Diagnostic Criteria and

Classification of Mastocytosis in
2014
a, b
Cem Akin, MD, PhD *, Peter Valent, MD

KEYWORDS
 Mastocytosis  Diagnosis  Classification  World Health Organization  c-kit
 Tryptase

KEY POINTS
 The diagnosis of mastocytosis in skin is established by presence of characteristic macu-
lopapular skin lesions and confirmed by skin biopsy.
 Systemic mastocytosis should be diagnosed based on World Health Organization (WHO)
criteria. Presence of unexplained symptoms of mast cell activation should prompt the
pathologic investigation; however, the diagnosis cannot be based on symptoms alone.
 According to WHO, mastocytosis is classified into 7 categories, with distinct clinicopath-
ologic and prognostic features that guide the therapy.
 Tryptase level greater than 20 ng/mL is associated with systemic mastocytosis. However,
lower tryptase levels can be seen in patients with cutaneous mastocytosis, monoclonal
mast cell activation syndrome, and systemic mastocytosis with limited bone marrow
involvement.
 More than 90% of adults and 80% of children with mastocytosis are detected to have
somatic gain of function mutations in c-kit. In most patients with systemic mastocytosis,
the c-kit mutation D816V is detectable.

DEFINITION AND OVERVIEW OF CATEGORIES

Mastocytosis is a disorder characterized by accumulation of pathologic mast cells in

tissues, which is accompanied by symptoms of mast cell activation in most pa-
tients.14 Most commonly affected tissues are skin, bone marrow, and gastrointestinal
tract, followed by liver, spleen, and lymph nodes. Mastocytosis can affect both chil-
dren and adults. In children, it commonly presents with skin lesions of urticaria

Conflict of Interest Disclosure: Dr C. Akin has a consultancy agreement with Novartis.

a
Harvard Medical School, Director, Mastocytosis Center, Brigham and Womens Hospital,
Harvard Medical School, 1 Jimmy Fund Way, Room 626B, Boston, MA 02115, USA; b Division
of Hematology and Hemostaseology, Department of Internal Medicine I and Ludwig Boltz-
mann Cluster Oncology, Medical University of Vienna, Wahringer Gurtel 18-20, A-1090, Vienna,
Austria
* Corresponding author.
E-mail address: [email protected]

Immunol Allergy Clin N Am 34 (2014) 207218

http://dx.doi.org/10.1016/j.iac.2014.02.003 immunology.theclinics.com
0889-8561/14/$ see front matter 2014 Elsevier Inc. All rights reserved.
208 Akin & Valent

pigmentosa (UP) or mastocytomas within the first year of life.57 Mastocytosis diag-
nosed in infancy has a good prognosis; there is no evidence of pathologic mast cell
accumulation in tissues other than skin (cutaneous mastocytosis), and most patients
experience resolution or fading of skin lesions by adolescence. In contrast, adult-
onset mastocytosis is almost always associated with bone marrow involvement and
has a persistent course. When mastocytosis is present in any extracutaneous tissue
(proved by biopsy) and shows multifocal or diffuse organ infiltration, it is termed sys-
temic mastocytosis (SM). SM is a heterogeneous group of disorders with variable
prognosis.8 Most patients have indolent SM (ISM), meaning that bone marrow exam-
ination shows abnormal mast cell collections but no other hematologic disease, and
there is no evidence of end-organ damage attributable to mast cell infiltration. Patients
with ISM have a comparable life expectancy with the general age-matched popula-
tion.911 Up to 20% of patients with SM may have a second bone marrow disease,
usually with myeloproliferative or myelodysplastic features. These patients have SM
associated with a hematologic nonmast cell clonal disease (SM-AHNMD). The prog-
nosis in these patients depends on the course of the AHNMD.10 A few patients
(approximately 5%) have evidence of end-organ damage caused by mast cell infiltra-
tion (aggressive SM [ASM]), in whom the disease follows an accelerated course
resembling a malignancy.12,13 Mast cell leukemia (MCL) is a rare subset of SM, which
is diagnosed when mast cells in bone marrow aspirate smears are greater than
20%.14,15 In several of these cases, circulating mast cells are found. Mast cell sar-
coma (MCS) and extracutaneous mastocytosis are extremely rare variants with solid
mast cell tumors, bearing malignant and benign pathologic features, respectively.16

