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Hematopathology / Pseudo–Pelger-Huët Anomaly Induced by Medications
Pseudo–Pelger-Huët Anomaly Induced by Medications
A Clinicopathologic Study in Comparison With Myelodysplastic
Syndrome–Related Pseudo–Pelger-Huët Anomaly
Endi Wang, MD, PhD,1 Elizabeth Boswell, MD,1 Imran Siddiqi, MD, PhD,2 Chuanyi Mark Lu, MD,3
Siby Sebastian, PhD,1 Catherine Rehder, PhD,1 and Qin Huang, MD, PhD4
Key Words: Pseudo–Pelger-Huët anomaly; Medications; Iatrogenic; Myelodysplastic syndrome; Neutrophilic dysplasia
Upon completion of this activity you will be able to:
• define the characteristics of iatrogenic pseudo–Pelger-Huët anomaly
(PPHA).
• distinguish iatrogenic PPHA from myeloid neoplasm–associated PPHA
based on differences in associated clinicopathologic features.
• list the common medications that have been reported to induce PPHA.
Abstract
Pseudo–Pelger-Huët anomaly (PPHA) has
been documented in association with transplant
medications and other drugs. This iatrogenic
neutrophilic dysplasia is reversible with cessation or
adjustment of medications but is frequently confused
with myelodysplastic syndrome (MDS) based on
the conventional concept that PPHA is a marker
for dysplasia. We investigated the clinicopathologic
features in iatrogenic PPHA and compared them with
MDS-related PPHA. The 13 cases studied included 5
bone marrow/stem cell transplantations, 3 solid organ
transplantations, 1 autoimmune disease, 3 chronic
lymphocytic leukemias, and 1 breast carcinoma.
For 12 cases, there was follow-up evaluation, and
all demonstrated at least transient normalization
of neutrophilic segmentation. All 9 cases of MDS
demonstrated at least 2 of the following pathologic
abnormalities on bone marrow biopsy: hypercellularity
(8/9), morphologic dysplasia (8/9), clonal cytogenetic
abnormality (7/9), and increased blasts (3/9), whereas
these abnormalities were typically absent in iatrogenic
PPHA. Iatrogenic PPHA displayed a higher proportion
of circulating PPHA cells than in MDS (mean, 47.4%;
SD, 31.6% vs mean, 12.3%; SD, 9.8; P < .01). A
diagnostic algorithm is proposed in which isolated
PPHA is indicative of transient or benign PPHA unless
proven otherwise.
The ASCP is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.
The ASCP designates this educational activity for a maximum of 1 AMA PRA
Category 1 Credit ™ per article. This activity qualifies as an American Board
of Pathology Maintenance of Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 312. Exam is located at www.ascp.org/ajcpcme.
Pelger-Huët anomaly (PHA) was first described by Karl
Pelger in 19281 and was further defined as a benign trait with
autosomal dominant inheritance by G.J. Huët in 1931.2 This
hereditary anomaly is characterized by round, oval, peanutshaped, coffee bean–shaped, or symmetric bilobed nuclei with
abnormally clumped chromatin in granulocytes. Despite these
morphologic abnormalities, granulocyte function, including
neutrophilic chemotaxis, phagocytosis, and cytolytic activity,
remains normal, and people with hereditary PHA do not have
increased susceptibility to bacterial infections.3 In contrast,
pseudo–Pelger-Huët anomaly (PPHA) is an acquired alteration
of neutrophils closely resembling hereditary PHA in morphologic features. While its presence in some myeloid neoplasms,
such as myelodysplastic syndrome (MDS), is well-established
and has important diagnostic implications,4-6 PPHA can also be
induced by a variety of nonneoplastic etiologies as a transient or
reversible phenomenon.7-20 Among the multiple other causes,
increased use of transplant medications7-10 and other drugs11-17 has
become a major etiology for this morphologic deviation.
Because of the conventional concept that PPHA is a
morphologic marker for myelodysplasia,4-6 the presence of
iatrogenically induced PPHA in the peripheral blood and/or
bone marrow may cause diagnostic confusion, particularly in
patients with a history of treatment for malignant neoplasms
and subsequent chronic cytopenias. As the diagnostic implications of iatrogenic PPHA vs MDS-associated PPHA are
markedly divergent, accurate distinction of these processes is
important. We compared peripheral blood and bone marrow
findings in iatrogenic PPHA with MDS-associated PPHA to
characterize and define features that can aid in distinguishing
these entities.
