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Mastocytosis (cutaneous and systemic):

Epidemiology, pathogenesis, and clinical
manifestations
Authors:
Mariana C Castells, MD, PhD
Cem Akin, MD, PhD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2019. | This topic last updated: Jun 12, 2018.

INTRODUCTION Mastocytosis refers to a group of disorders characterized by

excessive mast cell accumulation in one or multiple tissues. Mastocytosis is subdivided

into two groups of disorders [1,2]:
●Cutaneous mastocytosis (CM) describes forms of mastocytosis that are
limited to the skin.
●Systemic mastocytosis (SM) describes forms of mastocytosis in which
pathologic mast cells infiltrate multiple extracutaneous organs, with or without
skin involvement.

The epidemiology, pathogenesis, classification, and clinical manifestations of CM and

SM will be reviewed here. The evaluation, diagnosis, treatment, and prognosis of
mastocytosis are discussed separately. (See "Mastocytosis (cutaneous and systemic):
Evaluation and diagnosis in adults" and "Systemic mastocytosis: Management and
prognosis".)

EPIDEMIOLOGY Mastocytosis, in all of its forms, is a rare disorder. The

exact incidence is unknown. Mastocytosis affects males and females in equal ratios,
although there is a slight male predominance in childhood and a slight female
predominance in adulthood [3].
●In children, 80 percent of mastocytosis cases appear during the first year of
life, and the majority is limited to the skin. Most eventually improve or resolve
completely by adolescence [4-6].
●Adults who develop mastocytosis more often have systemic forms of the
disease, and these disorders tend to persist [7]. Cutaneous forms of the
disease account for less than 5 percent of adult cases.

PATHOGENESIS The pathogenesis of all forms of mastocytosis results from

both chronic and episodic mast cell-mediator release and excessive mast cell
accumulation in one or more tissues. Mast cells contain a variety of vasoactive
mediators and normally function to protect the body from microbial invaders and other
insults by releasing these chemicals to generate inflammatory responses. Mediators
released from mast cells include histamine, heparin, leukotrienes, prostaglandins,
platelet-activating factor, proteases, and cytokines, including tumor necrosis factor
(table 1). The signs and symptoms associated with sudden and extensive mast cell-
mediator release are similar to those associated with allergic and anaphylactic
reactions. (See 'Clinical manifestations' below and "Mast cell-derived mediators".)

In addition to mediator release, some advanced forms of mastocytosis involve signs and
symptoms arising from tissue infiltration by mast cells, effects of local accumulations of
these cells, and the presence of an associated hematologic neoplasm.

Molecular abnormalities — The molecular pathogenesis of mastocytosis is

incompletely understood. Stem cell factor (SCF), also called kit ligand, is a growth factor
that is essential for normal development and expansion of mast cells from
hematopoietic progenitors. Mast cells express a receptor for SCF on their surface, the
receptor tyrosine kinase KIT (CD117). Many of the molecular defects associated with
mastocytosis involve gain-of-function mutations in KIT, the gene encoding KIT [8,9].
There are limited data that SCF overexpression may play a role in some cases.

Most other hematopoietic cells express KIT early in their development and then lose it
during maturation, becoming unresponsive to SCF. Only mast cells maintain KIT and
remain responsive to SCF throughout the lifetime of the cell. Thus, abnormalities in SCF
regulation or KIT preferentially affect the growth, differentiation, apoptosis, and
activation of mast cells.

Mutations in KIT — Activating and nonactivating mutations of KIT have been

implicated in the pathogenesis of both CM and SM [1,10-12]. However, no consistent
correlation between the type of mutation and either phenotype or prognosis has been
recognized [3,13,14].

●Greater
than 95 percent of adults with SM have exon 17 KIT mutations, most
commonly D816V. D816V KIT mutations are also common in skin lesions of
 adults with systemic disease, although data are more limited. One study of 59
adults with mastocytosis in the skin that developed in adulthood found that 58
had D816V KIT mutations in bone marrow cells, although only 74 percent had
the mutation demonstrable in lesional skin [15].
●In children, available data suggest that approximately 40 percent of children
with CM have exon 17 mutations, with another 40 percent
carrying KIT mutations outside of exon 17 [3,16].

The precise mechanism by which KIT-activating mutations enhance signaling is not fully
characterized, but these defects lead to SCF-independent activation [17]. Clonal
expansion and apoptotic defects of KIT-mutated mast cells are thought to provide the
basis for pathologic accumulation of mast cells in tissues [18].

The most common mutation detected in human mast cell disease occurs in the codon
816 and consists of the substitution of valine for aspartate (Asp816Val). Asp816Val is
present in most patients with SM and in some patients with different forms of CM
[13,15,19-23]. This mutation results in a putative-activating loop in the kinase domain. In
transfection studies, it causes ligand-independent autophosphorylation of KIT and
induces constitutive activation of the Stat5-PI3K-Akt signaling cascade [24]. Several
other KIT mutations have been reported as well [11,12,16,25]. Mast cell signal
transduction is reviewed separately. (See "Mast cells: Surface receptors and signal
transduction", section on 'Signal transduction'.)

Increased expression of stem cell factor — Increased expression of stem cell factor
(SCF), the ligand for KIT, has been linked to mastocytosis lesions in the skin in a group
of adults and children with cutaneous forms of mastocytosis [26]. Local mast cell
hyperplasia was linked to increased free SCF in the dermis and the extracellular spaces
between keratinocytes in skin samples, suggesting the increased presence of soluble
SCF, although SCF in the peripheral blood was not elevated, and the messenger RNA
sequence was not mutated [26]. However, another study demonstrated no differences
in SCF levels in peripheral blood and skin [27], so this abnormality appears to be
variable. In other studies of patients with SM, increased mast cell numbers could be
attributable to autocrine secretion of SCF by mast cells [28,29].

