MAST CELL DISEASE
Mast cell
disease is an uncommon condition that has many clinical variants and subtypes.
It can be seen as a solitary finding, as in the solitary mastocytoma, or it can
result in widespread cutaneous disease, as in urticaria pigmentosa. Most mast
cell disease is caused by an abnormality in the c-kit gene (KIT).
There are many other forms of mast cell disease, most in the benign category;
some affect the skin predominantly, and others are more systemic in nature. One
systemic type is the rare mast cell leukemia. Other systemic forms have been
reported, such as mast cell sarcoma, and carry a poor prognosis. It is
important to recall that mast cells are derived from the bone marrow and share
certain things in common with other hematopoietic cells. The World Health
Organization (WHO) has developed a simplified classification system for mast
cell disease (see box to right).
Clinical
Findings: Solitary mastocytoma is one of the most common of all the mast cell
disease types. It manifests in early childhood, often in the first few years of
life. It appears as a yellowish to brownish macule, papule, or plaque. On rare
occasions, a lesion develops a vesicle or bulla. Most lesions are asymptomatic
until rubbed or scratched. When this takes place, a localized urticarial
reaction occurs above the mastocytoma and extends into the surrounding skin.
This sign, called Darier’s sign, can be used in any of the cutaneous mast cell
diseases to help make the diagnosis. These solitary mast cell collections
almost always spontaneously resolve with no sequelae.
Urticaria
pigmentosa is a more diffuse affliction of the skin with mast cells; it has
been reported to be the most common variant of mast cell disease. From a few to
hundreds of slightly hyperpigmented macules and plaques occur across the
surface of the skin. Some develop into vesicles and bullae. This most commonly
occurs in early childhood but has also been reported to occur in adulthood.
Most children are diagnosed on the basis of the clinical presentation and
demonstration of a positive Darier’s sign. The condition typically runs a
benign course in children, and most cases spontaneously remit over a few years
and then disappear at about the time of puberty. Adult-onset urticaria pigmentosa
is a more chronic disease that rarely remits. Special care should be taken to
continually screen adult patients for the development of systemic mast cell
involvement.
Telangiectasia
macularis eruptiva perstans is a less commonly seen variant of mast cell
disease. It occurs almost exclusively in the adult population. Patients often
present with widespread telangiectases in unusual locations such as the back,
chest, and abdomen. There can be a background erythema, and Darier’s sign may or may not be present.
The most common symptom is pruritus. The appearance can be bothersome for some.
It is most often limited to the skin, but the clinician should evaluate for
systemic involvement.
Measurement
of the serum tryptase level is the most accurate means of screening for
systemic involvement with mastocytosis. Levels in the normal range indicate
cutaneous disease only; levels greater than 20 ng/mL are indicative of
systemic involvement, and further systemic workup is warranted. Urine histamine
and histamine metabolites can also be assessed but seem to be less sensitive
and less specific than the serum tryptase level. If systemic involvement is
considered, further testing with a bone marrow biopsy may be indicated.
Molecular genetic testing can be performed on the bone marrow sample to assess
for the KIT gene mutation.
Histology:
The
histological features depend on the form of mast cell disease. Most biopsy
specimens show an excessive number of mast cells, typically surrounding the
cutaneous vasculature. These mast cells are best appreciated with special
staining techniques. The Leder (chloracetate esterase) stain, the Giemsa stain,
and the toluidine blue stain are the most commonly used special stains to help
highlight the cutaneous mast cells. CD117 immunostaining also stains mast
cells.
Pathogenesis:
Darier’s
sign is caused by direct release of histamine and other inflammatory mediators
from the excessive collection of mast cells within the affected skin. On direct
stimulation such as scratching or rubbing, the mast cells automatically release
the contents of their granules. These granules contain histamine and other
vasoactive substances that cause edema, redness, and pruritus.
Mast cell
disease is caused by a mutation in the KIT gene. KIT is a
protooncogene that encodes a protein called stem cell factor receptor (SCFR).
SCFR is a transmembrane protein tyrosine kinase protein. This receptor is
prominent in two skin cell types, mast cells and melanocytes. It is also
present on a host of other primitive hematological cell types. Stem cell factor
is also known by various other names, including KIT ligand, CD117, Steel
factor, and mast cell growth factor. It is the molecule that binds to the
transmembrane SCFR and acts to promote the reproduction of mast cells. The
activating mutation of SCFR seen in mast cell disease causes an upregulation of
signaling via this pathway and an uncontrolled proliferation of mast cells. The
continuous activation of the stem cell factor allows for prolonged survival of
mast cells, which also contributes to their increased number. Numerous
mutations of KIT have been described, and it is believed that the
different mutations play a role in the varied clinical expression of the
disease. The most common mutation is a D816V mutation that is caused by replacement
of the normal aspartic acid at the 816 position with a valine amino acid.
Treatment:
Cutaneous
mast cell disease in children is often self-limited and resolves spontaneously
with time. Therapy with antihistamines may help decrease the pruritus and
provide symptomatic relief until the condition resolves on its own. The most
important aspect for children with cutaneous mast cell disease, especially
urticaria pigmentosa, is to avoid agents or physical insults that may cause
massive degranulation of mast cells. These triggers include medications such as
anesthetics, narcotics, polymyxin B, and many others. Physical triggers include
extremes of temperature, vigorous exercise, repeated rubbing of the involved
skin, and many other stimuli
that differ from individual to individual.
Antihistamines
are the mainstay of therapy. The leukotriene inhibitors are also used as
adjunctive therapy to the antihistamines. Cromolyn is a mast cell stabilizer
that is not absorbed through the gastrointestinal tract. Its use is limited to
treatment of coexisting diarrhea caused by mast cell disease of the gut.
Telangiectasia macularis eruptiva perstans has been treated with the 585-nm pulsed dye laser
to decrease the redness and telangiectases for cosmetic purposes. Some success
has been achieved in treating systemic disease with the tyrosine kinase
inhibitor, imatinib. Depending on the symptoms and the body systems involved,
systemic chemotherapy may be warranted to decrease the mast cell load. These
agents rarely put patients into long-term remission, and the response is
transient. At this point, there
is no cure for mast cell disease.
