CRISBERT I. CUALTEROS, M.D. - Mastocytosis: molecular mechanisms and clinical disease
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CRISBERT I. CUALTEROS, M.D. Family and Medicine

Mastocytosis: molecular mechanisms and clinical disease

Dean D. Metcalfe, Cem Akin

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 11C205,
10 Center Drie MSC 1881, Bethesda, MD 20892-1881, USA

Received 25 October 2000; accepted 6 February 2001


Systemic mastocytosis has one unifying feature: an unexplained and pathologic increase in mast cells in specific tissues. This
observation, along with clinical disease heterogeneity has long suggested that mastocytosis is a disease of complex etiology. At the
same time, the last decade has witnessed significant progress in identifying the critical elements that regulate mast cell growth and
development. Human mast cells are now known to arise from CD34+
progenitors, particularly under the influence of stem cell
factor (SCF). This information in turn led to the critical observation that a substantial number of patients with mastocytosis
exhibit activating mutations in c-kit, the receptor for SCF. And while this observation may well be key in understanding
mastocytosis, this mutation alone does not explain all heterogeneity. It now appears that other influences such as genetic
polymorphisms within the host may influence the course of disease in those with KIT mutations; and that the search for additional
molecular events capable of creating disease diversity must continue. Published by Elsevier Science Ltd.

Keywords: Mastocytosis; Mutation; Stem cell factor

1. Clinical disease heterogeneity
1.1. Introduction
Mastocytosis is an unusual disease characterized by
variable mast cell hyperplasia and associated pathologic
changes in the skin, bone marrow, liver, spleen, lymph
nodes, and gastrointestinal tract. In 1869, Nettleship
described urticaria pigmentosa (UP) [1] and in 1887
Unna documented an increase in mast cells in UP [2].
Systemic disease associated with mast cell hyperplasia
was reported by Ellis in 1949 [3]. Patients with mastocytosis
also suffer from one or several of the following:
vascular instability, skin irritation, abdominal pain,
musculoskeletal pain, headache, diarrhea, and fatigue,
and problems due to abnormal hematopoiesis.

Abbreiations: SCF, stem cell factor; KIT, receptor for stem cell
factor; c-kit, gene for KIT; FceRI, high-affinity Fc receptor for IgE;
IL, interleukin; UP, urticaria pigmentosa; DCM; diffuse cutaneous

1.2. Patterns of disease
UP is the most common cutaneous manifestation of
mastocytosis and is the usual presenting feature of
mastocytosis in both children and adults. Lesions of
UP appear as small yellow-to-tan to red–brown macules
or slightly raised papules. UP in children may
resemble the adult pattern, although lesion size is variable.
In unusual cases, skin lesions may be nodular in
character. Diffuse cutaneous mastocytosis (DCM) is a
second, less common form of cutaneous mastocytosis.
The entire cutaneous integument is involved, resulting
in thickened skin that may appear yellow–brown.
Young children with UP or DCM may have bullous
eruptions with hemorrhage [4].

Clinical heterogeneity is a hallmark of mastocytosis.
Not only is this true for skin manifestations, but for
other clinical features as well. Both children and adults
with cutaneous or systemic disease may experience pruritus
and spontaneous episodes of flushing or hypotension.
Patients with systemic disease usually develop
gastrointestinal symptoms, including abdominal pain,
diarrhea, nausea, and vomiting [5]. These symptoms
may be associated with gastritis and peptic ulcer disease
due to hyperhistaminemia; in more advanced
cases, symptoms are associated with malabsorption
due to mucosal infiltration with mast cells and other
inflammatory cells. Significant liver disease,
splenomegaly, and ascites may occur, particularly
within advanced cases. Hypersplenism may exacerbate
thrombocytopenia and anemia. Pancreatic function remains
normal. Muskuloskeletal pain is a complaint in
advanced disease. Pathologic fractures of the femurs
and other weight-bearing bones have been reported.

Mastocytosis may be diagnosed in conjunction with
a hematologic disorder. It is unusual for a patient
diagnosed as having mastocytosis with an associated
hematologic disorder to present with UP. Most patients
are diagnosed after a bone marrow examination
in evaluation of an unexplained neutrophilia,
eosinophilia, neutropenia, thrombocytopenia, or other
peripheral blood abnormality reveals characteristic
mast cell infiltrates associated with a hematologic disorder.
These hematologic disorders include myelodysplastic
syndromes and myeloproliferative disorders.
These associated hematologic disorders are rarely seen
in children, particularly if the onset of cutaneous disease
is before 6 months of age.

