MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
The bone marrow in systemic
mastocytosis e an update
Mufaddal T Moonim
Abstract
The bone marrow is the most common site of involvement in systemic
mastocytosis (SM). The WHO has defined criteria for the diagnosis of
SM and this review discusses the various patterns of bone marrow
involvement by mast cell neoplasia and the roles of immunohistochem-
istry and flow cytometry in the diagnosis of SM. It also covers the
morphologic features and diagnostic criteria for SM with associated clonal
non-mast cell lineage haemopoietic neoplasms (SM-AHNMD) and aggres-
sive mastocytosis (aleukaemic and leukaemic mast cell leukaemia, myelo-
mastocytic overlap syndromes and mast cell sarcoma). In addition, this
review covers unusual entities including reactive mast cell hyperplasia,
well-differentiated systemic mastocytosis, chronic mast cell leukaemia
and monoclonal mast cell activation syndrome.
Keywords aspirate; bone marrow; flow cytometry; immunohistochem-
istry; mast cell; mast cell hyperplasia; mast cell leukaemia; mast cell
sarcoma; morphology; myelomastocytic overlap syndromes; SM-AHNMD;
systemic mastocytosis (SM); trephine biopsy; well-differentiated systemic
mastocytosis
Systemic mastocytosis (SM) is a heterogeneous disease with
myriad and often intriguing symptomatology, and a variable
clinical course which is indolent in the vast majority of patients
but can progress aggressively in a subset.1e4 The basic pathology
behind all of this is a clonal expansion of mast cells which
originates in the marrow, proliferates and expands there and
subsequently spills into the rest of the body. The current review
provides a comprehensive overview of how to make a diagnosis
of bone marrow-based mast cell proliferations.
Mast cell histogenesis
Mast cells are derived from CD34þ/CD117þ stem cells of the bone
marrow. They undergo a series of differentiation steps in which
they develop metachromatic granules to form a differentiated mast
cell. Expression of CD117 (C-KIT/SCF) gradually disappears dur-
ing the maturation of most haemopoietic cell lineages, but it is
retained and expressed on mature mast cells. The following stages
of mast cell differentiation can be recognized in the bone marrow
(1) ungranulated but tryptase-positive blast cells, (2) meta-
chromatic blast, (3) promastocyte, and (4) round mononuclear
mature MC with metachromatic granules in the cytoplasm.5
The ‘normal’ mast cell
Mast cells are distributed throughout the body, being best seen in
loose fascial connective tissue and in the perivascular spaces of
blood vessels. Within bone they are usually located around
Mufaddal T Moonim MD FRCPath Consultant Histopathologist, Guy’s and
St. Thomas’ Hospitals, London, UK. Conflicts of interest: none declared.
DIAGNOSTIC HISTOPATHOLOGY 21:5
sinusoids or near the endosteal surface of bone. In the normal
marrow, they are inconspicuous and difficult to find. In H&E-
stained sections, mast cells appear medium sized, have abundant
eosinophilic, granular cytoplasm and small round hyper-
chromatic nuclei without nucleoli (Figure 1a). Mast cell granules
can specifically be highlighted by toluidine blue (metachromatic,
purple) (Figure 1c) and chloroacetate esterase (orange-red) stains
(Figure 1d).
In aspirates stained using Romanowsky stains, mast cell
granules are metachromatic and stain intensely purple
(Figure 1b). Often the cells are squashed during the preparation
of films and one usually sees a bland nucleus surrounded by a
star-burst of pink/purple granules.
The ‘neoplastic’ mast cell
In contrast to the round/ovoid morphology of the normal mast
cell, neoplastic mast cells in indolent systemic mastocytosis are
spindle shaped. In H&E-stained sections (Figure 2a), they are
seen to possess delicate, elongated, ovoid, vesicular nuclei which
may also be reniform/bilobate. The cytoplasm is eosinophilic.
Rarely, cells with clear cytoplasm can be seen. In bone marrow
aspirates, cytoplasmic granularity ranges from paucigranular to
hypergranular with the granules often seen around bare nuclei
(Figure 2b & c). In aggressive systemic mastocytosis (ASM), mast
cell morphology may be more blast like (Table 1).
In routine practice, the vast majority of neoplastic mast cells
are spindle shaped, with few round forms identified (in biopsy
sections, the latter are most likely to be due to transverse
sectioning of spindle-shaped mast cells). Rarely, neoplastic mast