Other factors — Abnormalities in several other molecules have been noted in patients
with mastocytosis or cell lines derived from such patients, although their pathologic
importance requires further study:

●Constitutive expression of the stress-related survival factor heat-shock

protein 32 (Hsp32) in a human mast cell tumor line is another finding that may
prove relevant to the pathogenesis of SM [30]. Unregulated expression of
Hsp32 has also been implicated in chronic myeloid leukemia [31].
●Additional molecular aberrations were frequently identified
in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway in
patients with advanced forms of SM [32-35].
 ●Mast cells in patients with mastocytosis demonstrate abnormal expression of
surface interleukin (IL)-5 receptor, soluble CD25 (soluble IL-2 receptor alpha
chain), and soluble KIT [36,37].

Heritability — In the great majority of patients, mastocytosis does not appear to be

inherited, although it may be present at birth. It is also not passed down to offspring,
except in rare familial cases. KIT mutations are somatic mutations in most cases
[23,38]. They are rarely found in germline cells and are not polymorphisms but can be
found in some hematopoietic progenitor cells and other mature hematopoietic lineages
in some patients [39].

Rare familial cases have been reported, with KIT mutations demonstrated in some [40-
44]. Several pairs of monozygotic twins have been described in whom symptoms and
onset of disease were concordant, although other reports describe twins with discordant
disease [45].

CLASSIFICATION SYSTEMS A consensus clinical classification was

published by the World Health Organization (WHO) in 2001 and updated in 2008, which
represents the accepted clinical approach to categorizing mastocytosis [46-48].

Cutaneous mastocytosis — Cutaneous mastocytosis (CM) describes forms of

mastocytosis limited to the skin, in the absence of involvement of other organs. Skin
lesions in CM may be subdivided into subtypes:
●Urticaria pigmentosa (UP), also called maculopapular cutaneous
mastocytosis (MPCM), is the most commonly diagnosed form of CM. There
are several subtypes of MPCM:
•Monomorphic (picture 1), which is typically seen in adult patients
•Polymorphic MPCM (picture 2) (panel G), which is typically seen in
infants and young children
•Plaque form (picture 3)
•Nodular form (picture 4)
●Diffuse cutaneous mastocytosis (DCM) is rare (picture 5). Bullous forms
have been reported (picture 6 and picture 7) as a complication of DCM [49].
●Mastocytoma(s) of the skin is typically identified in infants and young
children (picture 8 and picture 9).
●Telangiectasia macularis eruptiva perstans (TMEP) (picture
10 and picture 11 and picture 12). (Note that the WHO classification does not
include this as a subtype of CM).

Systemic mastocytosis — Systemic mastocytosis (SM) involves an extracutaneous

site, most commonly the bone marrow and in some cases, the gastrointestinal tract [50].
SM presents with symptoms of mediator release, as well as signs and symptoms
related to infiltration of various noncutaneous organs by mast cells.
SM is further divided into four distinct disorders: indolent systemic mastocytosis (ISM),
systemic mastocytosis with an associated hematologic neoplasm (SM-AHN),
aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL) (table 2). The
different variants of SM are described briefly here and in more detail elsewhere.
(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".)

●Indolent systemic mastocytosis (ISM) – This is the most common form of

SM. As implied by the name, ISM follows a stable or slowly progressing
clinical course and carries a good prognosis in most patients. The following
are considered subvariants of ISM:
•Smoldering systemic mastocytosis (SSM) – This describes patients
with a high mast cell burden as evidenced by involvement of >30 percent
of the bone marrow space with mast cells and/or high tryptase levels
>200 ng/mL, liver or spleen enlargement without signs of hypersplenism
or functional liver impairment, and subtle signs of myelodysplasia or
myeloproliferation without overt diagnostic findings for myelodysplastic
syndrome or myeloproliferative disorder.
•Isolated bone marrow mastocytosis – This describes patients with
bone marrow involvement but without skin involvement.
●Systemic mastocytosis with an associated hematologic neoplasm (SM-
AHN) – The associated disorder may be myeloproliferative, myelodysplastic,
or lymphoproliferative.
● Aggressive systemic mastocytosis (ASM) – Patients with ASM have
tissue dysfunction, such as hepatic fibrosis and portal hypertension,
malabsorption, or cytopenias due to aggressive tissue infiltration by mast
cells.
●Mast cell leukemia (MCL) – This is a rare category of SM characterized by
presence of greater than 10 percent immature mast cells in the peripheral
blood or greater than 20 percent immature mast cells in bone marrow smears
in a nonspicular area.

Solid mast cell tumors — There are two types of solid mast cell tumors, both of which
are rare. These tumors are not categorized as either CM or SM:
●Mast cell sarcoma – These malignant tumors have been reported in the
tibia, skull, and other bones, as well as soft tissues [51-54].
●Extracutaneous mastocytoma – These are extremely rare benign tumors,
which are composed of mature mast cells and are located in a tissue other
than skin, such as the lung or skull, sometimes in older-aged patients [55,56].

CLINICAL MANIFESTATIONS Signs and symptoms of mastocytosis may

be grouped as follows (table 3):

●Skin findings (which may be present in both cutaneous and systemic forms
of mastocytosis)
 ●Symptoms arising from mediator release (which may be present in both
cutaneous and systemic forms of mastocytosis, as well as solid mast cell
tumors)
●Symptoms arising from (noncutaneous) organ infiltration (which are only
present in systemic forms of mastocytosis)

Skin findings and symptoms — Fixed accumulations of mast cells in the skin may
present as maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous
mastocytosis (DCM), or cutaneous mastocytoma [57,58]. The most common complaint
is pruritus, especially after exposure to a trigger, such as physical irritation or heat [41].
(See 'Triggers for mediator release' below.)

Patients or caregivers may also report flushing or blister formation. Generalized

urticarial and/or angioedema are not typical, and recurrent prominent urticaria should
prompt consideration of other allergic disorders.

