MASTOCYTOSIS.
The cellular proliferations of the skin,
especially malignant tumors, are rare in children as compared with
adults. However, such proliferations are concentrated in the first
months of age (Fig. 790). According to some Authors (25), this is why in
the neonatal period whatever tumefaction of doubtful diagnosis should
induce to rule out tumors.
Characteristically, the
proliferations of the first months present a very wide clinical
spectrum, ranging from an isolated cutaneous lesion to the generalized
involvement of the skin till the multisystem involvement. Their
prognosis is also very variable, ranging from the spontaneous
regression to the exitus. The tendency to the spontaneous regression
is much higher at this age. It does not depend on the cell type
affected, being practically detectable in all the neonatal
proliferations, both benign and malignant, from hemangioma to
mastocytoma, to juvenile xanthogranuloma,
myofibromatosis, Langerhans cell histiocytosis and neuroblastoma.
Mastocytosis
Etymology. The term mastocytosis comes (13) from the German word
"mästung", meaning to overfeed. Erlich (7) suggested this
term, believing that the metachromatic coloration (Fig. 792) with
aniline dyes of the cells involved in this disorder was due to an
excessive intake of dye. Hence the name "mastzellen" given
to these cells by Herlich. The mastcell or mastocyte (Fig. 793) is a
cell belonging to the myeloid series and derives from a totipotential
bone marrow stem cell expressing CD34 antigen (18).
Definition. The term mastocytosis means the proliferation of
mastocytes in the skin and/or in other organs. The term mastocytoma
indicates a single, usually cutaneous, nodule consisting of mastocytes.
As usually, intermediate forms with two or more nodules exist between
mastocytosis and mastocytoma. The term systemic mastocytosis usually
indicates the proliferation of mastocytes in more than one organ.
According to other Authors (14), this term should also be used when
the proliferation of mastocytes is shown in only an organ and there
are also clinical sign of involvement of an other organ or increased
plasma levels of products deriving from mastocytes. Finally, according
to other Authors (35), the term systemic mastocytosis should be used
when the presence of mastocytes in the bon marrow is shown.
Etiology.
Familial cases have been occasionally
described (34), but we are dealing with a minority of cases. In our
series of 255 cases in children under 12 years, we identified only 7
families with more than one member affected (two siblings and their
mother -Fig. 791- in 2 cases, one brother or sister in 2 cases, the
father or mother in 2 cases and a first degree cousin in 1 case). In
the family cases, however, the mechanism of inheritance was never
identified. There is no difference of sex in most series of cases. Our
previous series of 104 cases (2) included 55 males and 49 females,
whereas a more recent, larger series of 255 cases included 150 males
and 95 females with a male/female ratio of 3/2.
As well as for other cell proliferations the discussion regarding the
nature -neoplastic process or reactive hyperplasia- is still open 19).
The latter hypothesis is favored by the benign, self-healing clinical
course of most cases of mastocytosis, especially those starting in the
first months. Moreover, there is a biological finding favoring this
hypothesis, namely the identification of a growth factor of mastocytes,
which is called MGF (Mastcell Growth Factor) o SCF (Stem Cell Factor)
or KL (c-Kit Ligand). This factor binds to a receptor, which is
present on mastocytes and even on melanocytes and other stem cells,
stimulating their proliferation and activity. An alteration of this
mechanism might explain both the hyperplasia of mastocytes, which is
responsible for mastocytosis and the hyperplasia and hyperfunction of
melanocytes with secondary accumulation of melanin in the
keratinocytes, which is in turn responsible for the melanic
hyperpigmentation of the mastocytosis lesions.
On the other hand, the neoplastic nature of mastocytosis is favored by
a recent finding, which was underlined in the Wien Meeting on
Mastocytosis (36), namely that most, if not all cases of mastocytosis
are characterized by a monoclonal proliferation. In the patients with
mastocytosis there are chromosomial alterations, such as trisomy 8 and
9 (22, 42) and above all punctiform somatic mutations of c-Kit. This
finding, which favors the monoclonal nature of mastocytosis, is
responsible for activation of mast cell proliferation. It is important
that the latter occurs independently from the presence of MGF ligand.