cells can be round and hypergranular (seen in well-differentiated
SM and chronic mast cell leukaemia); this morphology has been
associated with non-D816V mutation status, which may be
Imatinib sensitive and associated with good outcome.
Immunohistochemistry
Normal mast cells express CD45 (LCA), CD33, CD68 (including
CD68R), mast cell tryptase and CD117. Neoplastic mast cells
express CD25 and CD2 aberrantly (Table 2 & Figure 3). The
former is readily identified by immunohistochemistry; expres-
sion of the latter tends to be variable.
Additional markers which are emerging as valuable in the
context of SM include CD30, CD123 and CD52.
CD30 has been proposed as a prognostic marker to try and
identify cases likely to behave aggressively. Sotlar et al. have
developed an IHC-based scoring system for SM: ‘negative’ ():
<10% of mast cells express CD30; ‘positive’ (þ): 10e50% of mast
cells clearly express CD30; ‘strongly positive’ (þþ): >50% of mast
cells clearly express CD30.6,7 CD30 expression was identified more
frequently in patients with aggressive/advanced SM; (85%),
compared to those with indolent systemic mastocytosis (27%). A
subsequent study evaluating CD30 expression by flow cytometry
and IHC concluded that flow cytometry was more sensitive at
detecting CD30 expression but found no correlation between
expression and SM subtype.8 CD123 expression by neoplastic mast
cells has also been described. Expression of these markers adds
mastocytosis to the list of CD30(þ) or CD123(þ) tumours.9 CD52
has recently been described as being expressed on mast cells in
ASM with the option of using this as a molecular target for therapy.
181 Ó 2015 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
Figure 1 Normal mast cells are round and granulated. (a) H&E 20; (b) Giemsa 60; The granules stain purple with toluidine blue (c, 20) or orange with
chloroacetate esterase (d, 20).
Systemic mastocytosis (SM)
Systemic mastocytosis is defined as a clonal proliferation of mast
cells in which there is involvement of at least one extracutaneous
organ with or without skin involvement. SM accounts for 20% of
all mastocytosis. Diagnostic criteria include 1 major criterion (ag-
gregates of at least 15 mast cells) and 4 minor criteria (>25% mast
cells are spindled/atypical; CD117 co-expressed with either CD25
or CD2; c-KIT point mutation at codon 816; Sr. tryptase: > 20 ng/ml
{unless CMD/AHNMD}). A diagnosis of SM is achieved if 1 major
and 1 minor criterion or 3 minor criteria can be satisfied.1
Bone marrow involvement
The bone marrow is the commonest site involved in SM. Marrow
involvement is seen in both the indolent (ISM) and aggressive
(ASM) forms of SM and in SM with associated clonal haemato-
logic non-mast cell lineage disease (SM-AHNMD), mast cell
leukaemia (MCL) and mast cell sarcoma (especially when the
latter involves bone).
Patterns of bone marrow involvement
 Nodular interstitial aggregate: (Figures 4 and 5a)
This constitutes the pathognomonic lesion and is composed of a
core of delicate, spindle-shaped mast cells surrounded by a cuff
of eosinophils and lymphocytes. The latter are a mixture of
CD20(þ) B-cells and CD3(þ) T-cells.
DIAGNOSTIC HISTOPATHOLOGY 21:5
 Perivascular: (Figure 5b)
Collections of mast cells which are seen around blood vessels.
 Paratrabecular: (Figure 5c)
Paratrabecular aggregates are often missed in diagnostic
practice as, at low power magnification they appear as foci of
fibrosis/scar tissue. Viewed at higher magnification, the spindled
mast cells are often difficult to detect as they are either com-
pressed or distorted by fibrosis to look like fibrocytes or myofi-
broblasts. Immunohistochemistry is very useful in this situation.
 Diffuse interstitial:
Singly scattered mast cells are identified scattered amidst
haemopoietic cells.
 Fibrotic: (Figure 5d)
Here large areas of the intertrabecular space are replaced by
bland scar-like tissue simulating an appearance of myelofibrosis.
Careful examination of the edge of these areas and around blood
vessels reveals spindle-shaped mast cells.
None of these patterns help in differentiating between indo-
lent and aggressive systemic mastocytosis.
Flow cytometric examination of bone marrow in systemic
mastocytosis
The minimum panel required to evaluate mast cells on flow
cytometry should contain CD45, CD117, CD25 and CD2.10e12
Mast cells are defined as CD117high/CD45þ cells with typical
182 Ó 2015 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY

