Mastocytosis: recent advances in defining the disease

British Journal of Dermatology 2001; 144: 682±695.

Mastocytosis: recent advances in defining the disease

K.HARTMANN AND B.M.HENZ*

Department of Dermatology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany*Department of Dermatology, ChariteÂ, Humboldt University of Berlin, Germany

Accepted for publication 22 November 2000

Summary Mastocytosis is a rare disease characterized by a primary pathological increase in mast cells in

different tissues, which may present in a variety of clinical patterns. Major advances have been

made in recent years in the understanding of the pathogenesis of mastocytosis. This review is aimedat familiarizing dermatologists with these recent findings, and at exploring their possible

implications for the diagnosis and treatment of the condition. The heterogeneous clinical

presentation of mastocytosis is detailed with respect to the type of skin lesions, age at onset,family history, organ systems involved, associated haematological disorders and prognosis. Recent

genetic findings also indicate different pathogenetic forms of mastocytosis, as adult patients and

those with associated haematological diseases usually express activating mutations of the stem cellfactor receptor c-kit, whereas most cases of childhood-onset and familial mastocytosis seem to lack

these mutations. Despite the presence of c-kit mutations, patients with cutaneous lesions generally

have a good prognosis, even when there is involvement of other organs. Some patients, particularlythose with childhood-onset disease, experience spontaneous remission, mostly by puberty. c-kit

mutations do not explain the initial cause of mastocytosis, and their prognostic significance is as yet

unclarified, as is the pathogenesis in patients without the mutations. Furthermore, these novelfindings have as yet not resulted in a more effective treatment of the cause of the disease, so that

counselling, prevention of exposure to mast cell secretory stimuli, and symptomatic treatment

remain the mainstays of current patient management.

Key words: c-kit, mastocytoma, mastocytosis, stem cell factor, urticaria pigmentosa

About 130 years ago, Nettleship and Tay described achild with brown cutaneous lesions associated with

wealing after scratching.1 In 1878, Sangster termed

this disease `urticaria pigmentosa'.2 This was just1 year after Paul Ehrlich had discovered a new cell

type with metachromatic granules that he named

`mast cells'.3 Ten years later, in 1887, Unna foundthat the brown lesions of urticaria pigmentosa are

associated with an accumulation of mast cells in

the dermis.4 Subsequently, several authors observedsystemic manifestations in patients with urticaria

pigmentosa. In 1936, SeÂzary et al. termed the

simultaneous occurrence of systemic and cutaneoussymptoms `mastocytosis'.5 Finally, in 1949, Ellis

introduced the concept that mastocytosis is often a

systemic disease and can involve internal organs aswell.6

Epidemiology

Mastocytosis is a rare disease. While there are no

reliable studies on its incidence, it has been estimatedthat one in 1000±8000 new patients visiting a

dermatology department is affected.7 Accordingly, arecent study from the U.K. estimated that there are two

mastocytosis patients per year in a population of

300,000, corresponding to an approximate incidenceof 0´0000667%.8 Mastocytosis occurs equally in both

sexes.9 Although patients from varied ethnic groups

have been described, mastocytosis has been morefrequently reported in caucasians. The prevalence of

atopy corresponds to that of the general population.10

Clinical presentation

Family history

Most patients have no familial association, yet more

than 50 cases of familial mastocytosis have been

682 q 2001 British Association of Dermatologists

Correspondence: Karin Hartmann.

E-mail: [email protected]

MASTOCYTOSIS 683

q 2001 British Association of Dermatologists, British Journal of Dermatology, 144, 682±695

published, with a dominant inheritance pattern in

about one-third of these families.8,11±13 In addition,mastocytosis has also been reported in more than 10

pairs of monozygotic twins and two sets of triplets

(Fig. 1). Interestingly, the cutaneous lesions in twinsare usually very similar, and the onset as well as the

spread of lesions occurs almost synchronously, suggest-

ing that at least in these patients, genetic factors play animportant part for the development of the disease.14±16

On the other hand, several pairs of identical twins who

were discordant for mastocytosis have also beendescribed.17 Recent data demonstrating that patients

with a familial association, in contrast to patients with

sporadic mastocytosis, seem to lack c-kit mutations;therefore, this indicates that familial mastocytosis is a

subgroup of the disease, with a different pathogenesis

and prognosis.13,18

Age at onset

In about 15% of all patients with mastocytosis, thedisease is congenital.19 Recently, the first case of an

in utero presentation of systemic mastocytosis was

reported, with an associated myeloproliferative diseaseand an activating c-kit mutation.20 A further 30% of

patients develop mastocytosis before the age of

6 months, another 10% by the age of 2 years, andabout 10% between 2 and 15 years of age. Most

mastocytosis patients (65%) are therefore children.12

In the remaining patients (35%), the onset of masto-cytosis is most commonly observed between 20 and