Moreover, the reported mutations are different in systemic
mastocytosis (20, 28, 31, 41) and in mast cell leukemia (9).
Interestingly enough, the above mentioned mutations lack in children
with self-healing mastocytosis (3). In fact, a different mutation
(Gly-839ŸLys) is present in children with the latter form of
mastocytosis (24).
Therefore mutations can be shown in all cases of mastocytosis,
favoring the hypothesis of a monoclonal proliferation and then of a
neoplastic process. Moreover, the benign clinical course of infantile
mastocytosis is not due to a different pathogenesis, but exclusively
to the age of the affected child.
Pathology.
Mast cells are present in the dermis and only
occasionally in the epidermis; several Authors (11) reported their
presence in the dermis in many dermatoses, especially in presence of
epidermal hyperplasia associated with chronic inflammation of the
dermis. According to the same Authors, however, their presence in the
epidermis is very unusual in cutaneous mastocytosis.
In normal skin mast cells are found mainly in the papillary dermis and
round the appendages. This localization reflects the distribution of
the capillary network of the dermis and the cells tend to be disposed
in pericapillary areas.
The fact that the numbers of mast cells found in the dermis are
significantly affected by the fixation technique and time and by the
staining method may suggest the existence of different mast cells
populations. It has been recently demonstrated that tryptase is
present in each of the two types of human mast cells so far defined:
TC mast cells, predominating in the skin and bowel, which also contain
chimase, and T mast cells, predominating in the lung, which contain
only tryptase (33). On Leder-stained preparations
-chloroaceto-esterase- (40) the mast cells appear brilliant red with
blackish-blue nuclei against pale yellow background. In malignant
mastocytosis (40) the mast cells take this stain but no metachromatic
reaction is observed with toluidine blue.
Finally, the dermal mast cells possess a unique affinity for the egg
white protein avidin. This binding is not limited by methods of
fixation.
The histologic diagnosis is easy in isolated mastocytoma and in
diffuse cutaneous mastocytosis: here the dermis is almost exclusively
occupied by mast cells. On the other side, the involved skin of
subjects with macular mastocytosis have only four to six times higher
mast cell counts than their uninvolved skin. Moreover, slightly higher
mast cells counts are detectable in uninvolved skin of subjects with
mastocytosis (40) when compared with skin of normal controls, thus
making the diagnosis of macular mastocytosis more difficult.
The hyperpigmentation of the lesions is associated to increased levels
of melanic pigment in the lower layers of the epidermis, probably due
to the presence of the receptor for c-kit ligand even on the surface
of melanocytes.
Clinical features. The characteristic lesion of
mastocytosis is polymorphous. The presence of mastocytes in the skin
may be not clinically evident, except for the moment of their
degranulation. Although rarely, mastocytosis presents with generalized
itching, without stable cutaneous lesions, but only with severe
lesions of urticaria factitia (Fig. 806). The latter finding can occur
when mastocytes heavily infiltrate the skin, as in diffuse cutaneous
mastocytosis. More often macules, macules and papules or nodules of
variable color are present. They are usually brownish, sometimes slaty
or yellowish.
Clinical manifestations of mastocytosis are connected with
degranulation of mast cells -whatever its cause- and the resulting
release of histamine and other factors of inflammation, such as
proteoglycans, neutral proteases, acid hydrolases, lipid mediators
-platelet activating factor and prostaglandin D2- and some cytokines
-tumor necrosis factor alfa and interleukines- (23).
This accounts for the pruritus, erythema and oedema progressing to
blister formation in individual lesions, episodes of facial flushing
and positive Darier’s sign.
The pruritus is usually less severe in children than in adults, mostly
episodic and rarely calls for sedation.