Figure 2 Neoplastic mast cells are spindle shaped and may appear triangular or kite shaped on aspirate. They posses elongated or bilobed nuclei. (a) H&E
20, (b & c) Giemsa on aspirate 100.

autofluorescence on forward/side scatter. Compared to normal
mast cells, neoplastic mast cells show lower levels of CD117
expression. All cases in addition express either CD2 or CD25
aberrantly.
CD25 is uniformly identified (100%) while CD2 is expressed
more variably (83%). Higher CD2 expression is identified when
PE is used as the conjugate (87%) compared to FITC (67%).10
Recent data indicate that specificity of immunophenotyping in-
creases if CD2 is excluded from diagnostic criteria (i.e. that
diagnosis is based on a CD45þ/CD117 bright/CD25þ phenotype)
(99.2% vs 99.0%).13 Loss of CD2 is seen more frequently in
ASM. CD25 expression has also been described in cases inter-
preted as clonal mast cell activation syndrome.
Overall, it has been proposed that flow cytometry is better
than morphological assessment for identifying neoplastic mast

Types of atypical mast cells identified on the bone

marrow aspirate Immunohistochemistry of normal and neoplastic mast
cells
Type Identifying features
Normal Neoplastic
Atypical mast A cell satisfying 2/3 of the following criteria:
cell e type 1 C Often spindle-shaped cells with elongated LCA D D
surface projections CD33 D D
C Hypogranulated cytoplasm CD68 D D
C Oval decentralized nucleus MCT D D
Atypical mast Immature cell with metachromatic granules, with CD117 D D
cell e type 2 bi- or multi-lobed nuclei CD25 Neg D
(Promastocyte) CD2 Neg D
Metachromatic Myeloblast with few or several metachromatic CD30 Neg D/L
blast granules CD123 Neg D/L