40 years of age.21

Classification

In view of the heterogeneous clinical presentation

and prognosis of mastocytosis, various classifications

have been proposed.9,22±25 The one currently most

widely accepted is that of Metcalfe,23 modified fromTravis et al.22 As it deals with the disease primarily

from a haematological viewpoint, we have further

subdivided category IA according to differentcutaneous manifestations (Table 1).25

Cutaneous manifestations

The skin is the organ most often involved in all forms ofmastocytosis. Most patients with systemic mastocytosis

have cutaneous lesions as well; rarely, a patient withsystemic disease may only demonstrate flushing and no

other skin features.21

Urticaria pigmentosa is the most common cutaneousmanifestation of mastocytosis. It presents as

symmetrically distributed red±brown macules or

papules (Fig. 2) that develop weals, erythema andoften pruritus on stroking, which is the diagnostic

Darier's sign (Fig. 3). Lesions may affect all sites of the

skin, including mucous membranes,21 with the highestdensity on the trunk, whereas the face, head, palms and

soles are often spared.26 In the initial phase of the disease,

the density of lesions may increase over several years.Flushing occurs in about 50% of patients, and pruritus in

33±46%.27,28 Blister formation may be associated,

particularly in infants up to the age of 2 years, andmay even be the presenting symptom.12 Healing of

blisters generally occurs without scarring, but residual

hyperpigmentation may persist at the involved sites.In children, solitary or multiple mastocytomas are

the most frequent lesions (Fig. 4). They usually develop

within the first 3 months of life and present as brownplaques, macules or nodules that can reach a diameter

of several centimetres. Blisters may be associated.

Figure 1. Identical twins aged 1 year with urticaria pigmentosa. Inthe older twin sister, the first lesions occurred at about 6 weeks of age

followed by the other twin about 3 weeks later. Both twin sisters

developed the first brown lesions at the lower abdomen and from

there, synchronous spreading of the lesions over the trunk and thethighs was observed over the following months.

Table 1. Classification of mastocytosis (modified from Metcalfe23 and

Haase et al.25)

I. Indolent mastocytosis

A. Skin onlyUrticaria pigmentosa

Mastocytoma (solitary or multiple)

Diffuse cutaneous mastocytosisTelangiectasia macularis eruptiva perstans

B. Systemic involvement

II. Mastocytosis with an associated haematological disorder

(with or without cutaneous involvement)A. Myeloproliferative disorders

B. Myelodysplastic disorders

III. Aggressive mastocytosis

(lymphadenopathic mastocytosis with eosinophilia)IV. Mast cell leukaemia

684 K.HARTMANN and B.M.HENZ


Diffuse cutaneous mastocytosis is a rare form of

mastocytosis where mast cells infiltrate the entire skin.This condition generally arises within the first years of

life and is often associated with systemic mastocytosis.

The skin may appear normal or may be thickened, witha reddish-brown or yellow colour demonstrating a

typical peau d'orange-like aspect.29 Bullous eruptions

are very common (Fig. 5). A rare erythrodermic form ofdiffuse cutaneous mastocytosis presents as thickened,

oedematous skin, with a leather-like appearance.21

Another uncommon form of mastocytosis,telangiectasia macularis eruptiva perstans, occurs

mainly in adults, supposedly particularly in obese

middle-aged women.21 The lesions typically have nosharply defined outlines and appear as red±brown,

telangiectatic, small macules. Darier's sign is usually

negative in this form of mastocytosis, and pruritus andblisters have not been observed so far. Only few patients

also demonstrate systemic involvement, with mast cell

infiltration of the bone marrow, and splenomegaly.30

Systemic manifestations

About 11±33% of patients with indolent mastocytosis

experience extracutaneous symptoms.27,28,31 These areeither due to massive mediator release in general or to

Figure 2. Urticaria pigmentosa.

Figure 3. Darier's sign: stroking of mastocytosis lesions causes

erythema, wealing and often also pruritus.

Figure 4. Solitary mastocytoma on the back of an infant.

MASTOCYTOSIS 685


secretory events associated with mast cell accumula-

tion in extracutaneous organs such as the skeletalsystem, gastrointestinal tract, spleen, liver or central

nervous system. Typical symptoms include nausea,

vomiting, abdominal pain, diarrhoea, palpitation,hypotension, vascular collapse, syncope, headache,

dyspnoea and wheezing. Occasionally, severe lethargy

lasting for several hours may follow attacks with severesystemic symptoms.9 Patients with systemic involve-

ment suffer more often from episodic flushing that can

be provoked by changes of body temperature, exercise,emotional upset, infections or drugs such as opioid

analgesics.9,32

About 50±60% of all adults with indolent cutaneousmastocytosis and also 30±50% of children have bone

marrow involvement in the form of diffuse or nodular

mast cell aggregates.28,33 In some patients, bone pain,osteoporosis, spontaneous fractures or fibrosis of the