Patients with aggressive forms of mastocytosis may
present with only a several-month history of progressive
flushing, gastrointestinal discomfort, and fatigue.
UP of recent onset is observed in 50% of cases.
Hepatomegaly, splenomegaly, lymphadenopathy, and
weight loss may be recorded on the initial examination
or may develop in the first few months after
recognition of disease. Mast cell infiltrates and fibrosis
within the bone marrow may lead to marrow expansion.
As the disease progresses, malabsorption
develops, thus leading to weight loss. Compression
fractures of the spine may occur in association with
generalized osteoporosis. Mast cell leukemia is the
most rapidly progressive form of mastocytosis and is

The variability in clinical patterns of disease is paralleled
in biopsy findings: Mast cell hyperplasia in UP
or in DCM is usually obvious, and the number of
mast cells is, on average, 10 times greater than that
in normal skin. In the absence of characteristic
macroscopic skin lesions, small increases in dermal
mast cells are insufficient for diagnosis. By examining
the bone marrow biopsy and aspirate, characteristic
abnormal focal to diffuse collections of mast cells
may be identified within the hematopoietic marrow,
providing additional information for diagnostic categorization
[6–8]. Biopsies of liver, spleen, and lymph
nodes may also reveal mast cell hyperplasia [9].

Laboratory findings reflect various patterns of disease
and their severity. Mastocytosis may be accompanied
by elevations in plasma tryptase [10], plasma

histamine [11], PGD2 metabolites, and urinary histamine.
Elevations in these mediators are not diagnostic.
Elevations in tryptase, PGD2 metabolites, and
histamine also occur in association with systemic allergic
reactions and in association with idiopathic
anaphylaxis. However, elevations in one or more of
these mediators should raise the suspicion of mastocytosis.
Mastocytosis has also been diagnosed in the
absence of demonstrable elevations in histamine or
tryptase. More recent approaches such as measurement
of soluble levels of CD117 or CD25 in plasma

[12] may provide additional information as surrogate
markers of disease activity, progression, and response
to therapy.
The treatment of indolent mastocytosis is structured
for the individual. Basic management is principally
for symptom control [13]. H1-receptor
antagonists, such as hydroxyzine, reduce pruritus. H2receptor
antagonists, such as ranitidine, inhibit gastric
hypersecretion and prevent gastritis and peptic ulcer
disease. Prophylaxis with H1-and H2-antihistamines is
valuable if unexplained hypotensive episodes are frequent.
Hypotension has also been observed after insect
stings and administration of contrast media.
Aspirin and other nonsterodial anti-inflammatory
drugs (NSAIDs) may have therapeutic value in the
treatment of recurrent hypotension and flushing in
that they block the synthesis of prostaglandin D2
(PGD2). These medications should be administered
initially under controlled circumstances.

If skin involvement is extensive, patients may be
treated with Methoxsalen with long-wave ultraviolet
radiation [4]. Patients may sometimes report a decrease
in the number or intensity of cutaneous lesions
after repeated exposure to natural sunlight. Topical
steroids may also be an option. Lesions do reappear
after therapy is discontinued.

The treatment of intestinal disease is variable and
determined by the degree of cramping, diarrhea, and
malabsorption. Anticholinergics may give some relief.
Oral cromolyn sodium may be useful in the management
of abdominal symptoms. Systemic glucocorticoids
are effective in patients with severe malabsorption.

Patients with mastocytosis and an associated hematologic
disorder are managed as dictated by the specific
hematologic abnormality as diagnosed [13].
Splenectomy may improve the length of survival in
patients with forms of mastocytosis associated with
poor prognosis. Ascites is more often seen in mastocytosis
with an associated hematologic disorder and
in aggressive mastocytosis, and is difficult to control.
Portal hypertension has been successfully managed
with a portacaval shunt; exudative ascites has been
successfully treated with systemic glucocorticoid therapy.
2. Understanding mast cell growth and differentiation
While clinical research continued to report on pathologic
features of mastocytosis and response of patients
with this disease to various therapeutic approaches,
parallel research in mast cell biology was also determining
the origin of mast cells and identifying critical
growth factors that regulate human mast cell proliferation
and differentiation. Such research led the way to
discoveries that have significantly increased our understanding
of the genesis of mastocytosis.

