis can occur with
(about 80 %) or without characteristic skin lesions. The risk of developing mast
cell leukemia is 1–3 % [25–28]. Smoldering systemic mastocytosis is characterized
by more pronounced mast cell proliferation (bone marrow infi ltration > 30 %),
organomegaly, and tryptase levels > 200 ng/mL.
A rare subgroup of patients with systemic mastocytosis develop hematologic
abnormalities, such as eosinophil, monocyte, or blast cell proliferation, indicating
clonal hematologic, non-mast cell lineage disease (SM-AHN). In this context, mye-
loid neoplasms are more common than lymphatic neoplasms [9].
ASM is characterized by mastocytosis-related organ dysfunction. Possible cli-
nical signs include cytopenia, splenomegaly, cachexia with malabsorption, hepatic
dysfunction, and/or osteolysis. By contrast, mast cell leukemia is defi ned by the
presence of more than 20 % atypical mast cells in bone marrow smears. Given
their life-threatening nature, both ASM and mast cell leukemia require cytoreduc-
tive therapy.

Mast cell sarcoma

A very rare variant, mast cell sarcoma is
characterized by aggressive growth and
a poor prognosis.
First described by Horny et al. in 1986, mast cell sarcoma is an extremely rare,
aggressive variant of mastocytosis and associated with a poor prognosis [29]. The
solid tumors consist of malignant mast cells that have the potential to infi ltrate the
surrounding tissue and metastasize. While the highly atypical cells can histological-
ly mimic other tumors [30], mast cell tryptase levels, which are frequently markedly
elevated, point to the correct diagnosis. Symptoms related to mast cell mediators
such as fever, flushing, diarrhea, and tachycardia occur in only one-third of all
cases [31]. These tumors frequently occur de novo in bone, more rarely in the oro-
pharyngeal and gastrointestinal tract, the lymph nodes, skin, liver, spleen, or other
organs. Progression to mast cell leukemia is possible. The D816V mutation, which
is common in other forms of mastocytosis, is found in only 21 % of cases [31].

Symptoms
Clinical symptoms in mastocytosis patients are attributable to the release of va-
rious mast cell mediators (mediator-related symptoms). Apart from histamine,
tryptase, heparin, leukotrienes and prostaglandins, various cytokines (e.g., TNFα ,
interleukins [ILs]) are released.
Pediatric forms of cutaneous mastocytosis are usually characterized by loca-
lized symptoms such as erythema, pruritus, and edema. Flushing or generalized
urticarial symptoms are more uncommon. If present, they are frequently triggered
by friction; more rarely, by drugs or foods.
Having a marked impact on quality of life, pruritus is the most common
symptom in adults with cutaneous mastocytosis [32]. Apart from histamine and
tryptase, other cytokines – such as IL31 – involved in the pathogenesis of pruritus
have been discovered in recent years [33]. Interleukin 31 is primarily produced
by Th2 lymphocytes and is associated with pruritus in atopic dermatitis. Besides
mast cells, tumor cells (T- and B-cell lymphoma, myeloproliferative disorders) also
secrete IL31 [34].
Nonspecific symptoms such as gastrointestinal complaints (predominantly di-
arrhea, abdominal cramps, nausea, vomiting), tachycardia, hypotension, headache,