marrow may be associated. Extensive fibrosis of the

bone marrow can lead to secondary haematologicalabnormalities such as anaemia, thrombocytopenia,

leucocytosis, leucopenia or eosinophilia.24,34

Gastrointestinal involvement is also common insystemic mastocytosis (33%).28 Symptoms include

nausea, vomiting, abdominal pain, cramps, malabsorp-

tion, peptic ulcers, diarrhoea, oesophagitis, oesophagealstrictures and gastrointestinal bleeding.32 In these

patients, ingestion of alcohol can provoke abdominal

pain as well as flushing.9

Patients with more aggressive disease may suffer

from hepatosplenomegaly, sometimes associated with

an accumulation of eosinophils and various degrees offibrosis, portal hypertension, ascites and peripheral

lymphadenopathy.9,35,36 Neuropsychiatric abnormalities

such as irritability, poor attention span, depression andimpairment of short-term memory have also been

observed.32 Prolonged bleeding of the skin or the

gastrointestinal tract has been reported in childrenwith diffuse cutaneous mastocytosis.12,37

In a few patients, systemic mastocytosis may

develop into an aggressive form, with severe systemicsymptoms including fever, hypotension, frequent

episodes of flushing, fatigue and cachexia. Whereas

mast cells are usually not detectable in peripheralblood, a leukaemic spread of circulating, immature

mast cells has been reported in these patients during

the terminal stage of their disease.24 Paradoxically,cutaneous mastocytosis lesions may at this point fade

or even disappear.23,24

Haematological abnormalities can occur eithersecondary to mast cell infiltration of the bone marrow

displacing other cell types, or as a separate entity.24 As

therapeutic and prognostic implications may be differ-ent, it is important to distinguish between these two

conditions. Of adult patients with mastocytosis seen by

haematologists, up to 30% have been estimated todevelop additional systemic haematological diseases

such as a myeloproliferative or myelodysplastic syn-drome, Hodgkin's disease, hypereosinophilic syndrome

or Castleman's disease.22,34,38,39 Symptoms of the

haematological disorder may then predominate overthose related to mastocytosis.24 In paediatric patients,

an associated haematological disorder has only rarely

been observed, more so in children with late-onset andrapidly progressive disease.19 Compared with other

haematological disorders, lymphocytic leukaemia

appears to be more often associated with mastocytosisin children.40

Only a few cases of aggressive mastocytosis, also

known as lymphadenopathic mastocytosis with eosi-nophilia and classified as category III of mastocytosis

(Table 1), have been reported in the literature.9 Mast

cell leukaemia, corresponding to category IV, is anextremely rare disease which presents with atypical

immature mast cells that diffusely infiltrate the bone

marrow and that account for more than 10% of bloodcells.9,24 Diffuse mast cell hyperplasia and even a

leukaemic spread of mast cells may also accompany

different severe haematological disorders as a second-ary phenomenon (Table 2).32,41

Pathogenesis

While the relationship between the release of mediators

and the symptoms of mastocytosis is well recognized,the cause for the increase of mast cell numbers is

largely unknown. Owing to recent advances in the

Figure 5. Diffuse cutaneous mastocytosis associated with bullae.



understanding of mast cell ontogeny, growth and

differentiation, several hypotheses have been advancedto explain the pathological hyperplasia of mast cells

(Table 3).

c-kit mutations

The c-kit proto-oncogene codes for the transmembranetyrosine kinase receptor of the stem cell factor (SCF).

Activating mutations of c-kit lead to ligand-indepen-dent autophosphorylation of the receptor and auton-

omous cell growth. In 1993, two activating mutations

in codons 816 and 560 were first identified in thegrowth factor-independent human mast cell line HMC-

1, derived from a patient with mast cell leukaemia.42,43

Subsequently, adult patients with mastocytosis havealso been found to express the 816 mutation leading to

the substitution of valine for aspartase.44 Initial studies

suggested that the Asp816Val mutation may only occur

in patients with systemic mastocytosis or mastocytosiswith an associated haematological disorder.44,45 More

recent studies have, however, demonstrated that all

adults examined so far carry this mutation regardless ofthe classification or the prognosis of their disease,13,46,47

whereas it is found only in rare children with extensive

or progressive mastocytosis and not in familial masto-cytosis.13,20,48,49 Three of five adult patients investigated

have recently also been found to express the activating

560 mutation substituting glycine for valine.46,50 In apatient with aggressive mastocytosis, an additional