DIAGNOSIS

Mastocytosis commonly comes to clinical attention in one of the following clinical

scenarios:
1. The patient (or parents if the patient is a child) notices the hyperpigmented skin
lesions of UP (or mastocytoma in a child). Sometimes, these lesions may be noticed
in dermatology evaluations for other purposes rather than by patients themselves,
because they may resemble freckles earlier in the course.
2. The patient presents with symptoms of mast cell activation such as recurrent flush-
ing, hypotension, near syncope or syncope, abdominal cramps, and diarrhea.
Anaphylaxis is suspected, but an allergy evaluation often does not identify a culprit.
A variation of this presentation involves patients who experience severe systemic
reactions to Hymenoptera stings. Curiously, urticaria and angioedema are not
commonly seen in mast cell activation episodes in mastocytosis.
3. The patient is detected to have hematologic abnormalities such as cytopenias or
increased white blood or platelet counts, liver or spleen enlargement, fatigue,
and weight loss, prompting a hematologic workup.
4. The patient may be detected to have sclerotic or lytic bone lesions in imaging
studies, raising concern for metastatic disease.
5. A rare first presentation is osteoporosis and pathologic bone fractures (commonly
vertebral compression fractures). This finding should raise suspicion in younger
patients (especially males) who do not otherwise have any risk factors for
osteoporosis.
6. The patient is referred because of nonspecific gastrointestinal symptoms sugges-
tive of colitis and unexplained splenomegaly, and the hematologic evaluation
shows mastocytosis.
 Diagnosis and Classification of Mastocytosis 209

7. The patient has been diagnosed with a myelodysplastic syndrome, acute myeloid
leukemia (AML), or chronic myelomonocytic leukemia (CMML), and the molecular
workup showed a c-kit mutation. In these cases, no histology was available or
the pathologist had overlooked SM.
The first step in all patients who are suspected to have mastocytosis is a thorough
skin examination to detect typical skin lesions (UP type). These lesions range in size
from a few millimeters to a few centimeters and have a brownish hyperpigmentation
along with a hyperemic component. The lesions are fixed and do not appear and
disappear at different locations like classic urticarial wheals. They are usually nonprur-
itic at baseline but may be triggered to urticate with friction, temperature changes, fe-
ver, emotional or physical stress, exercise, alcohol, and spicy foods. Stroking of the
lesion results in a wheal localized to the lesion (Darier sign); however, some patients
may lack this sign if they are on H1 antihistamines. Skin lesions in young children
may not be hyperpigmented and may show blistering in the first 3 years of life.
Although most experts can diagnose UP-like skin lesions on visual inspection, skin bi-
opsy may confirm the diagnosis of mastocytosis (in the skin) in suspected cases. In
these patients, skin biopsy shows a perivascular mast cell infiltrate in the upper
dermis. Some scattered eosinophils may be mixed with the infiltrate, but other inflam-
matory cells are typically absent. Increased melanin deposition is noted in epidermis.
Mastocytomas are typically solitary and larger lesions with histologic evidence of a
solid mast cell tumor. Physical irritation of mastocytomas may cause systemic symp-
toms, such as hives. Teleangiectasia macularis eruptive perstans is a rare manifesta-
tion of cutaneous mastocytosis, in which the skin has flat teleangiactatic macules in a
generalized distribution. Skin lesions in adults generally spare sun-exposed areas,
such as face and hands, and tend to aggregate in areas prone to irritation, such as up-
per thighs and axillae. However, it is not uncommon to have lesions on scalp, face, and
neck in young children.
After visualization of skin lesions, the patient is said to have mastocytosis in the skin,
and a decision has to be made whether a bone marrow biopsy is necessary to look for
evidence (criteria) of systemic mastocytosis or to classify the patient as having cuta-
neous mastocytosis if bone marrow histopathology is normal or criteria for SM are not
fulfilled. A simple guide for this decision is the patients age. Children in whom the skin
lesions start in the first 2 years of life rarely have bone marrow involvement, and these
children are presumed to have cutaneous mastocytosis. A bone marrow biopsy in chil-
dren is not routinely recommended unless the child has a persistently high serum tryp-
tase level (or shows an increasing trend in serial measurements) or has abnormal
complete blood count or liver or spleen enlargement. In contrast, most patients with
adult-onset disease have evidence of bone marrow involvement when skin lesions
are detected, and therefore, a bone marrow biopsy is recommended to establish
the diagnosis of SM, to assess bone marrow mast cell burden, and to rule out pres-
ence of other hematologic disease.
Therefore, a bone marrow biopsy is recommended in adult patients presenting with
skin lesions of UP type as well as those presenting with clinical scenarios 2 to 5, out-
lined earlier. Biopsy of tissues other than bone marrow is not recommended to estab-
lish a diagnosis, because bone marrow is always involved, and the histopathologic
aspects of mast cell disease are not well studied in other tissues. Gastrointestinal bi-
opsies are sometimes needed to establish the cause of symptoms such as diarrhea
and malabsorption, whether they are caused by mast cell infiltration or simply caused
by systemic effects of mast cell mediator release, and a subset of patients were first
diagnosed on gastrointestinal biopsies by astute pathologists.17
210 Akin & Valent