Darier's sign — Darier's sign is defined as the development of localized urticaria and
erythema (within about five minutes) following rubbing, scratching, or stroking skin or
skin lesions that are heavily infiltrated with mast cells [57]. This finding arises when
physical irritation triggers the localized release of mast cell mediators. Darier's sign is
present in various forms of mastocytosis involving the skin, including MPCM, DCM, and
mastocytomas. Note that mastocytomas should not be purposefully rubbed, as this can
precipitate severe symptoms.

Urticaria pigmentosa — Urticaria pigmentosa (UP) (also called maculopapular

cutaneous mastocytosis [MPCM]) is the most common manifestation of mastocytosis in
children and adults [59]. Lesions of MPCM are characterized by small yellow-tan to
reddish-brown macules or slightly raised papules (picture 13 and picture 1 and picture
14). These may be mistaken for freckles initially. Plaque-like lesions (picture 3) and
nodules may also occur. The upper and lower extremities are most commonly affected,
followed by the thorax and abdomen. In adults, the palms, soles, face, scalp, and other
sun-exposed areas generally remain free of lesions. In children, the face and scalp may
be involved.

Pruritus associated with MPCM may be exacerbated by changes in temperature,

exercise, hot showers, local friction, ingestion of hot beverages, spicy food, ethanol,
emotional stress, or certain drugs. Bullous eruptions with hemorrhage can also occur in
children, a feature that is shared with DCM.

As stated previously, MPCM can represent a form of CM or may be a cutaneous

manifestation in patients with SM. Various KIT mutations have been identified in
patients with MPCM, none of which predict an association with systemic disease. In
those with systemic disease, MPCM is more typical of the less aggressive forms.
Specifically, UP is found in over 90 percent of patients with indolent systemic
mastocytosis (ISM) but in less than 50 percent of those with mastocytosis associated
with a hematologic disorder (systemic mastocytosis with an associated hematologic
neoplasm [SM-AHN]) or with aggressive systemic mastocytosis (ASM) [57].
Diffuse cutaneous mastocytosis — Diffuse cutaneous mastocytosis (DCM) is the
result of a diffuse mast cell infiltration in the dermis. The skin appears either normal in
color or possibly yellowish-brown, with increased thickness (picture 5). Involvement of
the whole skin, rather than discrete areas, is characteristic.

Bullous eruptions with hemorrhage can occur in patients with DCM and MPCM (picture
6 and picture 7). Eruptions can be spontaneous or triggered by infections or, rarely,
vaccinations. Blister fluid contains histamine, prostaglandins, and platelet-activating
factor. Blisters can be present at birth, and CM should be considered in the differential
of neonatal blistering disorders [60]. (See "Vesicular, pustular, and bullous lesions in the
newborn and infant".)

Mastocytomas of the skin — Solitary or multiple mastocytomas of the skin are less
common than UP and usually present in childhood (picture 8 and picture 9).
Spontaneous involution is frequently observed.

Lesions are similar in quality to those of MPCM but can be larger (up to several
centimeters) [61]. Some mastocytomas have a yellow to orange coloration [58]. Bullae
may be present, with typical localization in the extremities, axillae or groin or areas
where the skin is rubbed or scratched. Pruritus is variable. Flushing may also occur,
particularly after physical irritation of the tumor, so lesions should not be vigorously
rubbed, as this can precipitate severe symptoms including hypotension. Instead, the
patient or caregiver can usually provide the history that flushing occurs if the lesions are
disturbed.

Telangiectasia macularis eruptiva perstans — Telangiectasia macularis eruptiva

perstans (TMEP) is the least frequent form of CM, accounting for less than 1 percent of
cases. It occurs mainly in adults and is characterized by tan to brown macules with
telangiectasias (picture 10 and picture 11 and picture 12) [62]. There is an increase in
the mast cells around capillaries and venules of the superficial vascular plexus. Pruritus
and blistering do not occur with TMEP. Rarely, it is associated with systemic
involvement.

Symptoms arising from mediator release — In patients with either CM or SM,

release of mast cell mediators may occur in explosive episodes, presenting as apparent
"allergic" reactions and anaphylaxis or on a chronic basis, giving rise to problems, such
as chronic gastrointestinal complaints (table 3).

Episodic mediator release and anaphylaxis — Acute release of mast cell mediators
can result in episodes of vasodilation, hypotension, flushing, pruritus, syncope,
abdominal pain, nausea, vomiting, diarrhea, fatigue, and headache.

Anaphylaxis can be observed in both CM and SM. Symptoms typically include flushing,
syncope, gastrointestinal symptoms, and vascular collapse. Urticaria and angioedema
occur less frequently [63]. These reactions may result from either immunoglobulin (Ig)E-
mediated allergy or nonspecific activation of mast cells.
 ●Anaphylaxis without identified IgE-mediated allergies appears to be
particularly prevalent in males with ISM [64].
●Systemic anaphylaxis to insect stings with negative skin and in vitro tests for
venom-specific IgE has been described, and fatalities have been reported
[65,66]. (See "Fatal anaphylaxis" and "Systemic mastocytosis: Management
and prognosis".)

Over time, chronic mediator release is associated with cachexia, chronic gastrointestinal
symptoms, diffuse musculoskeletal pains, and/ortissue remodeling and fibrosis of some
organs (table 1) [67,68]. Fibrosis most often affects the bone marrow and, rarely, the
liver, in advanced forms of SM. (See 'Gastrointestinal complaints' below.)

Some patients have prominent anxiety and depression, which may also be due to
chronic release of mast cell mediators, although the exact cause of these symptoms is
not understood. Prostaglandins (prostaglandin D2 [PGD2] in particular) and histamine
have been implicated. Histamine acts as a neurotransmitter and is important in
wakefulness. (See 'Neuropsychiatric symptoms' below.)