As above mentioned, pruritus can be the only expression of
mastocytosis.
Urtication of individual lesions is characteristic of mastocytosis. A
brownish lesion becomes erythematous and edematous, loses its previous
color characteristics (Fig. 796, 800, 801)
and becomes reminiscent of an
urticarial wheal. This change may occur either spontaneously or as a
result of friction against clothing, local injury or scalding, as in
bath. When after 20-30 minutes the pruritus and urtication regress,
the initial hyperchromic lesion reappears. In most cases in children
the urtication of the lesions becomes less evident with the passage of
time.
Darier’s sign is urtication induced by the doctor stroking
the lesion of mastocytosis. It is pathognomonic of cutaneous
mastocytosis, though very rarely it may be demonstrated in other
dermatoses, such as juvenile xanthogranuloma (29). In our experience
weakly positive Darier’s sign may be obtained even in nodular
scabies.
Anyway, but especially in cases of macular mastocytosis and in
subjects with dermographism the sign should be evaluated by an
experienced dermatologist. For this purpose an area bearing two
similar lesions should be selected, close to each other but not so
close that the stroking of one may affect also the other. One lesion
is then stroked 5-6 times with the pulp of the index finger and the
appearances of the two lesions are compared 2-5 min. later. The
reaction of the normal skin to rubbing should also be tested,
especially when there are not similar lesions, close each other.
The inflammation resulting from the local release of histamine may be
so violent as to result in formation of a blister.
Such blisters are most unusual in adults but occur more frequently in
children, especially in the first year of life. In some cases a
mastocytic lesion, e.g. an isolated mastocytoma, may present more or
less numerous episodes of blistering in the first year of life (Fig.
797),
and then episodes of urtication (Fig.
798) that may become progressively less severe in the subsequent years,
only to disappear eventually completely (Fig. 799).
The blistering is more frequent in isolated
mastocytoma (in 30 of our 117 cases) than in urticaria pigmentosa (in
11 of 138 cases).
In 18 of 30 children with bullous isolated mastocytoma, local
blistering was associated with distant flushing of the face.
Episodes of flushing are another characteristic sign of mastocytosis.
The face (Fig. 794) is usually affected with the upper trunk till the
waist, the flushing occurs suddenly, lasts 10-30 minutes and regresses
spontaneously.
The episodes appear to be spontaneous but
sometimes are clearly connected with an endogenous or exogenous
stimulus capable of inducing degranulation of mast cells. In our
series the episodes of flushing were more frequent in isolated
mastocytoma, especially in the phase of blistering, than in urticaria
pigmentosa. In children the flushing episodes are more frequent in the
first year of life, become less frequent in the second and third year
and then disappear.
Besides these symptoms and signs, physicians should remember that,
although rarely, the most severe forms of mastocytosis can be
associated to anaphylactic signs. The latter occur, more frequently in
adults, following hymenopter stings, in sensitized subjects, also
suffering from mastocytosis (30) or during anesthesia (37). Even in
children anaphylactic manifestations may occur, for instance apnea
crises in systemic mastocytosis (1, 27).
Mastocytosis can be deteriorated with blister formation due to drugs
which release histamine (5). In our series of cases we observed only
one case of shock in a child with papular mastocytosis. This child
erroneously took antihistamines for more than one year and suddenly
withdrew them during a flu episode.
No child in our series reported histaminergic crises after intake of
foods or drugs which release histamine.
Clinical course and prognosis.
The age of onset of cutaneous mastocytosis
is in the first few years of life. As a matter of fact, 181 out of our
225 cases start in the first 6 months of age and 211 out of 225 in the
first 2 years (Table 1). This behavior is even more evident for
mastocytoma, whose age of onset is more precocious as compared with
other forms of mastocytosis.
Subsequently, new lesions develope for 3-18 months, only to involute
slowly so that in most cases the involution of lesions is complete in
5-10 years.