Asp820Gly mutation of c-kit has been reported.51

Interestingly, c-kit mutations are not only restricted tocutaneous mast cells, but may also be detected in other

cells of different lineages such as B cells, myeloid cells

and T cells.47,52,53 In patients with an associatedhaematological disorder, mutations of c-kit have some-

times also been found in both neoplasms,44,54,55 and

c-kit mutations can occur in myelodysplastic syndromeor acute myelogenous leukaemia without associated

mast cell hyperplasia.56 In several studies, it has beendemonstrated that none of the c-kit mutations is

present in the germ line, indicating that they are

somatic.13,44

Several studies suggest that activating c-kit mutations

may lead to an oncogenic transformation and

enhanced proliferation of mast cells in mastocytosis.Thus, in several haematopoietic cell lines, activating

mutations of c-kit have been shown to result in a

growth factor-independent kinase activity and atumorigenic phenotype.56±58 Anti-sense oligonucleo-

tides of c-kit mRNA inhibited the proliferation of a

rodent mast cell line expressing the 816 mutation,59,60

and in vivo, a murine mast cell line with the same

mutation induced the formation of mastocytomas in

syngeneic mice.61 In line with these observations,autonomous, ligand-independent growth of cultured

mast cells was observed in patients with rapidly

progressive mastocytosis,62 and mast cells culturedfrom CD341 peripheral blood mononuclear cells of

patients with mastocytosis resulted in higher numbers

of mast cells, compared with cultures of healthycontrols.63

In contrast to adult-onset mastocytosis, typical

paediatric patients have so far not been found to bearthe activating Asp816Val mutation.13,46 The observa-

tion that three of six children with sporadic and

presumably transient urticaria pigmentosa were foundto carry an inactivating, dominant c-kit mutation in

codon 839, substituting lysine for glutamic acid, is at

Table 2. Secondary mast cell increase in association with otherdiseases (examples are shown in parentheses)

I. Inflammation

A. Infections (parasitic infestations, toxoplasmosis140)B. Allergic reactions (urticaria, persistent insect sting reactions)

C. Immunological (graft-versus-host disease,

granulomatous reactions)

D. Connective tissue turnover (hypertrophic scars)II. Tumours

A. Benign (neurofibromas, haemangiomas)

B. Malignant (basal cell carcinoma, melanoma)III. Haematological disorders

A. Benign (dysmyelopoietic and myeloproliferative disorders,

chronic neutropenia, thrombocytopenia, hypereosinophilic

syndrome, Castleman's disease, porphyria)B. Malignant (acute non-lymphatic leukaemia,

malignant lymphoma, Hodgkin's disease)

Table 3. Possible pathogenetic mechanisms in primary mastocytosis

I. Alterations of the SCF receptor c-kit

A. Activating mutations (in adult-onset indolent and in

aggressive mastocytosis)B. Overexpression (in serum, in PBMC of patients with associated

haematological disorders)

II. Alterations of mast cell growth factors

A. Increased expression of soluble SCF by keratinocytes (variable)B. Increased SCF levels in serum (disproven)

C. Increased NGF levels in serum (one patient only69)

III. Chromosomal abnormalitiesIV. Dysregulation of apoptosis

A. Upregulation of antiapoptotic protein Bcl-2

(in aggressive mastocytosis)

B. Upregulation of antiapoptotic protein Bcl-X(in bone marrow of indolent mastocytosis)

SCF, stem cell factor; PBMC, peripheral blood mononuclear cells; NGF,

nerve growth factor.

MASTOCYTOSIS 687


present difficult to interpret regarding its pathological

relevance.13 While the pathogenesis of most childhood-onset mastocytosis is thus unclear, it has, however,

been suggested that paediatric mastocytosis represents

a clonal disease.55 Familial mastocytosis must beviewed as a separate entity as well, as genomic or

somatic c-kit mutations could not be found in

three families with several members suffering frommastocytosis.8,13,18

Expression of mast cell growth factors and of c-kit

In an earlier study, it was suggested that patients with

mastocytosis additionally express a soluble form of SCFin the epidermis, in contrast to healthy controls who

only express membrane-bound SCF.64 More extended

studies have, however, been unable to confirm theseresults;65,66 instead, they even found a decreased

expression of SCF in paediatric mastocytosis. Further-

more, SCF serum levels are not elevated in urticariapigmentosa patients.28,67 In vitro, mast cell cultures

from mastocytosis patients also failed to overexpress

SCF.62 Nerve growth factor, another mast cell growthfactor,68 has been reported to be elevated in the serum

of one patient with mastocytosis after ultraviolet (UV)irradiation.69

Mastocytosis patients with an associated haemato-

logical disorder or with aggressive disease have alsobeen found to express higher levels of c-kit mRNA in

peripheral blood mononuclear cells, compared with

indolent mastocytosis and normal controls.70 Further-more, soluble c-kit protein is elevated in the serum of

systemic indolent mastocytosis, mastocytosis with an

associated haematological disorder and aggressivemastocytosis, compared with urticaria pigmentosa

without systemic involvement and healthy controls.71

These observations are most likely to be due to anincrease of c-kit-bearing mast cell precursors in the

blood of these patients.