Gastrointestinal complaints — Gastrointestinal dysfunction caused by release of mast

cell mediators can be observed in both CM and SM [69]. Gastrointestinal symptoms can
be precipitated by the same triggers that cause systemic symptoms (table 4). Signs and
symptoms include abdominal pain, diarrhea, nausea, vomiting, peptic ulcer disease,
and gastrointestinal bleeding [70]. Some patients have infiltration of the gastrointestinal
tract with aggregates of more than 15 typical-appearing mast cells [50].

Abdominal pain and diarrhea were reported in up to 80 percent of patients with SM, with
duodenal ulceration and severe duodenitis in 30 to 50 percent of untreated cases [71].
Diarrhea can result from increased motility induced by PGD2 secretion. Histamine and
other mediators released from local and distant mast cells increase gastric acid
secretion. Serum histamine concentrations may be elevated, particularly in the setting of
ulcer disease, suggesting that circulating histamine contributes to basal acid
hypersecretion [69,71]. Malabsorption can result from extensive mucosal and
submucosal infiltration with mast cells.

Neuropsychiatric symptoms — Neuropsychiatric manifestations, including

depression, mood changes, lack of concentration, short memory span, increased
somnolence, irritability, and emotional instability, are frequently observed in adult
patients with mastocytosis [72-74]. These symptoms are sometimes referred to as
"mixed organic brain syndrome." These are often ignored or undertreated before the
diagnosis of mastocytosis is established. The precise cause of many of these
manifestations is not known, although PGD2 is thought to increase somnolence [75].
There are no data to suggest that mast cell numbers are increased in brain tissue of
patients with mastocytosis [76], and measurement of tryptase in cerebrospinal fluid did
not demonstrate an increase [76]. In infants and children, apneic spells, cyanosis, and
irritability may be seen, and older children can demonstrate aggressive behavior.
Musculoskeletal symptoms — Diffuse musculoskeletal pain of the long bones and a
pain syndrome resembling fibromyalgia may be reported in patients with SM.

Osteopenia and osteoporosis — A subset of patients with SM appears to be at

increased risk of developing osteopenia and osteoporosis [77-79]. This can be observed
even in young adult men [80,81]. Osteoporosis is fairly common in patients with ISM
and may be due to effects of mast cell mediators, such as histamine, tryptase, heparin,
and cytokines (tumor necrosis factor, interleukin- 6, transforming growth factor-beta) on
bone turnover [82,83].

A bone densitometry measurement is recommended to evaluate for osteoporosis in all

patients with SM. Patients may be asymptomatic and yet have findings on bone density
screening that include osteopenia (33 to 60 percent of patients), diffuse osteoporosis
(10 to 38 percent), or osteosclerosis (5 to 10 percent) [84].

Patients with SM may also experience poorly localized bone pain or fractures,
especially of the long bones and vertebrae [85]. Nerve damage can follow vertebral
compression fractures, even in patients with ISM. Evaluation of these symptoms can
reveal osteolytic, osteosclerotic, and/or osteopenic lesions [86,87]. These presentations
may be confused with metastatic malignancy. Skeletal scintigraphy and bone survey
may be helpful in characterizing the extent of disease in selected patients [88].
Management is discussed separately. (See "Systemic mastocytosis: Management and
prognosis", section on 'Osteoporosis and fractures'.)

Triggers for mediator release — The release of mast cell mediators in patients with
CM and SM may be precipitated by a variety of stimuli, although not all triggers cause
mast cell degranulation in all patients. A careful history is often helpful in determining
what can or cannot be tolerated by individual patients. Potential triggers include the
following (table 4) [49,72,89-93]:
●Medications, including narcotics, opioids, nonsteroidal anti-inflammatory
drugs, iodinated contrast agents, vancomycin, and muscle relaxants used in
anesthesia [94].
●Physical factors, such as exercise, massage or friction applied to the skin,
extremes of temperature, sudden temperature changes, and very spicy foods.
●Surgical procedures or instrumentation (including biopsies or endoscopy).
●Alcohol ingestion.
●Infections, including viral, bacterial, and parasitic.
●Emotional stress.
●Hymenoptera stings, either through nonallergic or IgE-mediated allergic
mechanisms. (See 'Concomitant allergic disease' below.)
●Toxic exposures, such as stings of jellyfish, snake bites, etc.
●Children with rare DCM can develop cutaneous blistering in response to
febrile reactions following vaccinations and can be premedicated with
antihistamines and acetaminophen. Note that patients with other forms of
mastocytosis should receive vaccinations normally.
Concomitant allergic disease — Patients with mastocytosis may have concomitant
IgE-mediated allergic diseases, including allergic rhinitis, food and drug allergies, and
Hymenoptera allergy [95,96]. They may also have asthma. The prevalence of allergic
disorders in patients with mastocytosis (both cutaneous and systemic) appears to be
similar to that of the general population (ie, between 20 and 30 percent in Westernized
nations) [64,95,96]. Total IgE levels are usually decreased in patients with mastocytosis,
possibly due to binding to an increased number of mast cells [96].

Patients with mastocytosis are more susceptible to anaphylaxis during allergic

reactions, particularly in response to Hymenoptera stings [97]. Accordingly, severe
systemic reactions to Hymenoptera stings should prompt screening for mastocytosis
with a serum tryptase level. A prospective study found elevated baseline tryptase levels
in 12 percent of patients with a history of systemic reactions to Hymenoptera stings.
Within this subset of patients with elevated baseline tryptase, 70 percent had
anaphylactic reactions, and 80 percent had diagnostic or subdiagnostic accumulations
of aberrant mast cells in the bone marrow [98,99].

Signs, symptoms, and laboratory findings arising from organ

infiltration — Infiltration and/or proliferation of mast cells in organs other than the
skin distinguishes SM from CM. In SM, the organ systems most often affected are the
bone marrow, gastrointestinal tract, lymph nodes, liver, spleen, and skeletal system
[73,100,101]. Involvement of these organ systems may give rise to a variety of
symptoms, physical findings, and abnormalities on routine laboratories (table 3).