48 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
CME Article
Mastocytosis patients frequently show
a variety of mediator-related symptoms
and anaphylactic reactions, in particu-
lar due to insect venom and foods. Os-
teopenia, osteoporosis, or osteosclero-
sis occur in about one-third of patients.
© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
myalgia, bone pain, flushing, fatigue, and neurological symptoms are frequently
reported, irrespective of tryptase levels. Up to 30 % of patients with mastocytosis
experience osseous involvement in the form of osteopenia (with/without lytic lesi-
ons)/osteoporosis (with/without atraumatic fractures) as well as osteosclerosis with
increased density or isolated lytic lesions [35]. Bone-related cytokines – RANKL
(receptor activator of nuclear factor kappa-B ligand), OPG (osteoprotegerin), and
SOST (sclerostin) – are elevated in patients with ISM and can interfere with bone
remodeling [36, 37 ].
Mastocytosis patients show a high prevalence of anaphylactic reactions; the
initial diagnosis of mastocytosis is frequently made in this context [38–40]. At
49 %, the incidence of anaphylaxis is much higher in adults than in children (9 %).
While pediatric cases of anaphylaxis have only been observed in children with
extensive skin involvement or high tryptase levels [40, 41], adult systemic mastocy-
tosis patients without cutaneous involvement are more commonly affected (56 %)
than those with typical mastocytosis-related skin lesions [38, 40, 42, 43]. The main
triggers of anaphylaxis in adults include insect bites (19 %), foods (16 %), and
drugs (9 %) [38, 40].
Diagnosis
Basic diagnostic workup includes a thorough inspection of the entire skin, testing
for Darier’s sign, as well as palpation of lymph nodes, liver, and spleen. Skin lesions
clinically indicative of cutaneous mastocytosis should be biopsied. In children, a
biopsy may not be required if clinical fi ndings are unequivocal and if there is no
evidence of extensive disease [44].
Histological staining methods employed include Giemsa and toluidine blue
stain. CD117 and tryptase staining are used for immunohistochemical mast cell
detection [45].
Patients should be explicitly asked about immediate-type hypersensitivities.
In particular, reactions to insect bites, foods, drugs, and X-ray contrast agents
should be inquired about and adequately worked up (specific IgE, prick and/or
intradermal testing). A detailed history should be obtained as regards mediator-re-
lated symptoms such as pruritus, flushing, bone pain, fatigue, as well as cardiac,
gastrointestinal, and neurological symptoms.
Recommended baseline studies include routine blood tests (CBC with diffe-
rential, liver and renal function tests, calcium, alkaline phosphatase) and serum
tryptase levels. The latter correlate well with total mast cell burden [46, 47 ]. Mea-
surement of urine methylhistamine levels – an indirect marker of mast cell de-
granulation – is more complex and reserved for special cases [48]. The majority
of patients with systemic mastocytosis show tryptase levels > 20 ng/mL. Patients
with cutaneous mastocytosis and serum tryptase levels < 20 ng/mL usually also
demonstrate bone marrow involvement [23]. It is therefore recommended that
adult patients undergo bone marrow aspiration during the course of the disease
to determine the subtype of mastocytosis. Given that the extent of bone marrow
infi ltration associated with cutaneous mastocytosis may be minor, the diagnosis of
“cutaneous mastocytosis” is maintained even in the presence of two minor criteria.
The term mastocytosis in skin (MIS) is also used, provided the WHO criteria of
systemic mastocytosis are not met [44, 45]. Criteria that warrant bone marrow
aspiration in children include serum tryptase levels of > 100 ng/mL, pronounced
cytopenia, lymphopenia, and/or splenomegaly [46 ].
It has been shown that tryptase levels rise during anaphylaxis, reach a peak
after about two hours, and then return to baseline after about 24 hours. Following
49
 CME Article
Measurement of serum tryptase levels
is necessary to assess the extent of mast
cell proliferation, especially in adult
patients.
Mutation analysis usually shows the
D816V mutation. Mutation-induced
activation of the KIT receptor results in
aberrant CD2 and CD25 expression on
mast cells.
50 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
an anaphylactic episode, measurement of tryptase levels should therefore be repe-
ated after 48 hours [46, 47 ]. In patients with systemic mastocytosis, the D816V
mutation can also be detected in peripheral white blood cells but – as yet – not as
reliably as in bone marrow [49, 50].
Any changes in the differential blood count such as eosinophilia, monocytosis,
or detectable blast cells require workup for a potentially associated hematologic
neoplasm.
Other recommended studies include ECG, lymph node and abdominal ul-
trasound (possibly computed tomography), and bone densitometry. Any gastroin-
testinal symptoms (including acid reflux, sensation of pressure, peptic ulcer, ab-
dominal pain, diarrhea, bloody stools, positive guaiac test) are an indication for
gastroscopy and colonoscopy.
In particular, serum tryptase levels > 20 ng/mL or a sudden marked increase
therein should prompt a bone marrow aspiration. The presence of compact mast
cell aggregates in bone marrow is the major criterion for systemic mastocytosis.
Mutation-induced activation of the KIT receptor leads to aberrant expression of
CD25 and CD2, a minor criterion [51, 52].
Given that 20 % of cases show no CD2 expression on mast cells, CD25 ap-
pears to be more specific for the diagnosis of systemic mastocytosis [53]; in this
context, a sensitivity of 100 % has been found for CD25, with a specificity of 99 %
[53]. CD30 expression, too, was recently reported in mastocytosis patients. In ca-
ses that exhibit neither CD25/CD2 nor the activating KIT mutation, detection of
CD30 on mast cells can broaden the diagnosis of systemic mastocytosis. CD30 is
also expressed in the cytoplasm of mast cells in patients with aggressive mastocy-
tosis and mast cell leukemia [54]. The diagnosis of mastocytosis in bone marrow
can be challenging; inconclusive fi ndings should therefore warrant patient referral
to specialized centers (Table 3).
Treatment
Treatment of mastocytosis is guided by symptoms and tailored on an individual
basis.
Education about potential trigger factors in adults and children is imperative.
These include physical stimuli, emotional stress, spicy and hot foods, alcohol, bac-
terial/viral infections, and drugs. No prospective controlled studies exist on the
frequency and severity of anaphylactic reactions to drugs in mastocytosis patients.
There have been isolated reports of anaphylaxis after local anesthesia. However,
given the limited data, there is to date no evidence that mastocytosis patients are at
greater risk for local anesthetic-induced anaphylaxis than the general population.
The same applies to radiocontrast agents [39]; here, anaphylactic reactions tend to
be more common in adults than in children [40]. While some authors recommend
avoidance of histamine-releasing drugs such as morphine, opioids, and muscle re-
laxants, there is confl icting data in the literature with respect to drugs that are
tolerated and those that may act as potential triggers. The benefit of premedicati-
on with antihistamines and corticosteroids has not been proven but is usually re-
commended. Mastocytosis patients should inform their doctors/anesthesiologists
about their disease. Following an anaphylactic reaction, patients should be worked
up in the same way as other anaphylaxis patients [39]. In case of concomitant in-
sect venom hypersensitivity, treatment should follow guidelines once the diagnosis
and indication have been established.
Children usually require no or only temporary treatment on an as-needed
basis: oral antihistamines as well as topical cromolyn or polidocanol [55–57 ].
CME Article