Diagnosis of SM is made according to the World Health Organization (WHO) criteria

(Box 1). These criteria were established by an international group of experts in a
consensus meeting in Vienna in 2000.1820 Until that time, the diagnosis was mainly
made by visualization of large aggregates of mast cells in bone marrow and subjective
assessment of increased mast cell numbers in tissues. The Vienna conference
retained the mast cell aggregates as the major diagnostic criterion but also introduced
the concept of minor criteria. Thus, the modern diagnostic criteria include 1 major and
4 minor criteria, as outlined in the following sections. The patient needs to have either
the major and at least 1 minor, or 3 minor criteria, to diagnose SM.

Major Criterion
Multifocal dense aggregates of mast cells with more than 15 cells per aggregate in an
extracutaneous tissue. The tissue of choice in diagnosis is bone marrow. Both a bi-
opsy and an aspirate should be obtained. Biopsy should be of good quality without
significant crush or bleeding artifact. Formalin-fixed, paraffin-embedded bone marrow
biopsy sections should be stained for tryptase, CD117 and CD25 in addition to routine
hematoxylin-eosin stains. In normal bone marrow, mast cells are distributed intersti-
tially and singly, with a predominantly round shape. Although even a small clustering
of mast cells should raise suspicion for mastocytosis, to meet the major criterion, the
clusters should contain at least 15 mast cells. Mast cell clusters in mastocytosis occur
paratrabecularly, perivascularly, or interstitially. Sometimes, a spindle-shaped infil-
trate is observed to line the bone trabeculae. Eosinophils are frequently found in
increased numbers around the infiltrate. Some samples may have a polytypic lympho-
cytic infiltrate around or within the lesions.21,22 Patients with smoldering or ASM or
MCL often have a high degree of involvement in bone marrow biopsy (>30%), with
associated marked fibrosis. The cells have spindle shapes, oval and eccentric nuclei
with pale cytoplasm in hematoxylin-eosin staining. Tryptase stain confirms the nature
of the infiltrate as mast cells.

Minor Criteria
1. More than 25% of the cells have morphologic abnormalities such as spindle
shapes, hypogranulation, eccentric nuclei, cytoplasmic projections, and multilobed

Box 1
Diagnostic criteria of SM

Major
Multifocal dense aggregates of mast cells with more than 15 cells per aggregate in an
extracutaneous tissue
Minor
1. Greater than 25% of mast cells have morphologic abnormalities such as spindle shapes,
cytoplasmic projections, hypogranulation (see text)
2. Expression of CD25 with or without CD2 by mast cells
3. Detection of a codon 816 c-kit mutation by a sensitive technique in lesional tissue or
peripheral blood
4. Serum baseline tryptase greater than 20 ng/mLa
a
Not valid if there is AHNMD.
Data from Refs.1820; see text for more detailed discussion; major 11 minor, or 3 minor, criteria
are required.
 Diagnosis and Classification of Mastocytosis 211

