|

Received: 17 August 2017    Accepted: 24 October 2017

DOI: 10.1111/ijlh.12776

REVIEW ARTICLE

How I investigate monocytosis

D. T. Lynch1  | J. Hall1 | K. Foucar2

1
Brooke Army Medical Center, Ft. Sam
Houston, TX, USA Abstract
2
University of New Mexico, Albuquerque, Monocytosis is a common finding that is caused by a wide variety of neoplastic and
NM, USA
non-neoplastic conditions. The adequate evaluation of monocytosis involves the inte-
Correspondence gration of laboratory data, morphology, clinical findings, and the judicious use of ancil-
David T. Lynch, Brooke Army Medical Center,
lary studies. We review the literature on monocytosis, including the 2017 revised 4th
Ft. Sam Houston, TX, USA.
Email: lynchpath@gmail.com edition of the World Health Organization classification of hematopoietic neoplasms.
We present a review of monocytosis with practical guidelines on how to approach
both routine and challenging cases.

KEYWORDS
blood, bone marrow, leukemia, monocytes, morphology, myeloid

1 | INTRODUCTION monocyte count (AMC) varying by age. At 24 weeks gestation, mono-

Circulating peripheral blood monocytes are key players in the innate
immune system. Although not distinct morphologically, dendritic cells
and precursors also circulate. These monocytic/dendritic cells are
derived primarily from bone marrow hematopoietic stem cells and
are highly versatile with capacity to migrate to sites of inflammation,
differentiate into tissue macrophages and specialized dendritic cell
subtypes, secrete cytokines and chemokines to attract other inflam-
matory cells, and phagocytose tissue debris and microorganisms. They
also participate in the initiation of adaptive immunity by presenting
antigens to antigen-­specific lymphocytes. The effector functions and
roles played by these cells in mediating acute and chronic inflamma-
tion, antimicrobial defense, and tissue repair and wound healing are
vital to the maintenance of a healthy steady state. When dysfunctional
or dysregulated, however, monocytes can contribute to and cause sig-
nificant disease. The purpose of this review was present a strategy to
investigate monocytosis primarily in the adult patient.
2 | BACKGROUND
In the healthy adult and child, monocytes typically comprise between
1 and 9 percent of total peripheral blood leukocytes, with the absolute
The view(s) expressed herein are those of the author(s) and do not reflect the official policy or
position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army
Office of the Surgeon General, the Department of the Air Force, the Department of the Army
or the Department of Defense, or the U.S. Government
cytes are 0.7 × 109/L (range 0.1-­2.5 × 109/L) and gradually increase
until the third week following birth where they reach 1.5 × 109/L
(0.3-­3.0 × 109/L).1 Over the next several months, the AMC gradually
decreases to below 1.0 × 109/L, which is the threshold that defines
absolute monocytosis in diagnostic criteria in the 2017 revised 4th
edition of the World Health Organization classification of hematopoi-
etic neoplasms (2017 WHO).2 Variability in monocyte count by race
and gender on the other hand is minimal.3
When seen on modified Giemsa-­stained blood smears, mature
monocytes can be readily recognized by their large overall size with
deeply folded or convoluted nuclei, condensed, mature-­appearing
chromatin, lack of prominent nucleoli, and abundant gray-­blue cyto-
plasm, often with a few vacuoles and/or azurophilic granules. Reactive
monocytes can exhibit a range of morphologic appearances including
variable cell size (12-­20 μm), increased nuclear to cytoplasmic ratio,
more open or immature-­appearing chromatin and small nucleoli, and
more prominent cytoplasmic vacuolization, basophilia, and/or gran-
ularity. A particularly critical morphologic distinction to make is the
accurate identification of monocyte precursors for the purpose of rec-
ognizing and classifying hematologic malignancies with myeloid and/
or monocytic differentiation.
Monoblasts and promonocytes are the monocyte precursors that
are considered blasts/blast equivalents. Monoblasts typically have
round or oval nuclei with finely dispersed, immature chromatin, prom-
inent nucleoli, and moderate amounts of basophilic cytoplasm, with
absent to rare azurophilic granules. Promonocytes, although similarly
having immature chromatin and visible nucleoli, are differentiated from