It is practically impossible establish the exact percentage of
mastocytosis, which completely regresses and the times of regression,
because, as well as for hemangioma, the regression process is very
slow.
For instance, a case of mastocytoma, which had become practically non
visible, consisting only of a very modest hyperpigmented halo, and had
been not associated to episodes of flushing for 5 years, can redden
due to a very strong rubbing. Therefore, the time of regression cannot
be indicative of prognosis. On the other hand, the onset of the
regression phase, which is characterized by the progressive decrease
of the local reddening crises and episodes of flushing is much more
important. When started, the regression process does not stop anymore
and eventually leads to the disappearance of the lesions or to modest
hyperpigmented or atrophic residua or to a modest increase of the
cutaneous pattern with grooves and reliefs.
Therefore, physicians and parents should pay attention to the onset of
the regression phase, usually occurring towards the end of the second
year.
When at the age of 5 years, the regression phase has not started,
mastocytosis likely persists or deteriorate with time.
The behavior of mastocytoma is slightly different from mastocytosis,
because the former is almost always present at birth, almost always
regresses, often more rapidly than mastocytosis with multiple lesions.
Clinical forms.
The clinical forms of mastocytosis are
classified according to the type and number of the cutaneous lesions,
the presence of symptoms and signs, which are secondary to the
involvement of other organs, and, finally, the clinical course of the
disorder. Isolated mastocytoma, urticaria pigmentosa and generalized
cutaneous mastocytosis are the most frequent forms in children.
Telangiectasia macularis eruptiva perstans, as well as systemic
mastocytosis and malignant mastocytosis are found only in adults.
In our series of 255 cases of infantile cutaneous mastocytosis,
urticaria pigmentosa was diagnosed in 132 cases, isolated mastocytoma
in 117 cases and, finally, diffuse cutaneous mastocytosis in 6 cases.
Isolated mastocytoma. It
is more frequent in children as compared with adults. In our series it
accounts for 46% of cases of mastocytosis. In other series including
adults, isolated mastocytoma accounts for 5% of cases (4).
In 4 of 117 cases we recorded two lesions each and in 1 case 3 lesions.
Multiple mastocytomas do not usually develop simultaneously.
In our series of 117 cases the affected sites were as follows: trunk
in 37 cases, lower limbs in 28, head and neck in 25 and upper limbs in
17.
From a morphological point of view, fully developed mastocytoma
presents as a more or less infiltrated plaque or as a roundish, oval
or elongated (Fig. 800), usually brownish in color macule.
After rubbing, mastocytoma increases in volume
and consistency and rapidly loses its brownish color to turn in a
wheal (Fig. 796, 798) or a blister (Fig. 797), which is filled in with
plasma.
Urtication till blister formation and flushing episodes are more
frequent in mastocytoma as compared with urticaria pigmentosa. As the
latter even isolated mastocytoma spontaneously regresses in years.
Maculo-papular mastocytosis or urticaria
pigmentosa is the most common form of cutaneous
mastocytosis and accounted for 132 of our 255 cases.
The lesions vary greatly in their diameter from one subject to another
but tend to be more extensive than in adults. The flushing episodes
are less frequent than in isolated mastocytoma and occur in
approximately 17% of cases. In 8% of our cases we recorded transient
blistering especially in children under 2 years. This type of
mastocytosis with blistering (Fig. 804) is to be distinguished from
the rarer form of diffuse bullous mastocytosis (Fig. 805).
Characteristically an improvement is observed
during the summer. We recorded 6 cases out
of 138 (about 4%) of persistent mastocytosis, namely a form which is
not characterized, within 5 years from the onset, by a tendency to
progressive improvement, as above mentioned. In 3/6 cases the onset
was late, after the second year of age, whereas in the other three
cases the age of onset was within the first 6 months of age as in the
majority of our cases.
Also the morphology of the lesions is not significant because in 3/6
cases the lesions were smaller and rather uniform in diameter (Fig.
807), thus reminiscent of the most frequent form of the adult (Fig.