Table 1 Table 2

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 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
Figure 3 Immunohistochemistry of neoplastic mast cells. (a) Mast cell tryptase, (b) CD117 [this is usually strongly expressed in contrast to this image], (c)
CD25, (d) CD2 (note strong expression in accompanying T-cells).
cells in bone marrow e it has a reported sensitivity of 95%,
which exceeds the sensitivity of morphological analysis (69% for
aspirate and 85% for biopsy).14,15 There are, however, limited
data available on this issue to draw firm conclusions and ex-
amination of bone marrow histology is currently the gold stan-
dard for diagnostic purposes.
Figure 4 Nodular interstitial mast cell aggregate in systemic mastocytosis
with spindle-shaped mast cells and accompanying eosinophils and lym-
phocytes. H&E 10.
DIAGNOSTIC HISTOPATHOLOGY 21:5
Other markers that are aberrantly expressed on neoplastic
mast cells include CD11c, CD35 (86%), CD59 (92%), CD63
(88%), and CD69 (81%).10,11,15
SM associated with clonal haematologic non-mast cell lineage
disease (SM-AHNMD)
When SM and another haemopoietic neoplasm occur together
the disease process is labelled as SM-AHNMD. The diagnostic
labels ISM-AHNMD and ASM-AHNMD are used to reflect asso-
ciation with the indolent or aggressive variants of SM. SM-
AHNMD is the second most common SM subtype (40%).16e19
Both myeloid and lymphoid neoplasms can occur in associa-
tion with SM, with myeloid neoplasms accounting for about 90%
and lymphoid and plasma cell neoplasms accounting for 10% of
cases. While both can occur at any time point in the course of the
other, the AHNMD component usually presents clinically with
the SM component largely constituting bystander disease.
Symptomatology, clinical course and prognosis are also largely
determined by the AHNMD component, with the exception of
patients in whom the AHNMD component is MGUS.
From a diagnostic point of view, the following features should
be borne in mind:
1. Myeloid neoplasms:
A. MDS/MPN overlap syndromes: Chronic myelomono-
cytic leukaemia is the most common myeloid
184 Ó 2015 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
Figure 5 Patterns of bone marrow involvement by mastocytosis. (a) Nodular interstitial, (b) Perivascular, (c) Paratrabecular, (d) Fibrotic.
neoplasm associated with SM. In addition to dysplasia,
and increased numbers of CD68(þ), CD14(þ) mono-
cytes, tissue sections may contain increased numbers
of CD123(þ) plasmacytoid dendritic cells, which can
be seen as clusters or rarely as sheets. The latter may
have a spindled morphology, but lack expression of
mast cell markers.
B. Acute myeloid leukaemia: The SM component is usu-
ally identified in post-therapy biopsy specimens and
becomes more prominent if AML therapy is successful
in controlling the leukaemic clone. The SM component
is by and large paratrabecular and appears as linear
patches of fibrosis within which stellate or compressed
mast cells can be identified (Figure 6a). Mast cells
simulate the appearance of myofibroblasts or fibro-
cytes and these areas are often misinterpreted as post-
chemotherapy scarring (Figure 6b). Immunohisto-
chemistry for mast cell markers is very useful in
identifying the mast cell component in this context.
C. MDS: The most common type associated with SM is
MDS-RCMD.
D. Myeloproliferative neoplasms: SM can be associated
with both JAK2V617F and JAK2WT MPNs. Microdissec-
tion studies have shown that even the mast cells can
be JAK2V617F positive. Pardanani et al. found a high
prevalence (56%) of eosinophilia in this subset, 48%
DIAGNOSTIC HISTOPATHOLOGY 21:5
of which could be categorized as SM-CEL (chronic
eosinophilic leukaemia).18
2. Lymphoid neoplasms:
A. Low grade B-cell non-Hodgkin lymphoma is the usual
AHNMD component.
B. T-cell lymphoma and Hodgkin lymphoma20 have been
described in rare individual case reports as AHNMD
components; a single case report documents coexis-
tence of hepatosplenic gamma-delta T-cell lymphoma
with SM.21,22
C. High grade precursor/mature B/T-cell lymphoma: B-