Int J Lab Hem. 2018;40:107–114. © 2018 John Wiley & Sons Ltd |  107
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108       LYNCH et al.
monoblasts by having a slightly convoluted or gently folded nucleus.
Importantly, monocytes with immature-­appearing chromatin but with
prominent nuclear folds or convolutions should not be counted as
blast equivalents (Figure 1). These cells may be referred to as “atyp-
ical,” “abnormal,” “immature,” or “dysplastic”. In clinical practice, it can
be quite difficult to apply morphologic criteria when distinguishing re-
active or dysplastic monocytes from promonocytes or monoblasts. As
4
such, interobserver variability can be quite high.
When the morphologic determination of lineage of immature-­
appearing cells is in question (eg, monocytic vs myeloid), cyto-
chemical stains can be quite useful. Monocytic cells at all stages of
maturation characteristically show strong and diffuse cytoplasmic
positivity for the nonspecific esterases (NSE), alpha-­naphthyl ace-
tate, and alpha-­naphthyl butyrate, while granulocytic lineage cells
are negative or very weakly positive for these stains. The addition of
fluoride will selectively inhibit positivity in monocytes, allowing for
increased diagnostic specificity. Conversely, monocytic cells typi-
cally show more finely granular and weak myeloperoxidase (MPO)
positivity compared to heavier, coarse staining seen in granulo-
cytic cells. In the most immature monocytic cells, MPO is usually
negative.
F I G U R E   1   Top left: normal monocyte
with convoluted nucleus and abundant
cytoplasm. Midleft: promonocyte (center of
image) with slightly indented nucleus, fine
chromatin, and visible nucleolus. Bottom
left: monoblasts (center of image) in a case
of AMML with more immature appearance
than the promonocyte. Top right: dysplastic
neutrophil in a case of CMML with
hypolobated and hyperchromatic nucleus
and hypogranular cytoplasm. Mid right:
abnormal monocytes that have convoluted
nuclei with immature-­appearing chromatin
and small nucleoli. Bottom right: myeloblast
in a patient with AML
Flow cytometric analysis can provide more sensitive and exten-
sive phenotyping of monocytic cells. By this technique, most normal
monocytes express moderate intensity CD45 with strong CD33,
CD13, CD36, CD4, CD14, CD64, CD11b, CD11c, dim CD15, and
HLA-­DR. In addition, 3 recently described subtypes of monocytes
can be discerned based on expression patterns of CD14 and CD16.
Using these 2 markers, “classical” CD14++ CD16− monocytes usually
account for approximately 90% of monocytes in healthy adults, with
only minor subsets of “intermediate” CD14+ CD16+ and “nonclassical”
CD14− CD16+ monocytes accounting for the remainder. The specific
functions and differentiation potential of these subsets, however, re-
main unclear and areas of active investigation.5 Despite the wealth of
immunophenotypic data provided by flow cytometry, it must be kept
in mind that an abnormal immunophenotype by itself is not specific
to malignancy or sufficient to diagnose a neoplasm. This is particu-
larly true in the case of CD56, one of the more commonly expressed
aberrant antigens in both reactive and neoplastic conditions. That
being said, the likelihood that one is dealing with a neoplastic process
increases with the number of aberrant antigens detected.6 It is also
worth emphasizing that markers of immaturity detected by flow cy-
tometry and/or immunohistochemistry, such as CD34 and/or CD117,
LYNCH et al.
are not reliably expressed on monoblasts or promonocytes.7,8 Thus,
the recognition and enumeration of these blasts/blast equivalents are
still best made by morphologic assessment of well-­prepared smears
with flow cytometry as an adjunct.
3 | REACTIVE MONOCYTOSIS
Monocytosis in and of itself is very nonspecific, and in most cases,
it is found to be secondary (or reactive) in nature (Table 1). A vari-
ety of non-­neoplastic causes for monocytosis have been described
including chronic infections, acute stress or trauma, systemic inflam-
matory disorders, autoimmune diseases, drug reactions, postsplenec-
tomy, neutropenia, and early bone marrow recovery/regeneration.
Underlying neoplastic disorders including hematologic as well as
nonhematologic malignancies may also elicit a peripheral monocy-
tosis and in some cases paraneoplastic autoimmune phenomena (eg,
immune-­mediated thrombocytopenia or anemia). Thus, when a com-
plete blood cell count (CBC) reveals monocytosis and the cause is not
known, a careful and thorough workup with close clinical follow-­up
is generally required.