In contrast, the respiratory, endocrine, and genitourinary systems are seldom involved
in patients with SM, although patients with SM may have concomitant asthma at rates
similar to the general population. The incidence of bacterial, fungal, or viral infections is
not increased, and patients are not immunocompromised unless there is an associated
hematologic disorder affecting other cell lines (ie, neutrophils).

Bone marrow and skeletal system — The most common hematologic abnormality is a
mild-to-moderate anemia, which occurs in up to 50 percent of patients [102]. The
etiology is probably multifactorial. Mast cells are not found in the circulation, except in
those with mast cell leukemia (MCL), and greater than 10 percent or more of circulating
nucleated cells may be mast cells in this disorder.

Eosinophilia is found in 25 percent of patients. In some patients, eosinophils exhibit the

same phenotype as those in the hypereosinophilic syndrome or chronic eosinophilic
leukemia (CEL) (ie, hypogranular and hypersegmented nuclei). Some patients with
mastocytosis may have associated CEL (a clonal disorder), while others may have a
reactive eosinophilia, possibly due to cytokine release [103]. (See "Hypereosinophilic
syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on
'Myeloid HES variants'.)

A monocytosis can be found in patients with ASM or SM-AHN and is found in

approximately one-half of patients with advanced mastocytosis [104]. This may
represent a sign of marrow dysplasia [32], although a patient with aggressive
mastocytosis had mast cell precursors in peripheral blood which were counted as
monocytes [28]. The hematologic disorders that occur in patients with SM-AHN are
discussed elsewhere. (See "Systemic mastocytosis: Determining the subtype of
disease".)

Excessive bleeding, which has been reported in a minority of patients, may be due to
the high levels of heparin released from mast cells, and a prolonged bleeding time may
be observed in skin areas infiltrated by mast cells [105-108]. Another proposed
mechanism involves proteolytic disruption of fibrinogen by tryptase [109]. Malabsorption
of vitamin K may also contribute to a systemic bleeding diathesis. Abnormal bleeding
has been observed in children with DCM, with one reported death [110]. Occasionally,
patients with very high mast cell burden may present with anticoagulation during mast
cell degranulation episodes. Thrombocytopenia, if present, is usually mild and
asymptomatic. However, in the authors' experience, most patients with mastocytosis
have normal coagulation studies.

Patients with mastocytosis are not immunocompromised unless there is an associated

hematologic disorder affecting other cell lines (ie, neutrophils). In the absence of a
hematologic disorder, the incidence of bacterial, fungal, or viral infections is not
increased.

Intestinal tract and liver — Peptic ulcer disease, steatorrhea, malabsorption, and
hepatomegaly may occur when mast cells infiltrate the intestine or liver in ASM
[28,70,111]. Liver function tests may be elevated. Liver biopsy demonstrates an
increased number of mast cells with eosinophilic infiltrates and extramedullary
hematopoiesis, which is more prominent in ASM, SM-AHN, and MCL [112]. Portal
hypertension and ascites may develop in these advanced categories of disease.

Lymphoid tissues and spleen — The lymph nodes and spleen are commonly
infiltrated in all types of SM [113].

●Central and peripheral lymphadenopathy are noted in 20 to 60 percent of

patients with ISM and in a higher proportion in those with SM-AHN, ASM, and
MCL [114].
●Splenomegaly is observed in 50 percent of patients with ISM and in over 70
percent of those with SM-AHN, ASM, and MCL. A marked increased in weight
(eg, 700 grams) may be seen. Hypersplenism (ie, nonimmune hemolytic
anemia and other hematologic abnormalities) may cause hematologic
abnormalities. Splenic enlargement can also cause left upper quadrant
discomfort or external compression of other organs. (See "Extracorpuscular
non-immune hemolytic anemia: Fragmentation hemolysis and
hypersplenism".)

CHARACTERISTIC CLINICAL PRESENTATIONS Patients with

mastocytosis may develop different combinations of the signs and symptoms described
above, although in the authors' experience, there are several characteristic clinical
presentations [115]:
● A child or adult with hyperpigmented skin lesions – The lesions may be
maculopapular cutaneous mastocytosis (children or adults) or a mastocytoma
(children). Cutaneous or systemic forms of mastocytosis may present this
way.

The remaining presentations are ways in which different forms of SM can present in
adults:

● An adult with recurrent episodes that resemble allergic reactions or

anaphylaxis – Symptoms typically include flushing, syncope or near-
syncope, hypotension, abdominal cramping, and diarrhea. Urticaria and
angioedema are not usually present. Evaluation does not reveal a causative
allergy.
● An adult with anaphylaxis after a Hymenoptera sting – Symptoms
typically include flushing, syncope or near-syncope, and/orhypotension.
Urticaria and angioedema are not usually present. Evaluation can reveal
specific IgE to bee, wasp, or other Hymenoptera [99]. Fifty percent of the
patients will not have CM.
● An adult with hematologic abnormalities, splenomegaly, fatigue, and
weight loss prompting a hematologic evaluation – Cytopenias, such as
anemia, leucopenia, and thrombocytopenia, may develop in systemic forms of
mastocytosis due to infiltration of the bone marrow by mast cells and
interference with normal hematopoiesis. In contrast, patients with
myeloproliferative variants of systemic mastocytosis with an associated
hematologic neoplasm (SM-AHN) more typically present with leukocytosis or
thrombocytosis. Hepatomegaly due to infiltration with either mast cells or cells
of the associated hematologic malignancy may also develop.
● An adult with sclerotic or lytic bone lesions on imaging studies,
prompting an evaluation for metastatic malignancy – Bone marrow biopsy
then reveals mast cell infiltrates.
● An adult with nonspecific gastrointestinal symptoms suggestive of
colitis and unexplained splenomegaly, in whom hematologic evaluation
has revealed mastocytosis – Gastrointestinal biopsies from such patients
typically show dense infiltrates of CD117-positive mast cells that also express
CD25.
● An adult with a diagnosed hematologic disorder, in whom the
molecular evaluation showed a KIT mutation – Such patients have usually
been diagnosed with myelodysplastic syndrome, acute myeloid leukemia, or
chronic myelomonocytic leukemia. The diagnosis of SM was not made earlier,
because either no bone marrow histology was available, the necessary stains
to reveal mast cells were not performed, or the other hematologic neoplasm
overwhelmed the mast cell infiltrate.
● An adult with osteoporosis and pathologic bone fractures, particularly
if risk factors for osteoporosis are lacking – Occasionally mastocytosis will
present in this manner in a young adult, particularly a male, in whom an
 evaluation for unusual causes of osteoporosis is undertaken. Patients may
have vertebral compression fractures. This is the least common presentation.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Mast cell disorders".)