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Materials and Methods
Case Selection
For the study, 13 cases of iatrogenic PPHA and 9 cases
of MDS with PPHA were identified from our bone marrow
biopsy databases using the search phrase “Pelger-Huët
anomaly.” These included 14 cases (7 iatrogenic PPHAs
and 7 MDS with PPHA) from Duke University Medical
Center, Durham, NC; 3 cases (iatrogenic PPHAs) from
University of California at San Francisco; 2 cases (MDSs
with PPHA) from San Francisco Veteran Affairs Medical
Center, San Francisco, CA: 2 cases (iatrogenic PPHAs)
from City of Hope National Medical Center, Duarte, CA;
and 1 case (iatrogenic PPHA) from USC Medical Center,
Los Angeles, CA. The diagnoses of iatrogenic PPHA
were confirmed by clinical history, laboratory tests, and/
or, ultimately, by resumption of normal segmentation in
neutrophils or a significant change in proportion of PPHA
cells occurring spontaneously or in correlation with dose
adjustment of relevant medications (see later text). The
diagnoses in 9 cases of MDS with PPHA were confirmed
according to the 2008 World Health Organization classification.21
Cytomorphologic and Histologic Evaluation
Peripheral blood smears were stained with Wright
stain, bone marrow aspirate smears and biopsy touch
imprints were stained with Wright-Giemsa, and bone
marrow core biopsies and clot sections were stained
with H&E. The cases were reviewed independently by 4
hematopathologists (E.W., I.S., C.M.L., and Q.H.). PPHA
neutrophils were identified by their unilobed or symmetric
bilobed nuclei, abnormally clumped chromatin, and relatively abundant cytoplasm with pink or yellowish granules.
We examined 200 neutrophils in peripheral blood smears,
and proportions of PPHA cells were calculated as percentage of total neutrophils. In addition, other morphologic
dysplasia, bone marrow cellularity, and blast counts were
also evaluated. The presence of other dysplastic changes
in erythroid, granulocytic, and megakaryocytic lineages
was determined according to the description in the 2008
World Health Organization Classification.21 Bone marrow
cellularity was defined as hypercellular when it was higher
than 1 SD above the age-adjusted mean, as hypocellular
when lower than 1 SD, and as normocellular when within
1 SD.22
Conventional Cytogenetic Studies
Cytogenetic analysis was performed on 2 to 4 mL
of bone marrow aspirate from each case. Two cultures
were initiated from each fresh, anticoagulated specimen in
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complete tissue culture medium. Cells were incubated for
24 and 48 hours without mitogen stimulation, except for
the 2 CLL samples, in which both B cell–stimulated and
B cell–unstimulated cultures were initiated and examined.
Chromosome preparations including harvesting and GTWbanding were made using standard methods. Cytogenetic
abnormalities were classified according to the International
System for Human Cytogenetic Nomenclature.
Bone Marrow Engraftment Analysis
Highly purified DNA was extracted from the pretransplantation, donor, and posttransplantation samples following routine laboratory methods. For positive selection
of lymphocytes or granulocytes from posttransplantation
samples, magnetically labeled antihuman CD3 or CD15
antibodies (isotype, mouse IgG1 and IgM κ, respectively)
and the RoboSep automated cell separator (StemCell
Technologies, Vancouver, Canada) were used. The extracted sample genomic DNA was subjected to multiplexed
polymerase chain reaction (PCR)-mediated amplification
reaction targeting a total of 15 autosomal short tandem
repeat (STRs) markers and 1 STR marker on the pseudoautosomal region of the X and Y chromosomes (PowerPlex
16 System, Promega, Madison, WI). Following PCR
amplification, the fluorescently labeled PCR products were
resolved by capillary electrophoresis on the ABI 3130xl
Genetic Analyzer and analyzed by GeneMapper software
(Applied Biosystems, Foster City, CA) to resolve the number of repeats and relative abundance of each repeat for
each STR locus. These data were then used to calculate the
percentage of donor and/or recipient cells in the posttransplantation sample using the donor and pretransplantation
recipient STR profiles.
