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Mastocytosis
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Definition
Mastocytosis is a proliferation of mast cells and
their subsequent accumulation in one or more
organ systems.
Mast cells are derived from hematopoietic
progenitors, thus mastocytosis is a
hematopoietic disorder.
The manifestations of mastocytosis are
heterogeneous, ranging from skin lesions that
may spontaneously regress to highly aggressive
neoplasms associated with multisystem
involvement and short survival times.
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Definition
In cutaneous mastocytosis (CM), the mast
cell proliferation is confined to the skin.
Systemic mastocytosis (SM) is characterized
by involvement of at least one extracutaneous
organ, with or without evidence of skin
infiltration.
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Synonyms
Mast cell disease
Mast cell proliferative disease
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Epidemiology
Mastocytosis may occur at any age.
Cutaneous mast cell disease is most common
in children.
It may be present at birth, and 80% of afflicted
children demonstrate lesions by 6 months of
age.
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Epidemiology
In adults, CM usually appears in the third and
fourth decade of life.
There is no sex predilection reported for CM.
Systemic mastocytosis is generally diagnosed
after the third decade of life; the male to female
ratio has been reported to vary from 1 to 1:3.
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Sites of Involvement
Skin: in approximately 80% of patients, only the
skin is clinically involved. Skin lesions occur in
50% or more of the patients with SM, and when
present they usually imply an indolent course.
BM: in patients who have SM, BM involvement
is almost always morphologically apparent, and
a BM biopsy is the usual specimen from which
the diagnosis of SM is established.
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Sites of Involvement
PB: PB rarely shows circulating mast cells.
Other organs: spleen, lymph nodes, liver
or GI tract, but any tissue may show
deposits of abnormal mast cells.
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Clinical findings: Cutaneous Mastocytosis
Includes several distinct clinicohistopathological
entities.
The lesions of all forms of CM may urticate
when stroked (Darier's sign) and most may
show pigment which is epidermal in location.
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Clinical findings: Cutaneous Mastocytosis
The term "urticaria pigmentosa" describes
these two clinical features (urticaria and
hyperpigmentation) and has been used as a
general term for all forms of cutaneous
mastocytosis.
Blistering or bullous mastocytosis represents
an exaggerated Darier's sign, usually in very
young patients, and can occur in any form of
pediatric mastocytosis.
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Cutaneous matocytosis, macular lesions
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Darier’s sign (urticaria)
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Clinical findings: Systemic Mastocytosis
Organ dysfunction may be due to infiltration by
mast cells or to the release of various biochemical
mediators, such as histamine, eicosanoids,
proteases or heparin.
GI complaints, such as peptic ulcer disease and
diarrhea, are more commonly due to release of
biologically active mediators than to infiltration of
the GI tract by abnormal mast cells.
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Clinical findings: Systemic Mastocytosis
Signs and symptoms at presentation that can
generally be grouped into the following categories:
1) constitutional symptoms: fatigue, weight loss,
fever, sweats
2) skin manifestations: pruritus, urticaria,
dermatographism
3) mediator-related events: abdominal pain, GI
distress, flushing, syncope, hypertension, headache,
hypotension, tachycardia, respiratory symptoms
4) bone-related complaints: bone pain, fractures,
arthralgia
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Clinical findings: Systemic Mastocytosis
Physical findings at the time of diagnosis may
include splenomegaly.
Lymphadenopathy and hepatomegaly are found
less frequently.
Symptoms are mild in many patients, but in
others the mediator-related events or organ
impairment may be life threatening.
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Clinical findings: Systemic Mastocytosis
Hematological abnormalities occur in a significant
number of patients with SM.
Anemia, leukocytosis or leukopenia, and
thrombocytopenia or thrombocytosis may occur;
bone marrow failure can be seen in patients with
marked marrow infiltration.
Eosinophilia may be observed, and is sometimes
so marked that it mimics the hypereosinophilic
syndrome.
Circulating mast cells are infrequently observed,
except in rare cases of mast cell leukemia.
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Clinical findings: Systemic Mastocytosis
In up to 20-30% of cases of SM, an
associated, clonal hematopoietic, non-mast
cell lineage disorder (AHNMD) may be
discovered simultaneously or after the
diagnosis of mastocytosis.
In such cases, symptoms may be related to
the associated hematological disorder as well
as to the SM.
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Clinical findings: Systemic Mastocytosis
Serum total tryptase is a useful test in the
evaluation of patients with mastocytosis.
In the absence of other myeloid disorders, the
finding of serum total tryptase levels >20 ng/mL
is indicative of SM.
In contrast, serum total tryptase levels are
normal (<1 to 15 ng/mL) or only slightly elevated
in patients with pure CM.
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Systemic mastocytosis: X-ray shows lytic lesions, osteosclerosis, and osteoporosis
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Etiology
The cause of mast cell disease is unknown.