4 | NEOPLASTIC MONOCYTOSIS
When a sustained monocytosis is detected and secondary causes
have been thoroughly excluded, then a primary hematologic malig-
nancy must be considered, especially in the elderly or in patients who
also have unexplained cytopenia(s). Among the entities included in
the 2017 WHO classification, the top differential diagnostic consid-
eration is likely to be a myelodysplastic/myeloproliferative neoplasm
(MDS/MPN), specifically chronic myelomonocytic leukemia (CMML).
However, before a diagnosis of CMML can be made, specific criteria
T A B L E   1   Example causes of peripheral monocytosis
Neutropenia and bone marrow recovery21
Chronic infections (eg, viral, tuberculosis, malaria, subacute bacterial
endocarditis, and congenital syphilis)21-24
Immune/inflammatory disorders (eg, collagen vascular diseases,
inflammatory bowel disease, sarcoidosis, and immune
thrombocytopenia)21,25,26
Myocardial infarction27
Sickle cell disease and other hemolytic anemias28,29
Chronic stress30
Postsplenectomy31
Iatrogenic causes (eg, cytokine therapy, steroids, ziprasidone, and
radiation therapy)21,32-35
Cutaneous myeloid dendritic cell dyscrasia36
Myeloid malignancies (eg, MPN, MDS, MDS/MPN, and AML)21,37
Lymphoid and plasma cell malignancies (eg, B cell and T cell
types)21,38-40
Solid tumors (eg, carcinoma)41
|
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must be met including the exclusion of other less common but clinico-
pathologically distinct neoplasms with monocytosis mimicking CMML.
It is also worth stating that the presence of sustained absolute mono-
cytosis ≥1 × 109/L at the outset excludes a diagnosis of myelodysplas-
tic syndrome (MDS).2,9
The following section includes a brief discussion of the main
neoplastic entities in the differential diagnosis and highlights key pa-
rameters important for narrowing the differential. A comprehensive
discussion of each diagnosis is beyond the scope of this review. That
said, greater focus is given to CMML, as it is the most common neo-
plastic diagnosis made once other rare and/or genetically defined en-
tities have been excluded.
4.1 | Myelodysplastic/Myeloproliferative neoplasms
Chronic myelomonocytic leukemia is the most likely of the MDS/
MPNs to present with an absolute monocytosis ≥1 × 109/L and rela-
tive monocytosis ≥10%. This is important to keep in mind as BCR-
ABL1-­negative atypical chronic myeloid leukemia may meet the
first criterion of absolute monocytosis, while the presence of ≥10%
monocytes will exclude this diagnosis. Parameters fulfilling criteria
for MDS/MPN with ring sideroblasts and thrombocytosis (MDS/
MPN-­RS-­T) such as ring sideroblasts ≥15%, sustained thrombocyto-
sis ≥450 × 109/L, and SF3B1 and/or other MPN-­related mutations
including JAK2 mutations would be unlikely in CMML. However, as is
typical for most MDS/MPNs, CMML will exhibit a combination of my-
eloproliferative features, such as leukocytosis including neutrophilia,
marrow hypercellularity with or without reticulin fibrosis, intramedul-
lary or extramedullary plasmacytoid dendritic cell nodules, and sple-
nomegaly, plus features of myelodysplasia, including cytopenia(s)
and morphologic dysplasia in at least one hematopoietic lineage (ie,
granulocytic, erythroid, or megakaryocytic dysplasia). Exclusion of
other myeloid neoplasms with monocytosis or myelomonocytic differ-
entiation is also mandatory. The possibility of systemic mastocytosis
with an associated hematologic neoplasm (SM-­AHN) should also be
excluded, particularly as CMML is one of the more common associ-
ated neoplasms seen in this category.10
The workup of these cases generally requires chromosome analysis
with fluorescent in situ hybridization (FISH) and/or PCR-­based molecu-
lar genetic testing to exclude a BCR-ABL1 fusion gene (including occult
or complex translocations). When eosinophilia is present, exclusion of
cytogenetically occult rearrangements of PDGFRA, rearrangement of
PDGFRB, FGFR1, or PCM1-JAK2 gene fusion, and acute myeloid leu-
kemia (AML)-­defining rearrangements including inv(16)(p13.1q22)
or t(16;16)(p13.1;q22)/CBFB-MYH11 must also performed. Careful
morphologic assessment with consideration given to other laboratory
parameters including thrombocytosis or increased hemoglobin levels
should prompt exclusion of BCR-ABL1-­negative MPNs that happen
to have monocytosis at diagnosis, including polycythemia vera (PV),
essential thrombocythemia, and primary myelofibrosis. In these types
of cases, dysplasia would not be expected. Likewise, the presence of
a MPN-­related somatic mutation (eg, JAK2, CALR, or MPL) would also