or clefted nuclei.23,24 Normal bone marrow mast cells have round cytoplasm, with a
centrally located nucleus and dense granulation. In bone marrow aspirate smears,
mast cells are usually located in or near bone spicules. The percentage of mast
cells in bone marrow aspirate smears has been shown to correlate with advanced
mastocytosis and prognosis. If mast cell percentage is greater than 20% in an as-
picular area, the diagnosis is MCL. Mast cells of less than 5% are generally seen in
ISM, whereas mast cells between 5% and 19% signify an intermediate prog-
nosis,23 which is often the case in ASM, and termed ASM in transformation
(ASM-t), because these cases often progress to MCL.15
2. Mast cells aberrantly express CD25 and CD2.25,26 Normal or reactive mast cells
usually do not express these markers. CD25 is more sensitive and specific than
CD2.27,28 Expression of these markers can be detected by immunohistochemistry
(IHC) or flow cytometry. IHC has the advantage of being applicable to archived
paraffin-embedded samples.29 Serial sections should be stained for tryptase to
detect coexpression of CD25 in mast cells. CD2 staining does not always yield pos-
itive results, especially in advanced disease. Flow cytometry is also a sensitive and
reliable method of detecting aberrant mast cell marker expression, if it is performed
in reference centers with expertise on this technique. Because the mast cell per-
centage of the marrow aspirate is usually low (in many cases <1%), special gating
techniques and acquisition of many events (at least 500,000 or preferably higher)
are required for an accurate analysis.26,30
3. Using a sensitive technique, c-kit point mutation at codon 816 is detectable in
peripheral blood or lesional tissue.3134 Detailed accounts of c-kit mutations in
mastocytosis in pathogenesis of mastocytosis and their roles in altered signal
transduction are discussed in other articles by Cruse and colleagues, Arock and
colleagues in this issue. D816V c-kit mutation is detectable in more than 80% of
patients with SM in bone marrow mast cells34,35 and in approximately 40% of chil-
dren with cutaneous mastocytosis in lesional skin.36 Analysis of peripheral blood
may yield false-negative results in most commercially available tests, because of
the somatic nature of the mutation, although recently introduced polymerase chain
reactionbased sensitive tests approach the sensitivity in bone marrow sorted
mast cells.33 Mutation may be confined to mast cells in patients with indolent dis-
ease, whereas it may involve multiple other myeloid and even lymphoid lineages in
patients with advanced disease.35,37,38 Patients with multilineage involvement were
shown to have a higher risk of progression to aggressive mastocytosis and carry a
poorer prognosis. c-kit D816V mutation renders the mast cells resistant to the
currently available tyrosine kinase inhibitors, including matinib.3941
4. Serum tryptase greater than 20 ng/mL.4246 Normal median tryptase level in the
healthy population is 5 ng/mL. Mast cells are the major source of the neutral pro-
tease tryptase. Basophils and myeloid progenitors also produce smaller amounts
of this enzyme. Therefore, tryptase levels may be increased in other myeloid
neoplastic processes and do not count as a minor criterion in SM-AHNMD.47
Commercially available tryptase assay uses an enzyme-linked immunosorbent
assay method to measure a combination of mature tryptases and protryptases.
Mature tryptase (b tryptase) is stored in mast cell granules and is released after a
mast cell degranulation or anaphylactic event, with peak levels found in approxi-
mately 1 hour after the degranulation. b Tryptase levels are undetectable in sera
from healthy individuals. In contrast, protryptases (mainly encoded by a tryptase)
are targeted to cell membrane and constitutively secreted out of the mast cells.
Therefore, the total tryptase level at baseline reflects a (pro) tryptase and correlates
with total body mast cell burden. A basal tryptase level less than 20 ng/mL does not
212 Akin & Valent