808),
whereas in the other three cases the shape and
size of the lesions was superimposable to those ones of classic
urticaria pigmentosa. In one case we were dealing with an adolescent,
who had also his mother and sister affected by mastocytosis.
In some rare cases the papules show a yellowish hue and hence the term
of mastocytosis xanthelasmoidea.
Diffuse cutaneous mastocytosis is
seen in children as in adults and was diagnosed in 6 of our 255 cases.
Its onset is usually early (10), generally in the first month of life.
The diffuse mastocytic infiltration of the skin gives it a leathery
quality which initally may not be clinically obvious.
In the child the first manifestation of diffuse cutaneous mastocytosis
may be a bullous rash difficult to interpret (Fig. 805). The blisters
do not easily undergo impetiginization and heal rapidly without
complications. They arise on apparently intact skin or with no evident
individual papulo-nodular lesions; this is in stark contrast to the
more common form of mastocytosis with blisters arising on pre-existent
papular or nodular lesions.
Bullous mastocytosis is the most severe form
of the disease in children, as it may be associated with complications
such as gastrointestinal bleeding and shock (10). However, even in
those cases the long term prognosis is good, with the severity of
symptoms and signs diminishing in time and with tendency to
spontaneous resolution.
We encountered no cases of telangiectasia macularis eruptiva perstans
in children, a variant typically seen in adults.
Our series included no patients with systemic
mastocytosis. That this form of the disease is typically
found in adults (Fig. 809) was confirmed in a recent study (6) of 26
cases, where the mean age of the patients was 32 years.
However, the involvement of other organs
increases with the effort expanded in demonstrating it. In the study
of Webb et Al. (38), laboratory investigations brought to light
systemic involvement in almost half the adult patients (14 of 30) with
the diagnosis of urticaria pigmentosa.
When called upon, the most useful technique for demonstration of
systemic involvement in those cases is bone scan with 99-Tc methylene
diphosphonate.
Bone involvement may also be demonstrated with non invasive techniques
in approximately one seventh of children with urticaria pigmentosa
(34). However, this involvement can not always be confirmed by bone
biopsy, as the lesions may be focal and, as they regress spontaneously
together with the skin lesions, their presence does not affect the
prognosis in cutaneous mastocytosis. Consequently, bone biopsy is not
usually justified.
The same considerations apply to involvement of the liver, spleen and
lymph node: in urticaria pigmentosa focal accumulations of mastocytes
may be demonstrated in biopsies of these tissues (34).
Our series also did not include cases of malignant
mastocytosis, another form of the disease restricted to
adults. In a series of 500 cases of urticaria pigmentosa a recent
study of the incidence of malignant diseases (6) identified 6 cases of
haematological malignancies. Of these the onset of the disease was in
the first few months of life in 2 and later in 4 cases.
Laboratory findings.
Although numerous metabolites of mastocytes
can be measured in plasma and urine, none of these stood out in the
diagnosis or prognosis of the disorder, probably because the clinical
features are enough good indicators from a diagnostic and prognostic
point of view.
According to Van Gysel et Al. (12) the urinary levels of
N-methylhistamine are directly related to the extension and activity
of mastocytosis. Morrow et Al. (26) prefer the main urinary metabolite
of prostaglandin D2.
The dosage of triptase is promising. There are two classes of triptase,
namely alpha and betatriptase. The plasma levels of alpha-protriptase
are related to the overall quantity of mastocytes, whereas
betatriptase, which usually lacks in the plasma, is related to the
degree of mastocyte activation (16).
Diagnosis.
The diagnosis of mastocytosis is clinical in most cases. The clinical
history of transitory reddening and wheals or blisters and flushing
episodes, when associated with the clinical signs, is usually
pathognomonic. Some difficulties arise in case of macular mastocytosis.
In the latter form reddening and wheals can lack and also Darier’s
sign can hardly be elicited. Also the pathological findings may be
doubtful due to the scarce number of mastocytes. In this case the
immunohistochemical staining for triptase can be helpful (15).