SUMMARY Mastocytosis comprises a group of rare disorders of excessive

mast cell proliferation and accumulation, which can be limited to the skin (cutaneous
mastocytosis [CM]) or involve bone marrow and other extracutaneous tissues (systemic
mastocytosis [SM]). (See 'Introduction'above.)
●Children are usually affected by cutaneous forms of mastocytosis. Most
improve or resolve completely by adolescence. In contrast, adults more often
present with systemic forms of mastocytosis and have persistent disease.
(See 'Epidemiology' above.)
●Mast cell development is dependent upon stem cell factor (SCF) and its
receptor, KIT. Activating mutations of KIT (the gene for the KIT protein) are
strongly associated with both cutaneous and systemic forms of mastocytosis
and thus have been implicated as the major contributor to the pathogenesis of
mastocytosis. (See 'Pathogenesis' above.)
●CM is characterized by accumulations of mast cells in the skin and can take
various forms. CM is further divided into three major subtypes: maculopapular
cutaneous mastocytosis (including urticaria pigmentosa [UP]), diffuse
cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin.
(See 'Cutaneous mastocytosis' above.)
●SM is divided into four distinct disorders: indolent systemic mastocytosis,
systemic mastocytosis with an associated hematologic neoplasm, aggressive
systemic mastocytosis, and mast cell leukemia. (See 'Systemic
mastocytosis' above.)
●The many signs and symptoms of mastocytosis may be categorized into skin
findings, symptoms due to release of mast cell mediators, and symptoms
arising from mast cell infiltration of organs other than the skin (table
1 and table 3). (See 'Clinical manifestations' above.)
●With cutaneous involvement, flushing and pruritus are the predominant
symptoms. The most common skin finding is UP (picture 1 and picture
13 and picture 14), which can be present in patients with either CM or SM.
Other specific skin findings include solitary or multiple cutaneous
mastocytomas (picture 8), DCM (picture 5), and telangiectasia macularis
eruptiva perstans (picture 12). (See 'Skin findings and symptoms' above.)
●In patients with both CM and SM, a variety of triggers can precipitate mast
cell-mediator release (table 4). Release of mediators may occur in explosive
episodes, presenting as apparent allergic reactions and anaphylaxis or on a
 chronic basis, giving rise to problems, such as chronic gastrointestinal
complaints (table 3). (See 'Symptoms arising from mediator release' above.)
●Extracutaneous organ involvement is only present in systemic forms of
mastocytosis. Depending on the organs involved, findings include steatorrhea,
malabsorption, lymphadenopathy, splenomegaly, hematologic and liver
abnormalities, and skeletal lesions. (See 'Signs, symptoms, and laboratory
findings arising from organ infiltration' above.)
●Patients with mastocytosis may develop different combinations of the signs
and symptoms described above, although there are several characteristic
clinical presentations. (See 'Characteristic clinical presentations' above.)
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Topic 4786 Version 24.0

GRAPHICS
Effects of mast cell mediators in mastocytosis

Histamine

Pruritus, urticaria, gastric hypersecretion, bronchoconstriction

Increased vasopermeability and systemic hypotension

Heparin

Local anticoagulation, osteopenia, and osteoporosis

Proteases (tryptases, chymase)

Fibrinogen degradation, stimulation of fibroblast proliferation, activation of procollagenase, and tissue remodeling (degrade fibronectin)

Cysteinyl leukotrienes (LTC4, LTD4, LTE4)

Increased vasopermeability, vasodilation, bronchoconstriction

Prostaglandins (PGD2)

Vasodilation, bronchoconstriction, flushing

Platelet-activating factor

Increased vasopermeability, vasodilation

Cytokines (TNF-alpha, TGF-beta, nerve growth factor) and growth factors (IL-3, IL-5, IL-6)

Activation of vascular endothelial cells, cachexia, and fibrosis

Mast cell and eosinophil proliferation

B cell proliferation with polyclonal increase in immunoglobulins and paraproteins

LT: leukotriene; PG: prostaglandin; TNF-alpha: tumor necrosis factor-alpha; TGF-beta: transforming growth

factor-beta; IL: interleukin.

Graphic 52832 Version 9.0
Urticaria pigmentosa (maculopapular cutaneous mastocytosis)
Lesions of maculopapular cutaneous mastocytosis, also called urticaria pigmentosa, in an adult patient

with systemic mastocytosis.

Reproduced with permission from: Soter AN. J Invest Derm 1991; 96(3):S32. Copyright © 1991 Blackwell

Science.
Graphic 63025 Version 6.0
Maculopapular cutaneous mastocytosis in children
MPCM in patients with childhood-onset mastocytosis. (A-G) Most children have characteristic large

brown lesions of different sizes (polymorphic). Lesion margins can be sharp (A and E) or indistinct (B

and G) and elevated (C and E) or flat (B and F). Nodular lesions present during infancy (C and E) may

develop into plaques or macules at the age of 5 to 10 years (D and F) before they regress by

adolescence. (G) Lesions on the forehead are characteristic for polymorphic MPCM. (H and I) Few

pediatric patients show small monomorphic lesions like the ones observed in adults. (J) Atypical

variants can also occur in children, such as one with yellow, firm lesions, which was previously also

termed "xanthelasmoid CM."