Table 3 Diagnostic features and prognosis of mastocytosis.

Category Diagnostic features Prognosis in terms of life expectancy

Cutaneous mastocytosis Typical skin lesions; no systemic involvement; Good
onset usually in early childhood
Indolent systemic mastocy- Onset usually in adulthood with/without skin Good
tosis involvement; pronounced mast cell proliferation
Smoldering mastocytosis No skin involvement; mast cell infiltration only in Usually good
bone marrow
Systemic mastocytosis with Usually myelodysplastic/ myeloproliferative Corresponds to the associated
associated hematologic syndromes, AML, chronic eosinophilic leukemia; hematologic disorder
neoplasm (SM-AHN), rarely lymphoma
Aggressive systemic mastocy- Organ dysfunction due to massive mast cell Variable, usually poor
tosis infiltration:
– Myelofibrosis, cytopenia
– Liver failure with ascites
– Splenomegaly
– Osteolysis, fractures
– Malabsorption, cachexia
Mast cell leukemia > 20 % mast cells in bone marrow aspirate; mast Poor
cells usually immature, often blast cells; in the ty-
pical variant, > 10 % mast cells in the blood smear
Mast cell sarcoma Malignant and destructive tumor; mast cells with Poor
highly abnormal morphological changes
AWMF guidelines no. 13/058.