Differential
diagnosis. Cutaneous
mastocytosis must be distinguished from ashy dermatitis or erythema
dyschromicum perstans, nodular scabies, neurofibromatosis, juvenile
xanthogranuloma and macular amyloidosis.
Ashy dermatitis (Fig. 811)
is characterized by the presence of greyish maculae mainly on the
trunk, often with a distribution pattern, which is reminiscent of
pityriasis rosea. It is more common in adolescents, but may occur in
children. The Darier’s sign is negative. If required, histological
examination will show normal numbers of mast cells and an accumulation
of melanic pigment in the papillary dermis.
In a few children scabies (Fig. 813) may present
in the form of inflammatory nodular lesions, which in advanced disease
may be its only clinical sign. The nodules may cyclically swell and
become intensely itchy. When stroked they may urticate slightly
simulating positive Darier’s sign. However, the history, the family
history and the lesions’ predilection for the axillae clinches the
diagnosis.
Neurofibromatosis (Fig. 812) must be
distinguished from certain superficial macular forms of mastocytosis (Fig.
810), where also the Darier’s sign is not well defined. In
neurofibromatosis there is usually positive family history, the
patches vary greatly in size, their edges are clear cut and they are
often found in the axillae and on the limbs. In time new lesions
develope and the pre-existent ones remain unchanged.
Cases of urticaria pigmentosa with yellowish
(Fig. 802, 803) discoloration (mastocytosis xanthelasmoidea) must be
differentiated from juvenile xanthogranuloma, a disease in which
positive Darier’s sign has been reported (29). In extreme cases the
problem of differentiation can be easily solved by histological
examination.
Cutaneous mastocytosis must also be distinguished from certain rare
conditions, such as macular amyloidosis.
Treatment. The
points to remember before treatment for children with cutaneous
mastocytosis is prescribed are the long clinical course of the disease
and its tendency to spontaneous resolution.
In a majority of the patients there is no need for symptomatic
treatment. Continuous administration of antihistamines is not free
from risks. The most severe crises resulting from release of histamine
were observed by us after sudden arrest of prolonged antihistamine
therapy. These drugs may be continued over some months only in diffuse
bullous mastocytosis.
Occasional administration of antihistamines in histaminergic episode
of non anaphylactic type is useless as the episode comes to its
spontaneous end before the drug reaches effective blood levels.
Exposure to sun in the summer is advisable, especially in children
over two years of age, but photochemotherapy in children may be
dangerous.
Cimetidine, disodium cromoglycate and aspirin have been used by
various Authors with contradictory results in the treatment of
mastocytosis (32, 34, 39).
Katoh et Al. (17) treat two cases of isolated mastocytoma with
tranilast, which is a mastocyte stabilizer used in the treatment of
atopic disorders. They reporte a rapid regression of symptoms and
signs and show by histological examination a decrease of mastocytes.
However, both children are treated for six months and one of them
starts the treatment at the age of 10 months. In a disorder such as
mastocytoma, which spontaneously regresses, sometimes rapidly,
whatever therapeutic result should not surprise.
Above all in cases of particularly massive mastocytic concentrations,
it may be advisable to avoid ingestion or exposure to
histamine-releasing substances. The latter include aspirin, morphine,
codeine, polymyxin B, thiamine, d-tubocurarine, ATP, stings of
hymenoptera, vasoactive polypeptides contained in sea foods, lobsters,
etc..
In most cases of urticaria pigmentosa and mastocytoma, which have
already entered the regression phase, is not necessary aprioristicly
avoid histamine releasing dyes and preservatives.
The only really usefule advice is avoiding mechanic, thus even the
application of creams, and thermic stimuli.
Sporadic cases of systemic mastocytosis in adults responded to the
treatment with cyclosporin, methylprednisolone (21) and interferon
gamma (8). These drugs are not useful in childhood mastocytosis.
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