MPCM: maculopapular cutaneous mastocytosis; CM: cutaneous mastocytosis.

Reproduced from: Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with

mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American

Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical

Immunology. J Allergy Clin Immunol 2015. Illustration used with the permission of Elsevier Inc. All rights

reserved.
Graphic 105581 Version 4.0
Congenital cutaneous mastocytosis in an infant

In this infant with cutaneous mastocytosis, brown-red plaques were spread over the whole body,

including the face but not affecting mucosal tissues. Episodic flushing and bronchoconstriction were
triggered by heat and breastfeeding.
Reproduced with permission from: Mann C, Sepp N, Simma B. Congenital cutaneous mastocytosis. J Pediatr

2004; 145:134. Copyright ©2004 Elsevier.

Graphic 61345 Version 5.0
Nodular cutaneous mastocytosis in a child
Reprinted by permission from: Springer: American Journal of Clinical Dermatology. Castells M, Metcalfe DD,

Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: Practical recommendations. Am

J Clin Dermatol 2011; 12:259. Copyright © 2011. https://link.springer.com/journal/40257.

Graphic 91053 Version 7.0
Diffuse cutaneous mastocytosis

Affected skin in a patient with diffuse cutaneous mastocytosis.

Reproduced with permission from: Soter AN. J Invest Derm 1991; 96(3):S32. Copyright © 1991 Blackwell

Science. http://www.blackwell-science.com.
Graphic 68182 Version 3.0
Bullous eruption in skin mastocytosis
Bullous eruption in a child with diffuse cutaneous mastocytosis.

Reproduced with permission from: Soter AN. J Invest Derm 1991; 96:S32. Copyright © 1991 Blackwell

Science. http://www.blackwell-science.com.
Graphic 52257 Version 4.0
Bullous eruption on the back of a child with diffuse cutaneous mastocytosis
Graphic 63556 Version 3.0
Solitary cutaneous mastocytoma
A solitary, tan plaque is present on this infant.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
Graphic 50284 Version 7.0
Cutaneous mastocytomas on the hand of a child
From: Soter AN. J Invest Derm 1991; 96:S32.
Graphic 76891 Version 4.0
Cutaneous mastocytosis: Telangiectasia macularis eruptiva perstans
Telangiectasia macularis eruptiva perstans (TMEP) in a patient with cutaneous mastocytosis.

Reproduced with permission from: Soter AN. J Invest Derm 1991; 96:S32. Copyright © 1991 Blackwell

Science. http://www.blackwell-science.com.
Graphic 52501 Version 5.0
Cutaneous mastocytosis: Telangiectasia macularis eruptiva perstans form

A) TMEP type of maculopapular CM. Lesions are strictly macular (ie, not elevated), reddish-brown,

and, as shown in the higher magnification (B), are ill-defined and exhibit fine telangiectasias.

TMEP: telangiectasia macularis eruptiva perstans; CM: cutaneous mastocytosis.

Reproduced with permission from: Wolff K, Komar M, Petzelbaur P. Clinical and histopathological aspects of

cutaneous mastocytosis. Leukemia Research 2001; 25:519. Illustration used with the permission of Elsevier

Inc. All rights reserved.

Graphic 72163 Version 4.0
Telangiectasia macularis eruptive perstans (TMEP)
 Courtesy of Cem Akin, MD, PhD.
Graphic 59118 Version 4.0
Diagnostic criteria of subtypes (variant forms) of systemic mastocytosis
(SM)

ic mastocytosis (ISM)

criteria; no "C" findings

emic mastocytosis (SSM)

criteria plus two or more "B" findings; no "C" findings

emic mastocytosis (ASM)

criteria plus "C" findings; no features of mast cell leukemia

mia (MCL)

criteria plus features of MCL

cytosis with an associated hematologic neoplasm (SM-AHN)

criteria plus clonal hematologic nonmast cell lineage disorder (eg, MDS, MPN, AML, lymphoma, other)
diagnostic criteria: "B" findings: "C" findings: Features

one minor criterion OR three minor 1. Bone marrow biopsy showing >30% infiltration by 1. Bone marrow dysfunction manifested by one Bone marrow biop

mast cells (focal, dense aggregates) and/or serum total or more cytopenia (ANC <1 × 109/L, Hb <10 infiltration, usually

tryptase level >200 mg/mL. g/dL, or platelets <100 × 109/L) but no obvious atypical, immature

filtrates of mast cells (≥15 mast cells 2.
ted in sections of bone marrow and/or
s organ(s).
nonmast cell hematopoietic malignancy. marrow aspirate sm
Signs of dysplasia or myeloproliferation in nonmast
mast cells.
cell lineage(s) but insufficient criteria for definitive 2. Palpable hepatomegaly with impairment of
diagnosis of a hematopoietic neoplasm (SM-AHN) liver function, ascites, and/or portal
with normal or only slightly abnormal blood counts. hypertension.

f bone marrow or other 3. Hepatomegaly without impairment of liver function, 3. Skeletal involvement with large osteolytic

ns, >25% of the mast cells in the and/or palpable splenomegaly without hypersplenism, lesions and/or pathologic fractures.

-shaped or have atypical and/or lymphadenopathy on palpation or imaging. 4. Palpable splenomegaly with hypersplenism.
ll mast cells in bone marrow aspirate
5. Malabsorption with weight loss due to
mmature or atypical.
gastrointestinal mast cell infiltrates.
vating point mutation at codon 816 of

w, blood, or another extracutaneous

marrow, blood, or other

ns express CD2 and/or CD25 in

mast cell markers.

persistently exceeds 20 ng/mL

ssociated clonal myeloid disorder, in

meter is not valid).