Apoptosis of mast cells

As has been shown for other neoplasms such aslymphomas and malignant melanomas, prolonged

survival of mast cells in mastocytosis may also be

associated with the inhibition of apoptosis, the physio-logical form of cell death.72,73 Cervero et al. recently

observed a strongly enhanced expression over several

months of the antiapoptotic protein Bcl-2 in mastcells from the bone marrow of one patient with

mast cell leukaemia.74 In comparison, there was no

increased expression of Bcl-2 in patients with indolent

mastocytosis, paediatric mastocytosis or reactivemast cell hyperplasia due to other diseases. Using

immunohistology, bone marrow mast cells of masto-

cytosis patients have also been found to express theantiapoptotic protein Bcl-X.75

Chromosomal abnormalities

The rate of chromosomal abnormalities appears to be

increased in patients with mastocytosis.45,76,77 Patientswith an associated haematological disorder have

especially been found to show chromosomal breaks

and trisomies more often.45 The affected chromosomalregions, however, fail to correspond to genes that may

be related to the pathogenesis of mastocytosis, such as

c-kit, SCF, interleukin (IL)-4, IL-6 or IL-9. The authors,therefore, suggested that chromosomal abnormalities

in mastocytosis patients may not directly be associated

with c-kit mutations, but both defects could result froma common altered repair mechanism.45

Phenotype of mastocytosis mast cells

An increased expression of proliferating cell nuclear

antigen has been reported in mastocytomas andmalignant mastocytosis, in comparison with control

tissue and with urticaria pigmentosa lesions.78 Incontrast, in flow cytometric DNA analysis, there was

no increased proliferation of spleen mast cells isolated

from patients with systemic mastocytosis, comparedwith normal controls.79 Taken together, detailed

studies that clearly demonstrate an increased prolifera-

tion of mast cells in patients with mastocytosis are stillmissing. Immunohistochemical analyses of mast cells

in urticaria pigmentosa and mastocytoma skin lesions

for mast cell and monocytic markers have so far also notyielded any unusual features, except for a somewhat

immature phenotype in mastocytomas.80,81 Recent

analyses of bone marrow mast cells from mastocytosispatients by immunohistochemistry and multiparameter

flow cytometry showed, however, that mast cells

express more CD2 (LFA-2) than controls, a receptornormally restricted to T and natural killer cells.55,82

CD2 on these mast cells and on leukaemic HMC-1 cells

might bind to one of its natural ligands, CD58 (LFA-3),on other mast cells, thus possibly causing aggregation

of neoplastic cells.55,83 In addition, the cells express

CD25, the a chain of the IL-2 receptor, which is usuallyexpressed on activated T cells,84±87 and they over-

express CD35, CD63 and CD69.88 It remains to be



clarified whether these findings are significant for the

pathogenesis of mastocytosis or whether the abnormalexpression pattern just reflects activation of these mast

cells.

Diagnosis and evaluation

General diagnostic work-up

The diagnosis of mastocytosis is based on the charac-teristic clinical findings, history and physical examina-

tion, and should be confirmed and extended, dependent

on the special features of each individual patient(Table 4).25,89 A skin biopsy is essential for confirma-

tion of the disease and to rule out an increase in mast

cells due to other diseases (Table 2), as is a full bloodcount with peripheral smear to rule out associated

haematological disorders such as anaemia, leucopenia,

leucocytosis or thrombocytopenia. A bone marrowbiopsy should be performed in patients with abnormal

findings. In these patients and in those with progressive

disease, a follow-up review should take place aboutevery 6 months (Table 4), but a repeated bone marrow

biopsy should be done more rarely, as a rule only about

every 5 years. All special diagnostic procedures shouldbe considered carefully, particularly in children, as

skeletal lesions may be transient in some patients and

no correlation between skeletal abnormalities andsystemic involvement has been found.29,90

Histopathology of the skin

Skin biopsies should be taken with as little tissue

trauma as possible, infiltrating the local anaestheticinto the skin circumferentially at a slight distance from

the lesions. Routine formalin fixation and toluidine

blue stains are sufficient for diagnostic purposes.65,66,91

Toluidine blue staining at lower pH and an extended

staining period yields higher mast cell numbers,92 and

should be done in doubtful cases. Giemsa is notacceptable because it can also stain infiltrating

leucocytes.