favor a MPN with monocytosis over CMML. Along these same lines, in
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110       LYNCH et al.
rare cases with a previous documented history of MPN and new onset
monocytosis, a diagnosis of CMML should not be made.2
Despite the ongoing discovery of somatic mutations in myeloid
malignancies and greater availability of molecular genetic testing, the
utility of mutations in the diagnosis CMML is still limited. This is es-
pecially true in situations where CMML is considered but diagnostic
features such as overt dysplasia are lacking. While the overwhelm-
ing majority of CMML cases have detectable mutations, most often
SRSF2, TET2, and/or ASXL1, several of these mutations can also be
found in a minority of elderly individuals without morphologic evi-
dence of neoplasia (ie, clonal hematopoiesis of indeterminate poten-
tial, CHIP). In extremely rare situations, individuals with no apparent
disease may actually harbor a germ line mutation that is associated
with monocytosis, including circulating monocyte precursors (eg, rare
individuals with germ line DDX41 mutations); however, such individu-
als should be followed closely due to an increased risk for developing
a myeloid malignancy, to include CMML (ie, myeloid neoplasms with
germ line predisposition).11 In any case, caution should be exercised
before citing a somatic mutation as the sole evidence for establishing
a diagnosis of malignancy. On the other hand, finding certain somatic
mutations in the context of an established diagnosis of CMML can
be of prognostic value; for example, ASXL1 and less commonly NPM1
mutations in CMML have been shown to predict a more aggressive
12
clinical behavior. In contrast to mutations, the discovery of a cytoge-
netic abnormality in the setting of sustained monocytosis is far more
specific for CMML. However, only a minority of CMML cases (30%)
harbor a cytogenetic abnormality at diagnosis, thus limiting its utility
13,14
for this purpose.
As mentioned before, flow cytometric analysis of the blood, bone
marrow, or other involved tissues can play an ancillary role in the
workup of monocytosis. This technique may show aberrant antigen
expression on monocytes, for example underexpression of CD11c
or other myeloid antigens and aberrant positive expression of mark-
ers such as CD56 and other T/NK-­cell-­related antigens.15 Moreover,
finding a uniform population of “classical” CD14++ CD16− monocytes
(comprising >94% of total monocytes) has recently been shown to
support a diagnosis of CMML over reactive monocytosis, even when
the time course has been relatively short (ie, <3 months).16,17 Again,
immature monocytes (ie, promonocytes and monoblasts) are not easily
distinguished by flow cytometry, and thus, morphologic assessment
remains the more reliable method in this regard.
4.2 | Acute myeloid leukemia with monocytic
differentiation
By definition, if the percentage of blasts and/or promonocytes is 20%
or more in the peripheral blood or bone marrow, then the diagnosis is
AML. As previously noted, the distinction between promonocytes and
abnormal or dysplastic monocytes or even dysplastic granulocytes can
be quite challenging. Difficult cases should be reviewed by more than
one hematopathologist, if possible. Bone marrow examination is es-
sential in monocytic neoplasms as the bone marrow often has a higher
percentage of immature cells than the peripheral blood.
Many AML cases with monocytic differentiation will fall under
the general category of AML, not otherwise specified. This includes
acute myelomonocytic leukemia, acute monocytic leukemia, and
acute monoblastic leukemia. Distinction among these entities is
primarily morphological and based on the percentage and specific
types of monocytic precursors present. This distinction for cases
of AML, NOS, however, though retained in the 2017 WHO, is not
critical for treatment or prognosis. Far more important is recogniz-
ing or excluding recurrent genetic abnormalities that are common
in AML cases with monocytic differentiation. AML with trans-
locations involving the KMT2A gene (formerly known as MLL) on
11q23, inv(16)(p13.1q22), t(16;16)(p13.1;q22)/CBFB-MYH11, t(6;9)
(p23;q34.1)/DEK-NUP214, and AML with recurrent somatic mu-
tations involving NPM1 or biallelic mutations of CEBPA frequently
fall into this category. It is crucial to keep in mind that AML with
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11 is by defi-
nition acute leukemia regardless of the blast count. It is also worth
mentioning that AML with PML-RARA, particularly the hypogranular