Adult mastocytosis patients should be prescribed an emergency kit consisting of

Treatment is usually guided by sym-
ptoms. All adult patients should be
given an emergency kit, informed
about possible anaphylactic reactions,
and trained in what to do in case of an
emergency.
an epinephrine autoinjector, an oral corticosteroid, and an antihistamine, and be
trained in its use. An emergency kit is also recommended for children with exten-
sive skin involvement and a history of anaphylaxis. Both adults as well as children
at increased risk should be issued a mastocytosis alert card.
If antihistamines prove to be insufficient to control symptoms, they may be
combined with mast cell stabilizers or leukotriene antagonists. Updosing to up
to 4 times the recommended daily dose of non-sedating antihistamines may be
required, especially for severe pruritus. Treatment of adult patients may also in-
volve UVA/UVB therapy, possibly even short-term bath or cream PUVA therapy
[58]. However, UV therapy has only temporary effects on pruritus and cutaneous
mastocytosis lesions. Apart from a low-histamine diet, measures used to alleviate
gastrointestinal symptoms include H1 and H2 antihistamines, mast cell stabilizers
(cromolyn), proton pump inhibitors, and corticosteroids.
Gastrointestinal, dermatological, hematological, and mediator-related symp-
toms are treated with interferon-alpha, possibly in combination with corticoste-
roids. Patients should be informed in detail about possible side effects such as fever,
neutropenia and thrombocytopenia, autoimmune disorders, and depression [28].
Treatment of osseous involvement is likewise guided by clinical fi ndings. Cal-
cium and vitamin D replacement therapy may be instituted based on the severity of
osteopenia or osteoporosis. Treatment can be supplemented with antihistamines as
they may alleviate the effects of histamine on the bones. Treatment of osteoporosis
primarily involves bisphosphonates, sometimes in combination with the synergisti-
cally acting interferon-alpha [36, 59].

© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601 51
 CME Article
Interdisciplinary collaboration with
internists is mandatory. Cytoreductive
therapy is rarely necessary. Interferon,
cladribine, midostaurin, polychemothe-
rapy, and possibly stem cell transplan-
tation may be required.
Table 4 Treatment of mastocytosis.
Mastocytoma
Cutaneous mastocytosis, adults
Gastritis /peptic ulcer
Diarrhea, tenesmus, vomiting
Flushing
Osteoporosis
Aggressive systemic mastocy-
tosis (ASM), mast cell leukemia,
mast cell sarcoma, severe
disease
Systemic mastocytosis with as-
sociated hematologic neoplasm
(SM-AHN)
52 © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601
Only few mastocytosis patients require cytoreductive therapy, especially in
case of ASM or mast cell leukemia. The decision on whether and how to treat
is also based on the assessment of B fi ndings (borderline benign) and C fi ndings
(consider cytoreduction). B fi ndings encompass hypercellular bone marrow, dys-
plasia, organomegaly, bone marrow infi ltration by mast cells of > 30 %, and serum
tryptase levels > 200 ng/mL) and reflect an uncertain disease course. C fi ndings
(one/more cytopenias, severe osteoporosis, large osteolytic lesions, splenomegaly,
malabsorption) are alarming and signify a possible indication for cytoreductive
therapy.
Patients with severe disease should always be managed in close interdiscipli-
nary collaboration with internists, preferably hemato-oncologists. The multikinase
inhibitor imatinib is usually ineffective in patients with the D816V mutation. Re-
gardless of KIT mutation, cladribine (2-chlorodeoxyadenosine, 2-CdA), a purine
analog, is used in patients with ASM, MCL, and SM-AHN. While cladribine is as-
sociated with symptom relief, it does not lead to complete remission [60]. Common
adverse effects are neutropenia or persistent lymphopenia. The majority of patients
with ASM or MCL respond to midostaurin, a kinase inhibitor available for oral
use [61–65]. The response is usually only temporary, though. Other therapeutic
options include cytarabine, hydroxyurea, polychemotherapy, and allogeneic stem
cell transplantation [66 ]. Recent data suggests that brentuximab, a monoclonal
CD30 antibody, may possibly represent a promising treatment option in CD30-po-
sitive (Ki-1 antigen) ASM or MCL [54].
Treatment of SM-ANH (SM with associated hematologic neoplasm; or its sy-
nonym: SM-AHNMD [systemic mastocytosis associated with clonal hematologic,
non-mast cell lineage disease]) focuses on the associated neoplasm.
Treatment of mast cell sarcoma is difficult. Combined therapy using KIT inhi-
bitors, 2-CdA, anti-CD30 antibodies, and bone marrow transplants is a possible
option (Table 4) [67 ].
Mast cell activation syndromes
In recent years, there have increasingly been reports of variable symptoms consis-
tent with the effects of various mast cell mediators, without the presence of a mast
Oral treatment: antihistamines; topical treatment: corticosteroids, cromolyn, polidocanol
Antihistamines, topical polidocanol; for severe pruritus, short-term bath or cream PUVA
therapy if necessary; possibly leukotriene antagonists
Proton pump inhibitors, H2 antihistamines, low-histamine diet, cromolyn
H2 antihistamines, cromolyn, low-histamine diet, possibly oral corticosteroids
H1 antihistamines, cromolyn
Calcium, vitamin D, bisphosphonates, possibly interferon-alpha
Interferon-alpha, corticosteroids, cladribine, midostaurin, imatinib, chemotherapy,
allogeneic stem cell transplantation
According to the associated hematologic neoplasm
CME Article