Lesional biopsies from patients with urticariapigmentosa generally demonstrate only a four- to

fivefold increase of spindle-shaped mast cells in the

dermis.21,32,66,93 Infiltrates of mast cells are mainlylocated around blood vessels and skin appendages of

the papillary dermis. In patients with more confluent or

nodular lesions, mast cells may also infiltrate the entiredermis and occasionally even the subcutis. After

traumatization, oedema of the papillary dermis and

rarely subepidermal bullae may additionally be present.Eosinophils can then also accompany mast cell

infiltrates,21 but otherwise, eosinophilic or other types

of inflammatory cells are classically absent in masto-cytosis lesions, and alternative diagnoses should be

considered if they are present (Table 2). Mast cell

numbers are generally higher in lesional comparedwith non-lesional skin, and more than one biopsy may

be necessary to confirm the diagnosis. An increase in

mast cell numbers has, however, also been reported innon-lesional skin in patients with urticaria pigmentosa,

compared with normal controls.91,93 Biopsies from

mastocytomas show marked, tumour-like aggregationsof mast cells throughout the dermis.19,25 In diffuse

and erythrodermic forms of mastocytosis, band-like

infiltrates of mast cells can be observed in the upperdermis, comparable with mastocytomas. In contrast,

histopathological changes of telangiectasia macularis

eruptiva perstans usually demonstrate only scatteredmast cells lined up around capillaries and venules of the

superficial vascular plexus, associated with vascular

dilatation.21

Histopathology of the bone marrow

Bone marrow involvement presents mostly as focalaggregates of spindle-shaped or round mast cells

adjacent to paratrabecular and perivascular areas.94,95

Table 4. Recommended diagnostic work-up

First visit

Inspection of cutaneous lesions, clinical examination

Darier's sign, dermographism testSkin biopsy

Full blood count, blood chemistry, peripheral smear

In patients with suspected systemic involvement: bone marrow

biopsy and aspirate, abdominal ultrasound, bone densitometryOther work-up according to specific symptoms, e.g. endoscopy,

abdominal scan, skeletal surveys, bone scans

Possibly: levels of tryptase in serum, a-protryptase in serum,1-methyl-4-imidazole acetic acid in urine, N-methylhistamine

in urine, 11-dehydroxy-thromboxane B2 in urine

Follow-up every 6 months (only in patients with suspected or

confirmed systemic involvement)Inspection of cutaneous lesions, clinical examination

Darier's sign, dermographism test

Full blood count, blood chemistry, peripheral smear

Other work-up according to specific symptomsPossibly: levels of mast cell products in serum or urine

Additionally at follow-up every year (only in patients with

suspected or confirmed systemic involvement)

Abdominal ultrasoundAdditionally at follow-up every 5 years (only in patients with

suspected or confirmed systemic involvement)

Bone marrow biopsy and aspirate, bone densitometry

MASTOCYTOSIS 689


Rarely, a diffuse infiltration of mast cells can be seen,

ranging from scattered aggregates to near con-fluency.32 A focal increase of mast cells in the bone

marrow can be missed by a single biopsy or aspirate.33

Mast cell infiltration of the bone marrow is oftenaccompanied by focal or diffuse fibrosis and infiltrates

of lymphocytes, immature neutrophils, macrophages

with ingested nuclei, and eosinophils.31,32 Increasednumbers of fibroblasts, plasma cells, lymphocytes and

eosinophils have also been observed in urticaria

pigmentosa patients, without a significant mast cellhyperplasia of the bone marrow;33 conversely, rare

cases with an isolated mastocytosis of the bone marrow

and no other organ involvement have also beendescribed.96 On the other hand, in patients with

other systemic diseases such as infections, porphyria,

myeloid leukaemia, myelodysplastic and myelo-proliferative syndromes, a secondary increase of mast

cells may also occur and can sometimes even imitate

mast cell leukaemia (Table 2).41,55,95 Usually, bonemarrow mast cells are toluidine-positive and Giemsa-

positive, but in mast cell leukaemia or an associatedhaematological disorder, mast cells may be immature,

demonstrating only few, small granules, and are easily

missed. Staining with antibodies against the mast cell-specific enzyme tryptase or c-kit may help to identify

mast cells in these cases.55

Measurement of mast cell mediators

Plasma histamine levels are elevated in the majority ofmastocytosis patients. Measurement of urinary hista-

mine metabolites 1-methyl-4-imidazole acetic acid and

N-methylhistamine, of prostaglandin D2, and of thethromboxane metabolite 11-dihydroxy-thromboxane

B2 is, however, more sensitive and also correlates

with the mast cell burden.97±99 In addition, serumtryptase levels, especially levels of a-protryptase, closely

correlate with the course of mastocytosis and may

therefore be used preferentially for the follow-up ofpatients with systemic mastocytosis.100,101 Measure-

ment of a-protryptase appears to be even more sensitive

than a bone marrow biopsy for determining systemicinvolvement.102

Treatment

Counselling on mediator-releasing triggers and anaphylaxis

At their first visit, all patients with mastocytosis should

be thoroughly informed about specific triggers that

may lead to systemic mediator release and anaphylaxis.