variant, though not characterized by monocytic differentiation, can
closely resemble a myelomonocytic or monoblastic neoplasm on
morphologic review. In these cases, appropriate FISH or molecular
genetic testing is required to further exclude an occult PML-RARA
fusion.
4.3 | Myeloproliferative neoplasms
Rare examples of BCR-ABL1-­positive CML can present with mono-
cytosis, particularly those with a p190 BCR-ABL1 fusion protein. A
more common phenomenon is BCR-ABL1-­negative myeloproliferative
neoplasms (MPNs) presenting with or developing monocytosis during
the disease course. One recent study reports monocytosis in 21% of
PV patients.18 The identification of mutations in JAK2, CALR, or MPL
is supportive of a myeloproliferative neoplasm and is not expected in
CMML.
4.4 | Myeloid/lymphoid neoplasms with PDGFRA,
PDGFRB, or FGFR1 rearrangement or PCM1-
JAK2 fusion
Rare but important causes of monocytosis are neoplasms with
PDGFRA, PDGFRB, or FGFR1 rearrangement. Of these 3, the most
likely mimicker of CMML is myeloid neoplasms with rearrange-
ment with PDGFRB at 12p12.19 Eosinophilia in addition to features
of CMML should prompt exclusion of this group of neoplasms
as they may be amenable to treatment with tyrosine kinase in-
hibitors. Unlike PDGFRB and FGFR1, PDGFRA rearrangements
are cryptic or occult and must be excluded by FISH or molecular
genetic techniques. Importantly, rare reports suggest that these
rearrangements may also occur in cases morphologically consist-
ent with CMML in the absence of eosinophilia. 20 Recently, the
PCM1-­JAK2 fusion has been linked to rare lymphoid and myeloid
neoplasms, often with eosinophilia, and rarely, this too may also
mimic CMML.
LYNCH et al. |
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5 | APPROACH TO MONOCYTOSIS years) can influence the differential diagnosis and need for further
workup. A persistent, unexplained monocytosis, especially in the
5.1 | Initial steps to investigate monocytosis elderly, should raise suspicion for neoplasia.
• Evaluate size of spleen, liver, and lymph nodes for enlargement.
When monocytosis is recognized, steps should be taken to determine
Organomegaly may suggest neoplastic infiltration (eg, by myeloid,
the clinical significance and need for more extensive clinicopathologic
lymphoid, or nonhematologic malignancy) or extramedullary hema-
workup.
topoiesis (eg, in the setting of myelofibrosis).
• Integrate clinical data. (eg, clinical history, review of systems, ther-
• Confirm the presence of monocytosis by blood smear review.
apy history including chemotherapy, radiation therapy, and surgery,
Abnormal lymphocytes (eg, hairy cells or Sezary cells) can be mis-
physical examination findings, and radiologic studies.) These data
identified as “monocytes” by automated hematology analyzers.
may be crucial for recognizing potential cause(s) of monocytosis, in-
Certain leukemias (eg, hypogranular variant of AML with PML-RARA)
forming further workup or recommendations (eg, suggesting biopsy
can also mimic monocytic cells.
of enlarged nodes or prior splenectomy as a potential etiology), and
• Assess the absolute monocyte count. A relative monocytosis alone
disease classification or prognostication (eg, signifying a therapy-re-
is more likely secondary or reactive (eg, in the setting of neutropenia
lated myeloid neoplasm). In addition, signs and symptoms of infec-
or early bone marrow recovery/regeneration), and certain neoplasms
tion, systemic inflammatory disease, autoimmunity, or underlying
require an AMC ≥1 × 109/L (eg, CMML or JMML in young children).
malignancy may also be noted.
• Assess for other CBC abnormalities. Cytopenias (eg, neutropenia,
• Integrate prior pathology material and other laboratory data, if
anemia, or thrombocytopenia) or other cytoses (eg, neutrophilia,
available. Is there a prior diagnosis of a hematologic or nonhema-
eosinophilia, basophilia, and lymphocytosis) may suggest an etiol-
tologic malignancy? For example, a previous diagnosis of a MPN
ogy or need for specific testing. Neutropenia or atypical lymphocy-
excludes CMML, or the possibility of metastatic disease or therapy
tosis without dysplasia may suggest viral infection. Eosinophilia may
effects may be considered more likely. Other laboratory data may
prompt the need to exclude PDFGRA/B or FGFR1 rearrangement,
also point to a cause for monocytosis or influence further workup
PCM1-JAK2 fusion, mastocytosis, infection, parasite infestation, au-
decisions.
toimmune disease, etc.
• Examine a peripheral blood smear with particular attention given to:

(i) Monocyte morphology (eg, maturity and atypia). The presence
of promonocytes or monoblasts should raise concern for a my-
elomonocytic neoplasm.
ii) Neutrophil morphology (eg, maturation, toxic changes, and dys-
plastic features including abnormal nuclear segmentation and/
or hypogranularity). The presence of significant granulocytic
dysplasia and/or blasts should raise suspicion for a myelomono-
cytic neoplasm.
iii) Red cell morphology (eg, anisopoikilocytosis including dacro-
cytes, spherocytes, schistocytes, and sickle cells, Howell-Jolly
bodies, Pappenheimer bodies, coarse basophilic stippling, and
normoblastemia). These changes are less specific for neo-
plasia and may suggest other etiologies such as hemoglobin
disorders, red cell membrane defects, hemolytic disorders, or
splenectomy.
iv) Platelet morphology (eg, number, size, and granularity).
Thrombocytosis or thrombocytopenia may indicate a reactive
process such as inflammation or immune thrombocytopenia;
dysplastic changes including large size and/or hypogranularity
may suggest neoplasia.
v) Other features may also suggest an underlying cause (eg, the
presence of microorganisms such as Plasmodium spp., atypical
lymphocytosis associated with viral infections, or erythrophago-
cytosis due to immune-mediated hemolytic anemia).
• Determine the duration of monocytosis and other blood cell abnor-
malities, if present. The duration (hours, days, weeks, months, and
5.2 | Next steps to take
If monocytosis is sustained, unexplained, and/or features concerning
for a hematologic neoplasm are present (Table 2), then further clin-
icopathologic workup should be considered including bone marrow
examination with cytogenetic analysis and other testing as necessary:
flow cytometry, immunohistochemistry, cytochemical stains, special
stains, and molecular genetic studies.
5.3 | Bone marrow examination
A bone marrow trephine biopsy and aspirate should be performed.
Potential causes for monocytosis that may be detected or excluded by
this route include acute and chronic hematologic malignancies, lym-
phoma, metastatic disease, infection, agranulocytosis, chemotherapy,
and/or other drug or toxic effects. Apparent CMML based on blood
findings may prove to be AML in the bone marrow (Figures 2 and 3).
Adequate material should be obtained for ancillary studies (eg, chromo-
some analysis, flow cytometry, and molecular testing) whenever possible.
5.4 | Flow cytometry
This can be performed on blood and/or bone marrow and may be
helpful for assessing blast populations, other populations including
lymphocytes, and recognizing monocytic differentiation when mor-
phology is equivocal.
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112       LYNCH et al.