acute lymphoblastic leukaemia and diffuse large B-cell
lymphoma23 have been described as AHNMD compo-
nents in a very small number of patients. A case of c-
KITD816V SM occurring with two AHNMD components,
myeloproliferative disease - unclassifiable (MPN-U)
and precursor B-cell acute lymphoblastic leukaemia is
documented. In this case, both AHNMD components
carried the wild-type KIT gene, but had a novel t(13;
13) (q12; q22) involving the FLT3 locus at 13q12.24 T-
cell acute lymphoblastic leukaemia and Burkitt lym-
phoma have not yet been described in association with
SM.
3. Plasma cell neoplasms:
Both MGUS and myeloma have been described as AHNMD
components.25,26
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 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
Figure 6 SM-AHNMD: Bone marrow involved by acute myeloid leukaemia with paratrabecular aggregates of mast cells (a, H&E 4); post-chemotherapy
there are zones of scarring within which the mast cells look like myofibroblasts (b, 20). Myelomastocytic leukaemia (c, H&E 40) with tryptase
expressing blasts (d, Mast cell tryptase 20).
The pathogenesis of SM-AHNMD is yet to be clarified. 95% of
SM cases harbour c-KIT D816V mutations with the remainder
having other, less frequent auto-activating mutations (D816Y,
D816H, D816F). In patients with isolated mast cell disease, the
KIT mutation is the sole characteristic genetic alteration. SM-
AHNMD patients might have further genetic alterations
depending on the associated condition: RUNX1-RUNX1T fusion
gene in AML, JAK2V617F in MPN, TET2 mutation in MPN/MDS.27
When examining the AHNMD component, Sotlar et al. detected
c-KITD816V in most CMML (89%), a third of AML (30%) and
some of the MPN (20%) cases, while none of the lymphoproli-
ferative AHNMD cases harboured this mutation.28 Another study
showed that SM-AHNMD cases harboured a higher mutated c-
KIT burden compared to ISM.
Mast cell leukaemia
Mast cell leukaemia (MCL) accounts for w1% of all mast cell
disorders and is defined as the presence of 20% neoplastic mast
cells in the BM aspirate. Two variants are described e the
commoner aleukaemic form (62%) (<10% of WBC in peripheral
blood are mast cells) and the leukaemic form (>10% of WBC in
peripheral blood are mast cells). In ISM, mast cells do not aspi-
rate well and are usually difficult to find in bone marrow films.
The presence of large numbers of mast cells in the aspirate cor-
relates very well with very aggressive and often leukaemic
DIAGNOSTIC HISTOPATHOLOGY 21:5
disease. It is important to remember that mast cell counts from
the bone marrow aspirate rather than those from biopsy sections
are relevant in making a diagnosis of MCL.
Mast cells in MCL tend to have high grade cytomorphology
and are round to ovoid with a high nucleo-cytoplasmic ratio
rather than the delicate spindle-shaped forms seen routinely in
SM (these are only rarely seen in MCL). The mast cells may show
other morphological abnormalities including bi- or multi-lobed
nuclei, prominent nucleoli, polarized or coalescent granules or
cytoplasmic lacunar areas. In trephine sections normal bone
marrow components are replaced by plump, round and ovoid
cells with eosinophilic cytoplasm and vesicular nuclei with small
nucleoli (Figure 7). Multinucleation can be seen. MCL is often
associated with morphologically abnormal marrow-based and
circulating eosinophils. In a small subset of patients, necrosis
may be seen or the entire tumour as seen within biopsy sections
may be infarcted. Immunophenotypically, there is frequent loss
of CD25 (25%) and CD2 (48%) with about a third of cases being
negative for both markers. Mast cells in MCL are likely to be
Ki67(þ) (>50%). Molecularly, more patients harbour non-
D816V mutations (exons 9, 10, 11, 13) which is why the entire
c-KIT gene needs to be sequenced in cases of MCL. Some of these
mutations (i.e. Phe522Cys or the exon 9, 501e502/502e503
mutation in the extracellular domain of c-kit) have been associ-
ated with response to Imatinib or Masitinib.
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 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY

finding in de novo MCL compared to secondary MCL. Serum

Figure 7 Mast cell leukaemia: diffuse replacement of marrow by plump
mast cells accompanied by eosinophils. H&E 10.
tryptase levels are elevated (>200 ng/ml) and increase rapidly
over weeks in contrast to ISM. Median survival was <6 months
until the availability of Midostaurine (PKC412), a FLT3 inhibitor.
Recent trial data using this agent indicates that MCL patients
have survived beyond the median survival time expected with
MCL. Allogeneic stem cell transplantation has been used in a
subset of these patients and, from a diagnostic point of view, it is
worth noting that donor mast cells (with normal morphology and
immunophenotype) can rapidly engraft post-transplant and these
should be evaluated carefully so as not to confuse them with any
persistence of the neoplastic clone.
A few recent reports describe an entity labelled as ‘chronic
mast cell leukaemia’, in which the leukaemic clone has features
of mature mast cells.30 These patients have stable serum tryptase
levels, lack end-organ damage and appear to have a less
aggressive course with symptoms and progression controlled
without chemotherapy. A subset of patients have progressed to
conventional/acute MCL.

MCL can occur de novo (w70%) or secondary to progression
of SM (w30%; usually in the context of SM-AHNMD or ASM).29
Average age at presentation is 51 years with a female prepon-
derance. Mast cell activation symptomatology and splenomegaly
are common; organ damage is usually found at diagnosis or
develops rapidly. Gastroduodenal ulcers are a more common
Myelomastocytic overlap syndromes
Myelomastocytic leukaemia/overlap syndrome represents a
group of disorders in which MDS/AML or, rarely, the blast phase
of CML occur in association with metachromatic/tryptase (þ)
blasts. The major diagnostic criterion of SM (aggregates of >15

Figure 8 Reactive mast cell hyperplasia in a myeloproliferative neoplasm (a) H&E 10, (b) Mast cell tryptase 10. Fibromastocytic lesion with zones of
fibrosis (c, 4) which are associated with many round, hypergranulated mast cells (d, 10).

DIAGNOSTIC HISTOPATHOLOGY 21:5 187 Ó 2015 Published by Elsevier Ltd.

 MINI-SYMPOSIUM: BONE MARROW PATHOLOGY
MC in tissue sections) is absent although a diffuse increase in
interstitial mast cells is present. If the metachromatic blasts in
peripheral blood or bone marrow account for <10% of the blast
component, then the entity is labelled as tryptase(þ) AML; if
metachromatic blasts account for >10% of the blast component
then this represents myelomastocytic leukaemia (Figure 6c & d).
Background dysplastic changes may be present. Immunopheno-
typically, the blasts express CD34 variably but are CD117(þ).
CD25 expression is also variable, with loss of expression in
myelomastocytic leukaemia. Serum tryptase levels are lower
than one would expect in MCL (<100 ng/ml). These disorders do
not show activating mutations in c-KIT, but most possess a
complex karyotype. The background AML component often
shows t(8; 21) or inv(16).31e33
Mast cell sarcoma
Tumorous mass lesions composed of neoplastic mast cells have
been described involving bone. These invariably occur in the
context of SM-AHNMD or ASM and progress to aleukaemic or
leukaemic MCL.
Reactive mast cell lesions
Increased numbers of normal mast cells may be seen in associ-
ation with a number of conditions including hypersensitivity
states, chronic myeloproliferative neoplasms and lympho-
plasmacytic lymphoma. The mast cells in these contexts are
round, granulated, singly distributed within the interstitium and
do not form aggregates (Figure 8a & b). They also do not express
CD25 or CD2. Sometimes these are associated with zones of
fibrosis and this association has been descriptively labelled as a
‘fibromastocytic lesion’ (Figure 8c & d).
Monoclonal mast cell activation syndrome
A subset of patients have mast cell degranulation symptoms,
with clonal mast cells in the marrow, but do not meet criteria for
SM (only 1 or 2 minor criteria satisfied, and no skin involve-
ment). These patients are labelled as having “prediagnostic ISM”
or “monoclonal mast cell activation syndrome”. In bone marrow
sections, mast cell clusters are not seen; however, diffusely
distributed interstitial mast cells which are spindle shaped, ex-
press CD25 or CD2, or harbour a c-KIT mutation are identified.
Serum tryptase levels are either normal or slightly elevated in
this cohort.34,35
Well-differentiated systemic mastocytosis
A very small proportion of SM patients may exhibit a well-
differentiated phenotype; the mast cells have normal mature
morphology (round, fully granulated mast cells) and lack evi-
dence of CD25 or CD2 expression. These cases are associated
with non-D816V c-KIT mutations (germline F522C, K509I or so-
matic I817V). The F522C-associated SM has been shown to be
sensitive to Imatinib therapy.36 A 17
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Practice points
C Bone marrow is the most common site of involvement in systemic
mastocytosis.
C Neoplastic mast cells in indolent SM (ISM) are spindle shaped,
express CD25 and/or CD2 and often have a c-KITD816V mutation.
C Patterns of bone marrow involvement include nodular, peri-
vascular, paratrabecular, diffuse interstitial and fibrotic.
C Neoplastic mast cells in aggressive SM (ASM) are more blast like.
C The SM component in SM-AHNMD is difficult to identify and is
frequently missed or identified only after therapy for the AHNMD
component.
189 Ó 2015 Published by Elsevier Ltd.