Research in mouse systems demonstrated that mast
cells arise from pluripotential hematopoetic cells in the
marrow. Much of this work employed genetically mast
cell-deficient mutant mice. One of the mutants, the
WBBYF1-W/Wv mouse, ordinarily is devoid of mast
cells, but develops mast cells if it receives bone marrow
cells either from its normal littermates (WBB6F1-+/
or mice) or from semisyngeneic C57BL/6-bg/bg (‘beige’)
mice. This approach revealed that mouse mast cells
develop from bone marrow precursors [14] and that
W/Wv mice have an abnormality within mast cell precursors.
In contrast to the WBB6F1-W/Wv mouse, the
genetically mast cell-deficient WCB6F1-Sl/Sld mouse
does not develop mature mast cells after either local or
systemic injection of WCB6FI-+/
cells containing
mast cell precursors [15]. The Sl/Sld mouse bone marrow
cells do, however, differentiate into tissue mast
cells after intravenous injection into W/Wv mice. The
mast cell deficiency of the Sl/Sld mouse thus reflects an
abnormality of tissue microenvironmental factors regulating
mast cell differentiation. These observations, as
well as others, led to the identification of products of
the W or Sl loci that regulate mast cell development.
The W locus is now known to encode the c-kit tyrosine
kinase receptor, Kit [16,17]. The Sl locus encodes Kit
ligand, also referred to as stem cell factor (SCF) [18–

Research into understanding human mast cell growth
and differentiation understandably followed behind observations
first reported in mouse systems, but in the
end yielded remarkably similar observations. Studies
employing in vitro culture techniques, first confirmed
that human mast cells were derived from human pluropotential
stem cells [21] and that SCF was the
critical growth factor supporting human mast cell proliferation,
differentiation, and survival [22,23].

3. Association of activation mutations in c-kit to
The identification of SCF as the essential growth
factor for human mast cell culture led to a search for an
elevation of SCF in serum obtained from patients with
mastocytosis. SCF was subsequently found to be the

same in normal individuals and those with mastocytosis.
However, it was observed that when equal numbers
of CD34+
cells obtained from normal donors, patients
with indolent mastocytosis, and patients with aggressive
forms of mastocytosis, were cultured under identical
conditions, and in the presence of equal concentrations
of SCF, more mast cells arose from CD34+
cells obtained
from those with aggressive disease [24].

This observation led our laboratory to search for
mutations in c-kit employing a variety of techniques
including single-strand conformation polymorphism
(SSCP) analysis of PCR products performed with overlapping
primer pairs. Employing this approach, four of
four adult mastocytosis patients with an associated
hematologic disorder with predominately myelodysplastic
features were found to have an A to T substitution
at nucleotide 2468 of c-kit mRNA (from peripheral
blood mononuclear cells [PBMC’s]) that causes an
Asp816 to Val substitution [25]. This point mutation is
identical to one of two mutations reported in the
HMC-1 cell line established from a patient with mast
cell leukemia and which has been shown to cause
ligand-independent phosphorylation of Kit [26]. The
clonality of mastocytosis was established when the
Asp816Val mutation was identified in mast cells from
more than one tissue in the same patient [27,28].

Further examination of c-kit mRNA levels in patients
with mastocytosis led to the observation that
c-kit mRNA was over-expressed in their PBMC’s, particularly
when PBMC’s were obtained from those patients
with clinical evidence of myelodysplastic
syndrome. Studies screening for the Asp816Val mutations
in PBMC’s in adult patients with mastocytosis
next documented that this mutation was not limited to
adult patients with myelodysplastic or myeloproliferative
syndromes, but could also be found in adults with
indolent mastocytosis. Asp816Val was also found in
children with severe mastocytosis [29]. Patients with the
Asp816Val mutation identifiable in PBMC’s more commonly
had osteosclerotic bone involvement as well as
immunoglobulin dysregulation and peripheral blood
abnormalities [29]. The Asp816Val mutation and chromosomal
abnormalities are both more common in patients
with mastocytosis with an associated hematologic
disorder [30]. Finally, the identification of Asp816Val in
lesional skin (UP) but not in PBMC’s or bone marrow
from an infant with mastocytosis suggested that involved
skin may be a preferable tissue to examine for
c-kit mutations due to the concentration of mast cells in
skin lesions which might bear the mutations [31].

Further mutational analysis of c-kit in children and
adults with mastocytosis has expanded our knowledge
of the extent of the occurrence of the Asp816Val mutation
and has identified additional mutations in Kit. In a
more recent study [32], an activating mutation
(Asp816Val, Asp816Phe or Asp816Tyr) was thus found 
in lesional skin of all adult patients. Among the children
examined, four with severe disease had codon 816
activating mutations; three had a dominant inactivating
mutation substituting lysine for glutamic acid in position
839. Three children with sporadic disease had no
mutations. No c-kit mutations were found in three
patients with familial mastocytosis [32]. Such data has
led to the suggestion that patients with mastocytosis
could be classified using molecular genetics [33].