Table 5 Mast cell activation syndromes (modified after [69, 71]).

Category Major criteria

Primary mast cell activation syndrome Detection of monoclonal mast cells (CD25+ mast cells
a) Mastocytosis and/or exon 17 KIT mutation, usually D816V)
b) Monoclonal mast cell activation syndrome
Secondary mast cell activation syndrome Presence of diagnostic criteria for hypersensitivity or
a) Allergic disorders some other disorder that is associated with mast cell
b) Mast cell activation in the context of chronic inflammatory, activation
autoimmune, and neoplastic disorders
c) Physical urticaria
d) Other hypersensitivity reactions, for example to bacteria,
drugs
Idiopathic mast cell activation syndrome Absence of any disease that might explain mast cell
a) Idiopathic urticaria/angioedema activation
b) Idiopathic anaphylaxis
c) Other forms hitherto unknown

cell disorder by defi nition. These include flushing, headache, pruritus, urticaria,
angioedema, nasal congestion, diarrhea, tenesmus, and fatigue. Mast cell activati-
on induced by various stimuli is thought to be the underlying cause.
It is frequently difficult to distinguish these clinical symptoms from those of
other diseases. There are no unequivocal, objective parameters. Serum tryptase le-
vels in particular are used for the diagnosis [68, 69]. A consensus conference has
proposed a transient increase in tryptase levels by at least 20 % from baseline + 2 ng/
mL as evidence for the presence of mast cell activation syndrome (MCAS). MCAS is
suspected if the following criteria are met: 1) relevant clinical symptoms, 2) response
to H1 and H2 antihistamines, mast cell stabilizers (cromolyn), or leukotriene anta-
gonists, and 3) increase in tryptase levels (as defined above). MCAS is classified into
a primary, secondary, and idiopathic form (Table 5). By definition, primary MCAS is
characterized by monoclonal mast cells (D816V mutation or other activating exon 17
KIT mutations and/or CD25 expression on mast cells). If the WHO criteria for sys-
temic mastocytosis are not met, the diagnosis to be considered is (primary) monoclo-
nal mast cell activation syndrome. Secondary MCAS includes a variety of disorders
without evidence of clonal mast cells yet associated with clinical symptoms of mast
cell activation: IgE-mediated hypersensitivity, autoimmune urticaria and physical ur-
ticaria, and mast cell activation in the context of chronic inflammatory or neoplastic
diseases. Idiopathic MCAS is a diagnosis of exclusion that requires a comprehensive
workup to rule out other causes; here, patients have neither allergies nor monoclonal
mast cells nor any other underlying disorders potentially associated with mast cell
activation [70, 71]. Given the clinical overlap with other diseases, further research is
required to elucidate the exact pathogenesis of mast cell activation syndromes [71].
Because of the variety of clinical symptoms, it is useful to provide patients
with written information about their disease. In addition, they should be advised
about the possibility to contact patient organizations.

Summary
Mastocytosis is characterized by clonal expansion of mast cells in various or-
gans, frequently in the skin and bone marrow. The majority of pediatric forms,
such as mastocytoma or maculopapular cutaneous mastocytosis, tend to resolve

© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601 53
 CME Article

spontaneously prior to adolescence. Adult-onset mastocytosis is often marked by

systemic involvement and persistent disease. In the majority of cases, there is no im-
pact on life expectancy. Clinical fi ndings and treatment are guided by mediator-re-
lated symptoms and the organs involved. Representing rare variants, aggressive
systemic mastocytosis and mast cell leukemia usually require cytoreductive therapy
and interdisciplinary collaboration with internists; they have a poor prognosis.