rule out mastocytosis, whereas slight tryptase increases greater than 20 ng/mL can
be seen in individuals other than those with mastocytosis (including those with
renal disease, myeloid neoplasms, and idiopathic) and even in apparently healthy
controls. Therefore, tryptase levels alone should not be used as the sole criterion
to diagnose mastocytosis.
Some patients with mast cell activation symptoms and lower tryptase levels may not
meet the full WHO criteria for the diagnosis of mastocytosis but may have CD251
mast cells in bone marrow biopsies or have the c-kit D816V mutation detectable.4850
These patients meeting only 1 or 2 minor criteria are termed to have monoclonal mast
cell activation syndrome (MMAS). It is not clear whether patients with MMAS progress
to full-blown mastocytosis with time.
A rare histopathologic variant of SM termed well-differentiated SM (WDSM) is char-
acterized by aggregates of mast cells with round shapes and fully granulated
morphology with no CD25 expression.51 Aberrant CD30 expression may be a useful
marker for these patients, who generally have childhood-onset mastocytosis with
skin lesions and progress to have adult-onset systemic disease.52,53 Most patients
with WDSM do not carry the D816V c-kit mutation and thus may respond to imatinib.54
The WDSM morphology may be found in patients with ISM but can sometimes also
be found in patients with advanced SM requiring therapy. Therefore also, the term
WDSM should be used as a descriptive appendix to the final diagnosis, for example,
ISM-WDSM, ASM-WDSM, or ASM with WDSM morphology. Sometimes, it is nearly
impossible to differentiate between WDSM and reactive mast cell hyperplasia.

CLASSIFICATION

The WHO classification divides mastocytosis into 7 categories (Box 2). A major check-
point in classification of mastocytosis is to determine whether the patient has cuta-
neous mastocytosis or SM. This determination correlates with the age of onset of
disease and is defined by histopathologic criteria, as discussed earlier. If a diagnosis
of SM is made, the next step is to classify the disease into 1 of 4 categories of SM.
1. ISM. Most patients with adult-onset disease fall into this category. Patients with
ISM satisfy the WHO diagnostic criteria for SM but do not have other hematologic

Box 2
Classification of mastocytosis

 Cutaneous mastocytosis
 ISM
 Smoldering SMa
 SM-AHNMD
 ASM
 MCL
 MCS
 Extracutaneous mastocytoma
a
The smoldering subtype of SM has recently been accepted as a separate category by the
consensus group, but was not implemented as such in the WHO classification of 2008.
 Diagnosis and Classification of Mastocytosis 213

disorders or evidence of tissue dysfunction caused by mast cell infiltration. Prog-

nosis of ISM is good, with chance of progression to one of the more advanced cat-
egories being less than 5%. Patients with ISM often have chronic symptoms of
mast cell degranulation, such as flushing, pruritus, abdominal cramps, and diar-
rhea, and usually require symptomatic management with antimediator therapy.
The risks of hypotensive anaphylaxis5557 and osteoporosis58 are increased. A sub-
stantial subset of patients who experience systemic allergic reactions to Hymenop-
tera stings have been described as having ISM or MMAS.59,60
A WHO subvariant of ISM called smoldering SM is characterized by increased
mast cell burden (>30% infiltration in bone marrow biopsy and tryptase
levels >200 ng/mL) and may have splenomegaly or hepatomegaly without sig-
nificant organ impairment and subtle dysplastic changes not meeting the full
criteria of another hematologic disease or ASM (B findings).6163 These pa-
tients may be at a higher risk of progression to a more advanced category.
WHO has included this variant as a subcategory of ISM. However, more
recently, the smoldering type of SM has been recognized as a major defined
category of SM, with unique clinical and molecular features. The key molecular
feature is the clonal multilineage involvement, which can be shown by the
presence of KIT D816V in various hematopoietic lineages.
2. SM-AHNMD. These patients meet the criteria for SM as well as a second hemato-
logic disorder. The associated hematologic disorder is usually myeloid: myelodys-
plastic syndromes, CMML, myeloproliferative disorders (including those associated
with JAK2 V617F mutation), and AML have all been described.10,64 Lymphoprolifer-
ative disorders such as non-Hodgkin lymphoma and myeloma have also been
occasionally described.65,66 The SM component in SM-AHNMD may be indolent
or aggressive, and each component should be diagnosed and treated according
to its own treatment guidelines.
3. ASM. This category of mastocytosis has a clinical course similar to other malig-
nancies leading to organ damage and is associated with poor prognosis. The
symptoms are caused by extensive mast cell infiltration, causing tissue dysfunction
(C findings).1820 Tissues involved in ASM include hematopoietic, gastrointestinal,
and skeletal systems.12 Pulmonary, renal, and central nervous system involvement
is rare. C findings include cytopenias (absolute neutrophil count <1000/mL, hemo-
globin <10 g/dL, platelets <100,00/mL) with a high degree of bone marrow involve-
ment (usually >30%) or splenomegaly, increased levels in liver function tests with
evidence of portal hypertension or ascites, extensive gastrointestinal infiltration
documented by biopsy accompanied by malabsorption, hypoalbuminemia, weight
loss and chronic diarrhea, or large osteolytic lesions with pathologic bone frac-
tures. The last finding should not be confused by osteoporosis and resulting verte-
bral compression fractures, which are common in indolent mastocytosis. The local
mast cell infiltration should be documented whenever possible. Tryptase levels in
ASM are usually higher than 100 ng/mL and often increase rapidly over time.67 In
some of these patients, progression to MCL is seen within a few months. These
cases may suffer from ASM-t, a condition defined by a mast cell count of 5% to
19% in bone marrow smears. Patients with ASM are candidates for mast cell cyto-
reductive or investigational therapies. In this regard, many patients with ASM have
concomitant AHNMD (ASM-AHNMD). In these cases, the overall treatment plan
has to be adapted to both conditions.
4. MCL. Mast cells are not components of normal peripheral blood. MCL is defined by
a mast cell count of 20% or greater in bone marrow smears.15 Although some mast
cells in circulation can be detected in ASM, presence of 10% or more mast cells in
214 Akin & Valent