Analysis of the occurrence of the c-kit Asp816Val
mutation in sorted peripheral blood cells has also contributed
to our understanding of the biologic diversity
of mastocytosis. The Asp816Val mutation has now
been detected in at least one lineage (T cells, B cells,
myelomonocytic cells) in the bone marrow of seven
patients examined with mastocytosis [34]. This mutation
was also observed in at least one lineage of cells in
peripheral blood where it could be identified most
frequently in B cells and myeloid cells. The finding that
ac-kit mutation exists in different hematopoietic cells
in addition to mast cells suggests that mastocytosis
(much like chronic myeloid leukemia) is a clonal hematopoietic
stem cell disorder. The central role for Kit in
this disease is also shown by the demonstration that
soluble levels of Kit (CD117) correlate with severity of
disease and bone marrow pathology [12].

3.1. Relationship of kit mutations to clinical diersity
It is thus clear that patients with mastocytosis exhibit
substantial disease heterogeneity in the age of onset of
disease, patterns of skin disease, degree of gastrointestinal,
liver spleen and lymph node involvement, hematopathology,
mediator levels, response to medications,
and prognosis. Given what is known about the receptors
and growth factors that regulate mast cell growth,
differentiation and survival and the prominent role for
an activating mutation in c-kit such as Asp816Val in
the many patients with this disease, it would seem that
a single mutation at codon 816 found in the majority of
mastocytosis patients is unable to explain this remarkable
disease heterogeneity.

Analysis of disease heterogeneity and specific examples
of disease progression suggests that there may be at
least four possibilities for the diversity of clinical manifestations
within patients with mastocytosis. The first
and most direct of these possibilities is that an activating
mutation at 816 is variably effective at promoting
exaggerated mast cell division in a given individual in
part because of genetic polymorphisms within the host
that influence the expression of the activating mutation
or mitigate its effects. One apparent example of this
possibility is the identification within this laboratory of
a polymorphism within the alpha chain of the IL-4
receptor. This polymorphism is statistically more common
in mastocytosis patients with more benign patterns

of disease, and is one that is believed to result in an
overactive IL-4 receptor. As it is reported that activation
of mast cells via the IL-4 receptor may decrease
mast cell proliferation or even induce apoptosis, this
then becomes an example of polymorphism that
benefits the host and limits expression of disease (Fig.

An equally possible scenario is that an activating
mutation at position 816 functions as a ‘permissive
mutation’ which allows the disease to develop if a
second (and even a third) mutation in critical pathways
were to arise. There are yet no proven examples of a
second mutation furthering the biologic effect of a
mutation at 816. But it would not be surprising, for
example, that some patients might develop mutations in
pathways that disrupt normal apoptosis and would
facilitate the survival of mast cells which bear the 816
mutation (Fig. 1(B)).

We have also observed one patient with myelodysplastic
disease in conjunction with mastocytosis who
exhibited a mutation at 816 identified in the initial
phases of disease. However, as the patient’s illness
evolved into leukemia, cells that came to predominate
in peripheral blood did not bear the 816 mutation [34].
Thus, at least in some patients, there may be an independent
second mutation in another group of cells and
where the second clone becomes the dominant clone
(Fig. 1(C)).

Equally possible is that the disease in this patient is a
result of a yet to be identified chromosomal instability
which in turn predisposed the patient to both the 816
mutation and other adverse events (Fig. 1(D)). The

Fig. 1. Molecular origins of mastocytosis: Theoretical possibilities
*Asp816Val or other activating mutation, **Variably expressed.

identification of chromosomal abnormalities in patients
with severe disease who have an 816 mutation suggests
that chromosomal instability may be a real possibility.
In reality and with time, as further information is
obtained from cells of involved lineages in mastocytosis,
it is likely that several, if not all of the possibilities
illustrated in Fig. 1, will eventually be determined to be
the means by which disease evolved in one or more

Yet to be determined also, is the genetic basis of
familial mastocytosis and the majority of childhood-onset
UP. The identification of the genetic basis of these
diseases should be extremely valuable in understanding
the genesis of mastocytosis. Thus, as defects in the
immune system involving lymphocytes have facilitated
the understanding of the regulatory pathways of
lymphocyte proliferation, survival, and expression of
function, so do diseases of mast cell hyperplasia and
proliferation help us understand the influences that
regulate the numbers and behavior of mast cells. It is
hoped that by understanding clinical disease heterogeneity,
mast cell growth and differentiation, and the
molecular basis of mastocytosis, those patients with
mastocytosis will benefit as these insights lead to new
and improved methods of treatment.


DD Metcalfe provided the concept, design, analysis
and interpretation of data, drafted the original article
and provided critical input for the revisions. In addition,
he provided administrative support and gave final
approval. C Akin contributed to the drafting of the
manuscript, provided critical revision of the article and
gave final approval.



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