They should also know about signs and symptomsindicating an anaphylactoid reaction. Although

controlled studies investigating the significance of

specific mediator-releasing agents for mastocytosispatients are still missing, it is well accepted that the

most important triggers of systemic reactions include

animal venoms (hymenoptera, jellyfish, snakes), drugs(codeine, narcotic analgesics, polymyxin B, morphine,

dextran, radiological contrast dyes, muscle relaxants,

sympathomimetics), sudden cold exposure, heat (hotbath or sun bathing), alcohol and mechanical irritation

(vigorous towelling, massages).89,103±105 Anaphylactoid

reactions may also occur in response to bacterialtoxins, infections and polypeptides in food (fish, lobster,

crabs). Allergens or agents to which patients have an

individual intolerance (e.g. aspirin) should, of course,be avoided in sensitive patients. In view of the risk of

anaphylaxis, we recommend that all mastocytosis

patients at risk, especially those with a history ofanaphylaxis, regularly carry a set of emergency

medicines with them (antihistamines, corticosteroidsand adrenaline). In some patients with a history of

food-induced systemic reactions, a histamine-restricted

diet may cause improvement, although we do notroutinely recommend diets. Venom immunotherapy

has been reported to be beneficial for some patients

with anaphylactoid reactions after hymenopterastings.104,106 Interestingly, even patients who failed

to demonstrate venom-specific IgE by skin tests and

RAST have been shown to benefit from venomimmunotherapy, although the mechanisms are

unclear.106,107

Antihistamines

Except for the avoidance of mediator-releasing agents,

the treatment of mastocytosis is generally only sympto-matic and will not change the course of the disease

(Table 5).108 Non-sedative H1 antihistamines are

preferentially administered to provide relief of pruritus,flushing, wealing, malaise, abdominal pain and bullae.

Patients with severe pruritus, flushing and bullae may

also benefit from potent sedating H1 antihistaminessuch as hydroxyzine or doxepin. H2 antihistamines are

used to treat gastrointestinal symptoms, especially

gastritis and peptic ulcer disease. Patients with repeatedanaphylactoid reactions should take H1 and H2

antihistamines prophylactically on a regular basis.



Cromolyn sodium and anti-inflammatory agents

Gastrointestinal symptoms such as abdominal pain,

nausea and diarrhoea also respond well to cromolynsodium. Owing to the low absorption rate of cromolyn

sodium (only 1±2%), it has no effect on systemic

mastocytosis symptoms, including flushing, urticariaand bone pain.27,109 Pruritus may decrease, however,

with a delay of 2 weeks.27 Aspirin and other non-

steroidal anti-inflammatory agents have been found toimprove prostaglandin-dependent flushing in some

patients. Care should, however, be taken that patients

have no history of aspirin intolerance.

Ultraviolet irradiation

Oral psoralen plus UVA (PUVA) and UVA1 irradiation

are effective in reducing numbers of mast cells aswell as histamine and leukotriene levels in the

skin.110±112 Usually, mastocytosis lesions gradually

fade due to general tanning, and patients experienceimprovement of pruritus and other symptoms.113

Lesions and symptoms almost invariably recur within

several weeks, however, in adults with urticariapigmentosa,110,111 and therefore the benefits of UV

irradiation should carefully be weighed against the

potential adverse effects of prolonged irradiation. Thechance of persistent improvement in patients bound

to go into spontaneous remission should also be

considered.26,111 Regarding the type of UV treatment,

oral PUVA is superior to UVA1 irradiation, in ourexperience, even though other groups have reported

similar responses to both.114 In contrast to oral PUVA,

bath PUVA treatment appears to be ineffective.26

Immunomodulatory agents and chemotherapy

Several groups have reported on the improvement of

various aspects (flushing, cutaneous lesions, infiltrationof the bone marrow, hepatomegaly, lymphadenopathy,

ascites, anaemia, osteoporosis and urinary excretion of

histamine metabolites) of systemic mastocytosisinduced by interferon-alfa 2b and 2a.98,115±124 In

some cases, systemic steroids had been added.85,115,124

In contrast to these encouraging reports, other studieshave failed to demonstrate improvement with inter-

feron-a.125,126 In addition, interferon itself may induce

dose-limiting adverse effects such as anaphylactoidreactions, hypothyroidism, thrombocytopenia and

depression.98,115,127 Several authors also observed a

relapse of mastocytosis symptoms several monthsafter the discontinuation of interferon treat-

ment.85,119,124 A recent study from Japan reported a

patient with aggressive systemic mastocytosis whoresponded well to cyclosporin combined with low-

dose methylprednisolone.128 Temporary treatmentwith systemic steroids is recommended for patients

suffering from malabsorption as well as for aggressive

mastocytosis.24,108

Mast cells appear to be relatively resistant to classical

chemotherapy, and chemotherapeutic agents usually

fail to alter the course of mastocytosis.108 In patientswith an associated haematological disorder corre-

sponding to type II mastocytosis, the haematological

disease but not the mastocytosis improves. On the otherhand, there are exceptional reports demonstrating the

prolonged survival of patients with aggressive masto-

cytosis after treatment with specific combinations ofdaunorubicin, vincristine, vinblastine, mercaptopurine,

methotrexate or prednisone.24,108,129 Furthermore,

circulating mast cells disappeared in a patient withmyelodysplastic syndrome associated with a secondary

spread of circulating mast cells after treatment with

daunorubicin, etoposide and cytarabine.41 Similar tochemotherapy, bone marrow transplantation is helpful

to treat the haematological disorder in patients with

type II mastocytosis, but fails to ameliorate anassociated mast cell increase in the same

patients.130,131 Some patients with type II and type

Table 5. Treatment of mastocytosis

All patients at risk of Set with emergency medicines

anaphylaxis H1 antihistamines

CorticosteroidsAdrenaline

Pruritus, flushing, H1 antihistamines

wealing UV irradiation (PUVA, UVA1)