Rare familial cases are reported.
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Mast cells are covered with IgE and a variety of receptors. When engaged by appropriate antigens, they release their contents, including histamine, heparin, proteases and prostaglandines.
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Morphology
The diagnosis of mast cell disease requires
the demonstration of multifocal clusters or
aggregates of mast cells in an adequate
biopsy specimen.
Staining of tissue sections with Giemsa or
for mast cell tryptase are strongly
recommended for confirmation of the
diagnosis.
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Morphology
The histological pattern of the mast cell
infiltrate may vary according to the tissue
sampled.
If the mast cells are loosely scattered
without forming aggregates, it may be
impossible to establish the diagnosis
without additional studies, such as
demonstration of an aberrant phenotype,
detection of point mutations of KIT, or
additional biopsies.
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Morphology: Normal Mast Cells
On H&E, normal mast cells usually display a round
to oval nucleus with clumped chromatin, low N/C
ratio, and no or indistinct nucleoli.
They have moderately abundant oval or polygonal-
shaped cytoplasm filled with small, faintly visible,
slightly eosinophilic granules.
They are usually sprinkled diffusely in tissues
without forming clusters.
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In smear preparations, mast cells are readily
visible in Romanowsky stains as round, oval
or polygonal cells with cytoplasm densely
packed with small, deeply basophilic
granules, and round or oval nuclei.
Morphology: Normal Mast Cells
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Normal mast cells, gastric biopsy Mast cell hyperplasia, bone marrow
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In mastocytosis, the cytology of mast cells
is variable.
In some cases they may closely resemble
normal mast cells, but more frequently at
least a proportion of the cells have
abnormal cytologic features, in that they are
more spindle-shaped, and have reniform or
indented nuclei.
Morphology: Mastocytosis
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In some cases, neoplastic mast cells have
abundant cytoplasm with sparse granules.
This feature may be appreciated in tissue
sections as pale, almost clear cytoplasm, in
which case the mast cells may resemble
histiocytes, or the cells of hairy cell
leukaemia, monocytoid B cell lymphoma, or
other disorders characterised by "clear"
cells.
Morphology: Mastocytosis
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In smear preparations, mast cells may
demonstrate so few granules that their mast
cell origin may not be readily appreciated
even in the Romanowsky stains.
This is particularly true of immature mast
cells ("nonmetachromatic" and
"metachromatic" blasts) seen in the high
grade lesions, such as mast cell leukemia.
Morphology: Mastocytosis
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The finding of mast cells with bi- or multi-
lobated nuclei usually indicates an
aggressive mast cell proliferation, and
although they are commonly observed in
mast cell leukemia, they may be seen in
other subtypes of the disease as well.
Mitotic figures are generally scarce, even in
the aggressive variants.
Morphology: Mastocytosis
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Morphology: Stains
All mast cell proliferations should be
confirmed by special stains. Metachromatic
stains (Giemsa, toluidine blue) are strongly
recommended as routine stains for mast
cells.
Fixation methods commonly employed for
bone marrow biopsies, however, may result
in no or diminished toluidine blue staining.
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The most specific method for identification
of mast cells in all tissues is
immunohistochemical staining for mast cell
tryptase.
Naphthol ASD chloroacetate esterase and
CD117 are also characteristic markers of
mast cells, but they are not specific.
In contrast to normal mast cells, CD2 and
CD25 are reportedly expressed on the
surface of neoplastic mast cells.
Morphology: Stains
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Systemic mastocytosis, bone marrow aspirate and biopsy
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Toluidine blue
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Tryptase, bone marrow Urticaria pigmentosa, skin
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C-kit (CD117)
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c-kit (CD117)
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Tryptase
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Cutaneous mastocytosis
The diagnosis of CM requires the
demonstration of typical clinical findings and
histological evidence of infiltration of the skin
by mast cells.
In cases of pure cutaneous mastocytosis,
there is no evidence for any systemic
involvement, such as elevated levels of total
serum tryptase or organomegaly.
Three major variants of CM are recognized
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Cutaneous mastocytosis Urticaria pigmentosa (UP) /
Maculopapular Cutaneous
Mastocytosis (MPCM).
This is the most frequent form of CM.
In children, the lesions of UP tend to be papular,
and are characterised by aggregates of elongated
or spindle-shaped mast cells which typically fill the
papillary dermis and extend as sheets and
aggregates into the reticular dermis, often
following the vasculature.
A subvariant is a non-pigmented, plaque-forming
lesion that most often occurs in infants.
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Cutaneous mastocytosis Urticaria
pigmentosa (UP) / Maculopapular Cutaneous
Mastocytosis (MPCM).
In adults the lesions tend to be macular, more darkly
pigmented, and sometimes associated with
telangiectasia.