Solid mast cell tumors (mast cell sarcoma and extracutaneous mastocytoma) are not forms of SM.

MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; AML: acute myelogenous leukemia;

KIT: the receptor for stem cell factor; ANC: absolute neutrophil count.

Modified with permission from: Horny HP, Metcalfe DD, Bennet JM, et al. Mastocytosis. In: WHO

classification of tumours of haematopoietic and lymphoid tissues, 4th ed, Swerdlow SH, Campo E, Harris NL,

et al (Eds), IARC: Lyon, 2008. Copyright © 2008.

Additional data from:

1. Arber DA, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid

neoplasms and acute leukemia. Blood 2016; 127:2391.

Graphic 82828 Version 24.0

 Clinical manifestations of cutaneous and systemic mastocytosis

Symptoms due to acute and/or chronic mast cell- Symptoms, physical findings, and abnormalities of routine la
affected
mediator release to organ infiltration

Flushing, pruritus Multiple: Urticaria pigmentosa, plaque-like or nodular lesions, diffuse skin inv

eruptions, isolated mastocytoma, or telangiectasias

t Nausea, bloating, chronic diarrhea, hyperacidity, gastroduodenal ulcer Stomach and duodenal infiltration: Gastroduodenal ulcers (possibly, althoug

disease, chronic abdominal pain, vomiting related to mediator release), steatorrhea, malabsorption

Liver infiltration: Elevated transaminases, portal hypertension, and ascites (on

forms of the disease)

Adults: Fibromyalgia-like diffuse musculoskeletal pain, pain in long In mast cell sarcoma of the bone (rare), local symptoms (eg, pain, deformity, p

bones, osteoporosis, osteopenia, pathologic fractures occur at the involved site

Adults: Episodes of vasodilation, tachycardia, hypotension, collapse

Infants: Apneic spells, cyanosis

h nodes, Lymph nodes and spleen: Lymphadenopathy, splenomegaly (with hematolog

w) hypersplenism: nonimmune hemolytic anemia)

Bone marrow: Anemia (mild-to-moderate, in approximately 50%), thrombocy

asymptomatic), eosinophilia (approximately 25%), myeloproliferative or myelo

findings, fibrosis

tric Adults: Anxiety, depression, headache, mood changes, inability to

concentrate, hypersomnolence, irritability, "mixed organic brain

syndrome"

Children: Aggressive behavior

Adults: Fatigue, cachexia

Signs and symptoms of both acute and chronic release of mast cell mediators are seen in patients with

cutaneous and systemic forms of mastocytosis. Episodic symptoms tend to occur in patterns that are

characteristic for a given patient, but not all patients demonstrate all of the signs and symptoms

described in the table. In patients with cutaneous mastocytosis, mast cells infiltrate the skin. In

patients with systemic mastocytosis, mast cells may infiltrate the skin, gastrointestinal tract and liver,

lymph nodes, spleen, and bone marrow.

* Rare in children.
Graphic 91167 Version 10.0
Urticaria pigmentosa in an infant
This infant has multiple lesions of urticaria pigmentosa (UP). Lesions of UP are characterized by small,

yellow-tan to reddish-brown macules or slightly raised papules. Pruritus associated with UP may be
exacerbated by changes in temperature, exertion, local friction, or certain medications. UP lesions, as

well as other lesions rich in mast cells, may demonstrate Darier's sign, which is the development of a
localized whealing and erythema within about five minutes following rubbing, scratching, or stroking of

the lesion.

Reprinted by permission from: Springer: American Journal of Clinical Dermatology. Castells M, Metcalfe DD,

Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: Practical recommendations. Am

J Clin Dermatol 2011; 12:259. Copyright © 2011. https://link.springer.com/journal/40257.

Graphic 105069 Version 3.0
Detail of urticaria pigmentosa

Urticaria pigmentosa (UP) lesions are small, yellow-tan to reddish-brown macules or slightly raised

papules, most commonly on the upper and lower extremities. Lesions of UP display Darier's sign,

which is the development of localized urticaria and erythema at the site a few minutes after a lesion is

rubbed or scratched. This occurs because UP lesions are rich in mast cells, and physical irritation

causes the cells to release inflammatory mediators.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
Graphic 97908 Version 6.0
Potential nonallergic triggers for mast cell activation

Insect stings, envenomations

 Hymenoptera

Jellyfish

Snakes

Drugs

Narcotic analgesics (eg, codeine, morphine)

Radiocontrast materials

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs)

Muscle relaxants

Some antibiotics (eg, vancomycin)

Changes in temperature

Heat, cold

Mechanical irritation

Massage, friction, pressure

Invasive procedures (eg, surgery, biopsies, endoscopy)

Other

Alcohol

Emotional stress

Exercise

Spicy foods

Infections (viral, bacterial, parasitic)

Fever
Graphic 70309 Version 11.0

Contributor Disclosures
Mariana C Castells, MD, PhDNothing to discloseCem Akin, MD, PhDConsultant/Advisory Boards:
Novartis [Mastocytosis (Midostaurin)]; Blueprint Medicines [Advanced systemic mastocytosis (Exon 17
mutant KIT kinase inhibitor)]. Patent Holder: LAD2 cell line [Mast cells].Sarbjit Saini,
MDGrant/Research/Clinical Trial Support: Novartis [Asthma, urticaria (Omalizumab)]; Regeneron
[Allergic rhinitis (Dupilumab)]; Genentech [Urticaria]. Consultant/Advisory Boards: Genentech
[Urticaria (Omalizumab)]; Medimmune [Urticaria (Omalizumab)]; AstraZeneca [Asthma
(Benralizumab)]; Pfizer [Atopic dermatitis]; Allakos [Urticaria].Anna M Feldweg, MDNothing to
disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

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