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Fragen zur Zertifizierung durch die DDA

1. Welches ist weder Haupt- noch 5. Bei welcher Konstellation ist die e) Ein Updosing der Antihistaminika ist
Nebenkriterium einer systemischen Serumtryptase am wahrscheinlichsten bei Mastozytose nicht indiziert.
Mastozytose? nicht erhöht?
a) Serumtryptase > 20 ng/ml dauerhaft a) systemisch indolente Mastozytose
b) Mediatorsymptomatik b) smoldering mastocytosis 9. Welches klinische Bild der
c) Koexpression von KIT und CD2/ c) Mastozytom Mastozytose ist untypisch?
CD25 auf Mastzellen d) 2 Stunden nach einer Anaphylaxie a) Flush
d) atypische/spindelige Morphologie e) Mastzellsarkom b) Herzrasen
der Mastzellen im Knochenmark c) Miktionsbeschwerden
e) multifokale Mastzellaggregate im d) Kreislaufabfall
Knochenmark 6. Auf welches Medikament sprechen e) Diarrhöen
derzeit die meisten Mastozytose-Pa- f) urtikarielle Beschwerden
tienten mit einer D816V-Mutation im 10. Welche Formen der Mastozytose
2. Welcher Befund passt nicht zur Falle einer erforderlichen Therapie an? gibt es?
Diagnose einer systemisch indolenten a) Cladribin a) makulopapulöse
Mastozytose? b) Interferon α b) makulös
a) disseminierte rotbraune Maculae c) Imatinib c) kleinfleckig
b) Serumtryptase von 80 ng/ml d) Hydroxyurea d) ulzerös
c) Osteoporose e) Midostaurin e) großfleckig
d) Splenomegalie
e) Nachweis D816V-Mutation auf Mast-
zellen im Knochenmark
7. Welche Aussage ist richtig?
a) Mastozytose bei Kindern zeigt meist
keine Tryptase-Erhöhung. Liebe Leserinnen und Leser,
3. Welche Aussage zur Mastozytose b) Ein Notfallset sollte bei Kindern ver- der Einsendeschluss an die DDA für
ist falsch? ordnet werden. diese Ausgabe ist der 28. Februar 2018.
a) Es handelt sich um eine Loss-of- c) Mastozytose bei Kindern bedarf im- Die richtige Lösung zum Thema „Nichtin-
Function-Mutation. mer einer Knochenmarksstanze. vasive Diagnostik in der Dermatologie“
b) Am häufigsten ist die D816V- d) Das therapeutische Vorgehen bei in Heft 10 (Oktober 2017) ist: (1a, 2d, 3d,
Mutation. Kindern ist dem bei Erwachsenen 4a, 5b, 6e, 7c, 8a, 9e, 10c).
c) Sie beruht auf einer somatischen ähnlich.
Bitte verwenden Sie für Ihre Einsen-
Mutation. e) Antihistaminika sind auch hier thera-
dung das aktuelle Formblatt auf der
d) Familiäre Mastozytose-Erkrankun- peutisch wirksam.
gen sind selten. folgenden Seite oder aber geben Sie
e) Es gibt keine Geschlechtsprädispo- Ihre Lösung online unter http://jddg.
sition. akademie-dda.de ein.
8. Welche Aussage ist falsch?
a) Ein Notfallausweis sollte jeder
erwachsene Mastozytose-Patient
4. Was ist kein B-finding? erhalten.
a) Organomegalie b) Patienteninformationen vereinfa-
b) Serumtryptase > 200 ng/ml chen das Patientenmanagement.
c) hyperzelluläres Knochenmark c) Eine Schulung der Notfallmedikation
d) Infiltration des Knochenmarks mit sollte bei jeder Vorstellung erfolgen.
> 30 % Mastzellen d) Eine Überprüfung der Notfallme-
e) rezidivierende Anaphylaxien dikation sollte mindestens einmal
jährlich erfolgen.

© 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2018/1601 57