peripheral blood is highly suspicious (diagnostic) for MCL. In aleukemic variants of

MCL, bone marrow aspirate smears contain 20% or more mast cells in aspicular
areas, but circulating mast cells are less than 10%. Mast cells in MCL have high-
grade morphology, with significant degranulation, multilobular or clefted nuclei,
and may even show mitotic figures. Serum tryptase is often significantly increased
and may be found greater than 500 or even greater than 1000 ng/mL. MCL may
occur de novo or occasionally develop secondary to other mast cell disease cate-
gories, such as ASM. MCL has a poor prognosis, and patients often have C findings
at diagnosis or develop them shortly thereafter, although a chronic form with a rela-
tively stable course over several years has been recognized.14 Similar to ASM, pa-
tients with MCL require cytoreductive and investigational therapies. In many cases,
polychemotherapy is recommended, and in those who show a good response,
stem cell transplantation has to be considered.
MCS is a rare malignant form of solid mast cell tumor with destructive infiltration and
metastatic potential.16 This issue contains an excellent review article by Weiler and
Butterfield on all cases of this tumor published in the literature. MCS may progress
to MCL within a short period. Skin involvement has also been described and was re-
ported to develop in the background of UP. Extracutaneous mastocytoma is an
exceedingly rare benign mast cell tumor, and the clinical experience is limited to a
few case reports.68

SUMMARY

The current diagnostic criteria and classification of mastocytosis are well validated by
clinical studies and have been shown to correlate with prognosis and to guide in the
selection of therapy. As new knowledge is gained regarding clinical course, molecular
pathogenesis and therapy for disease, evidence-based revisions to improve the cur-
rent criteria should be considered by international consensus. Using the guidelines in
this article, it should be straightforward to establish a diagnosis of mastocytosis in
most cases. Cases with low mast cell burden or uncertain diagnostic interpretation
should be referred to centers of expertise. In Europe, centers of excellence have
been organized under the umbrella of the European Competence Network on Masto-
cytosis (http://www.ecnm.net). Although no similar organization exists in the United
States, there are several centers of excellence, including the Brigham and Womens
Hospital, Stanford, Mayo Clinic, MD Anderson, and National Institutes of Health. It
is the hope for the future that these centers will develop and merge as a robust collab-
orative competence network in the United States. The patient support groups, such as
the Mastocytosis Society, also provide valuable education and organize yearly meet-
ings (http://www.tmsforacure.org/) and should thereby support academic studies and
networking in this emerging field of science.

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