Gastrointestinal H2 antihistaminessymptoms Cromolyn sodium

Flushing Aspirin (beware intolerant patients)

Anti-inflammatory agents(beware intolerant patients)

UV irradiation (PUVA, UVA1)

Severe systemic H1 antihistamines

involvement H2 antihistaminesUV irradiation (PUVA, UVA1)

Interferon-alfa

Low-dose corticosteroids

Bullae Local careH1 antihistamines

Corticosteroids

Mastocytomas Topical corticosteroids or local PUVA

(where treatment is necessary)Surgical excision (if treatment is necessary)

UV, ultraviolet; PUVA, psoralen plus UVA.

MASTOCYTOSIS 691


III mastocytosis may also show prolonged survival after

splenectomy.108,132

Treatment of mastocytomas and bullae

Mastocytomas that cause systemic symptoms or that

cause mechanical problems can be treated with local

PUVA105 or potent topical steroids under occlusivedressings. Repeated application of steroids may, how-

ever, cause cutaneous atrophy and even adrenal

suppression.108 In contrast to mastocytomas, we donot recommend topical steroids under occlusion in

urticaria pigmentosa because of potential systemic

effects and because numbers of mast cells in thesepatients tend to increase again after treatment, as with

PUVA. Surgical excision of mastocytomas should only

be considered as a last resort in view of the naturalhistory of most mastocytomas.133 Bullae should be

treated locally like scalds to prevent infections; in rare

cases with severe bullous reactions, intravenouscorticosteroids in combination with antihistamines

have been used successfully.12,29

Anaesthetic management

Surgical procedures in mastocytosis patients are

associated with a high risk of anaphylaxis. Drugs,

trauma, stress and change of temperature may easilyprecipitate an intraoperative release of mast cell

mediators.134 Apart from the avoidance of mediator-

releasing drugs during the operation, prophylacticadministration of antihistamines and corticosteroids is

recommended.135 An H1 antihistamine may, for

example, be given in the evening before the surgicalprocedure, and additional corticosteroids (prednisolone

equivalent 1 mg kg21) and H1 antihistamines about

30 min prior to the procedure. Adrenaline should beavailable throughout the operation.136

Prognosis

The prognosis of mastocytosis strongly depends on the

category of the disease (Table 1). Patients with indolentmastocytosis, even those in category IB, usually have a

favourable prognosis; systemic symptoms, extent of

systemic involvement, mast cell burden, histologicalfeatures or age at onset seem to have no deleterious

impact. In about 50% of paediatric patients, symptoms

resolve spontaneously by adolescence.19 Furthermore,practically all mastocytomas involute within a few

years during childhood. If childhood-onset lesions

persist into adulthood, the prognosis corresponds to

that of adult mastocytosis. In contrast to children, mostadult patients have a chronic course of the disease, but

spontaneous resolution is possible.137 In our own

patient group of more than 100 patients followedover up to 25 years, including those with bone marrow

changes, none developed progressive disease. In a

recent survey of 30 dermatological patients, noprogression was seen over 10 years,28 nor was

malignant transformation observed over 0´5±

32 years in 14 other adult patients.34 Nevertheless,potentially life-threatening complications such as

anaphylaxis, cardiovascular collapse, haemorrhage

and perforating peptic ulcers can arise in indolentmastocytosis on massive mast cell mediator release,

and the prognosis in these events is accordingly grave.

Patients who initially present with systemic masto-cytosis have been estimated to develop a slowly

progressive disease,9 and haematologists estimate that

15±30% of patients seen by them develop associatedhaematological disorders.22 In these patients, the

prognosis mainly depends on the course of thehaematological disease. Patients with type III and

type IV mastocytosis have a poor prognosis, with a

median survival time of less than 2 years.108

Chemotherapy, bone marrow transplantation and

splenectomy appear slightly to improve survival.

Elevated lactate dehydrogenase and alkalinephosphatase levels, splenomegaly, bone marrow hyper-

cellularity, presence of circulating mast cells, associated

haematological disorders including thrombocytopeniaand anaemia, as well as lack of cutaneous lesions, are

associated with a poor prognosis.24,35,138,139

Acknowledgments

Supported by the Wilhelm Sander-Stiftung.

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Mastocytosis: recent advances in defining the disease