Some authorities refer to the small hyperpigmented
macular lesions of adult-type UP as the telangiectasia
macularis eruptiva perstans subvariant (TMEP).
Others reserve TMEP for a more rare form characterised
by a small number of larger lesions (>1cm) which are
lightly pigmented, telangiectatic macules with minimal
or no increase in the number of mast cells.
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Telangiectasia macularis eruptive perstans (TMEP), skin
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Telangiectasia macularis eruptive perstans (TMEP), skin
Toluidine blue
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Cutaneous mastocytosis Urticaria pigmentosa (UP) /
Maculopapular Cutaneous
Mastocytosis (MPCM).
Adult UP tends to have fewer mast cells than
the lesions in children, and in some macular
lesions the number of mast cells may overlap
with the upper range seen in normal or
inflamed skin.
In such cases, examination of multiple
sections for aggregates of mast cells or
biopsies of multiple lesions may be necessary
to establish the diagnosis.
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Cutaneous mastocytosis: Diffuse Cutaneous Mastocytosis
This lesion is less frequent than UP, and is
seen almost exclusively in children.
Patients lack the typical maculopapular
lesions of UP, and may have relatively
smooth skin, red skin, or skin which is
greatly thickened (peau chagrine, grain
leather skin).
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Cutaneous mastocytosis: Diffuse Cutaneous Mastocytosis
Histologically, in patients with less clinically
obvious infiltration of the skin, the biopsy
may show a band like infiltrate of mast cells
in the papillary and upper reticular dermis.
In nodular, plaque-like or greatly infiltrated
skin lesions, the histological picture may be
identical to that seen in solitary
mastocytoma.
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Cutaneous mastocytosis: Mastocytoma of Skin
This occurs as a single lesion, usually in
infants, with a predilection for the trunk and
wrist.
Sheets of mast cells with abundant
cytoplasm fill the papillary and reticular
dermis, and may extend into the deep
dermis and subcutaneous tissues.
There is no cytologic atypia.
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Mastocytoma, skin
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Solitary mastocytoma
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Systemic Mastocytosis (SM)
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Bone Marrow
-Distribution:
Multifocal, peritrabecular perivascular, random
-Central core of lymphocytes
mast cells in peripheral
reactive Eos in marginal
-Monomorphic spindle cells, streaming along trabecular
bones or diffuse resembling fibrosis
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BM
Careful inspection of BM in other areas for:
-Hypercellular marrow: Neutrophil, Eos
-Coexisting hematopoietic neoplasms:
AML, MPD, MDS, LPD
Hypercellularity and abnormal maturation: unfavorable outcome
Reactive non-clonal mast cells: no cytological atypia,
sprinkled interstitially
Diagnostic: core bx
aspirate could be underrepresented
mast cell leukemia: sheets, irregular nuclei, prominent nucleoli
poorly granulated, 20% or more in BM, 10% or more in PB smear
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Systemic mastocytosis, bone marrow
Tryptase
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Systemic mastocytosis associated with hairy cell leukemia, bone marrow
Tryptase CD20
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Mast cell leukemia, bone marrow
Tryptase
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Lymph node
-Infiltrate paracortical but any compartment
-Often accompany:
hyperplastic germinal centers and vessels
eosinophilia, plasmacytosis, fibrosis
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Systemic mastocytosis, lymph node
Tryptase
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Systemic mastocytosis with eosinophilia
Peripheral blood Lymph node
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Spleen
Any compartment, focal and diffuse, para-follicular
or -trabecular
Eosinophilia, fibrosis and plasmacytosis
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Liver
-Small foci of atypical mast cells
-Sinuses, periportal areas
-Fibrosis, 20%
-Occasional full cirrhosis
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Skeletal lesions
Osterosclerosis: most common
Lytic lesions and osterosclerosis concurrently
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-Exceedingly rare
-Localized destructive growth
-Highly atypical, immature mast cells
-Distant spread possible
-Leukemic phase
Mast cell sarcoma
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Extracutaneous mastocytoma -Localised, mature mast cells
-Very rare
-Most reported cases were in lung
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Cytochemistry/immunophenotype
Positive:
-Chloroacetate esterase(except of poorly differentiated)
-CD45,33,68,117
-Mast cell tryptase
-Chymase (subpopulation)
Negative:
-CD14,15,16 and T or B Ags
(except CD2 and CD25, contrast to normal mast cells)
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Genetics
C-Kit: vast majority of adults with SM
Rare cases of pediatric CM, atypical
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Prognosis and predictive factors
Favorable:
Cutaneous mastocytosis in children
SM with CM
Indolent SM, no impact on survival
Unfavorable:
Adults, CM rarely regress, often related with SM
Mast cell leukemia, weeks or months
Mast cell sarcoma
SM without CM
Hematological neoplasms