T A B L E   2   Determining the need for

AMC ≥1 × 109/L + + +
further hematologic workup for
RMC ≥10% + ± ±
monocytosis
Granulocytic dysplasia + − −
Promonocytes ± − −
Blasts + ± −
Cytopenias + − −
b,e
Left-­shifted neutrophilia ± + /− ±
Basophilia − +b/− −
Eosinophilia +a/− +f/− ±
d,e
Thrombocytosis − + /− ±
Polycythemia − +c/− −
Splenomegaly + + −
History of recent − − ±
chemotherapy,
infection, inflammatory
disease, trauma, and
malignancy
Assessment Possible neoplasm Possible neoplasm Likely reactive
such as MDS/MPN such as MPN with
(CMML); AML w/ monocytosis (eg,
monocytic CMLb, PVc, ETd,
differentiation; PMFe); systemic
myeloid neoplasm mastocytosisf
with PDGFRBa
Recommendation Bone marrow examination with appropriate Close clinical
ancillary studies (eg, chromosome analysis, correlation and
FISH, molecular testing, flow cytometry) follow-­up [If
persistent and
unexplained, then
consider bone
marrow
examination]

MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; CMML, chronic myelomonocytic

leukemia; CML, chronic myeloid leukemia, BCR-ABL1 + ; PV, polycythemia vera; ET, essential thrombo-
cythemia; PMF, primary myelofibrosis; FISH, fluorescent in situ hybridization.
Highlighted areas are most concerning for underlying neoplasia.
The key for ‘a–f’ is in the assessment portion of the table.

F I G U R E   2   Peripheral smear on a 54-­y-­old woman with F I G U R E   3   Bone marrow aspirate on the same patient from
leukocytosis and anemia. There are atypical monocytes with Figure 2 showing a predominance of promonocytes and blasts,
dysplastic neutrophils and only rare blasts, suggestive of CMML diagnostic of AMML
LYNCH et al.
5.5 | Immunohistochemistry/cytochemistry
As with flow cytometry, additional phenotyping may be necessary in
tissue sections to visualize normal and abnormal populations including
but not limited to myeloid cells, monocytic cells, erythroids, megakar-
yocytes, mast cells, lymphocytes, and plasma cells. Enumerating and
assessing the distribution of blasts may also be facilitated. The utility
of cytochemical staining for NSE and MPO in delineating immature
monocytic and granulocytic cells has been discussed earlier.
5.6 | Cytogenetic studies
Chromosome analysis should be performed on every case when bone
marrow is obtained for the workup of monocytosis. FISH studies may
also be warranted, particularly when BCR-ABL1, PDFGRA, inv(16) or
t(16;16), and PML-RARA must be confirmed or excluded.
5.7 | Molecular genetic testing
In select cases, testing for somatic mutations may be helpful for diag-
nosis and/or prognostication. MPN-­related mutations such as JAK2,
CALR, and MPL may favor an MPN with monocytosis in the appropri-
ate context. Certain mutations may be of prognostic value (eg, ASXL1
or NPM1 in CMML). The potential for recognizing mutations in the ab-
sence of disease (eg, clonal hematopoiesis of indeterminate potential)
should be kept in mind.
6 | KEY PROBLEM AREAS
• Distinguishing promonocytes from abnormal or dysplastic mono-
cytes and/or granulocytes.
• Distinguishing CMML from AML with less than 20% circulating
blasts/promonocytes based on peripheral blood smear morphology.
• Distinguishing hypogranular AML with PML-RARA from other AML
types with monocytic differentiation based on peripheral blood
smear morphology.
• Using somatic mutations to establish a diagnosis of CMML when
dysplasia and other key diagnostic features are absent.
• Identifying rare genetically defined neoplasms with monocyto-
sis mimicking CMML but with significantly different therapeutic
requirements.
7 | SUMMARY
Most cases of monocytosis will prove to be reactive in nature. Proper
evaluation is required to exclude the minority of cases which are neo-
plastic. This requires the initial assessment of clinical history, labora-
tory data, and morphology. Important clues to suggest a neoplastic
process include an unexplained and persistent monocytosis, the
|
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presence of blasts/blast equivalents, and neutrophil dysplasia. Finding
such clues should suggest the need for further workup to include
bone marrow examination and appropriate ancillary studies such as
flow cytometry, cytogenetics, and in some cases, molecular testing.
Ultimately, careful and thorough integration of all available data is
required for the most accurate diagnosis in this challenging area of
hematopathology.
O RC I D
D. T. Lynch  http://orcid.org/0000-0002-6720-9701
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How to cite this article: Lynch DT, Hall J, Foucar K. How I
investigate monocytosis. Int J Lab Hem. 2018;40:107–114.
https://doi.org/10.1111/ijlh.12776