Assessment of Resolution of PPHA Cells
To assess for resolution of PPHA neutrophils or normalization of neutrophilic segmentation, manual differentials of WBC on peripheral blood smears were evaluated
following the index bone marrow biopsy for each case.
Resolution of PPHA cells was defined by the absence of
PPHA cells on follow-up peripheral blood smears performed after the bone marrow biopsy. In cases in which
PPHA cells were absent in multiple peripheral blood
samples, the earlier time of resolution was recorded as the
“time of resolution.”
Statistical Analysis
The statistical analyses were performed with SAS version 9 (SAS Institute, Cary, NC). The Student t test and
Wilcoxon-Mann-Whitney test were used to test the statistical significance of differences in circulating PPHA cells
between the groups.
© American Society for Clinical Pathology
Hematopathology / Original Article
Results
Clinical Information
Of the 13 cases of iatrogenic PPHA, 5 were seen following allogeneic bone marrow or stem cell transplantation for acute myeloid leukemia (AML), including 2 de
novo AMLs and 3 AMLs arising from preexisting MDS.
Three cases occurred in the setting of chronic lymphocytic
leukemia (CLL), 2 in liver transplant recipients (history
of hepatocellular carcinoma and autoimmune hepatitis,
respectively), 1 in a heart transplant recipient (history
of cardiomyopathy), 1 in a case of autologous stem cell
transplantation with treatment for breast carcinoma, and
1 in autoimmune disease treated with mycophenolate
mofetil. Among these 13 cases, 9 were men and 4 were
women. Ages ranged from 20 to 75 years, with a median
of 57 years ❚Table 1❚. The 9 MDS cases with PPHA components included refractory anemia with excess blasts (3
cases), refractory anemia (2 cases), therapy-related MDS
(2 cases), refractory cytopenia with multilineage dysplasia
(1 case), and refractory anemia with ringed sideroblasts
(1 case). Among the MDS cases, 6 were men and 3 were
women. Ages ranged from 53 to 82 years with a median of
67 years ❚Table 2❚. Similar to the MDS cases, all patients
with iatrogenic PPHA had anemia, neutropenia, and/or
thrombocytopenia at the time of bone marrow biopsy, with
the exception of 1 case (case 13; Table 1). In the iatrogenic
PPHA cases, bone marrow biopsies were performed to rule
out relapsed acute myeloid leukemia or high-risk MDS
in 5 cases following bone marrow transplantation (cases
1-5), to rule out therapy-related myeloid neoplasms in 4
cases (cases 6-9), to assess disease status of CLL in 3 cases
(cases 10-12), and to rule out myelodysplastic/myeloproliferative neoplasm in 1 case (case 13).
Cytomorphologic and Histologic Evaluation
Circulating PPHA cells in the iatrogenic group typically displayed hypolobated nuclei with clumped chromatin ❚Image 1A❚, ❚Image 1B❚, ❚Image 1C❚, ❚Image 1D❚, ❚Image
1E❚, ❚Image 2A❚, ❚Image 2B❚, ❚Image 2C❚, and ❚Image 2D❚.
The majority of the cells had nuclear contours that were
round (Images 1A and 2A) or oval (Images 1B and 2B), but
coffee bean–shaped (Images 1C and 2C), peanut-shaped
(Images 1D and 2D), bilobed (Image 1E), and occasional
other forms were also noted. Some PPHA cells also contained detached round nuclear fragments in the cytoplasm,
so called Howell-Jolly–like inclusions (data not shown).
Eosinophils were unaffected, retaining their lobated morphologic features ❚Image 1F❚. The median proportion of
circulating PPHA cells was 33% of neutrophils (range,
11%-94%; mean, 47.4%; SD, 31.6%) in the iatrogenic
PPHA group, while in the MDS group, it was 9% (range,
2%-28%; mean, 12.3%; SD, 9.8%). The difference was
statistically significant between the 2 groups (P < .01). In
addition, PPHA cell nuclei in the iatrogenic group were
more uniformly unilobed and contained homogeneously
clumped chromatin; in comparison, those in the MDS
group contained irregularly hypolobated nuclei, although
their nuclear chromatin was clumped in a similar manner
in some cases ❚Image 3A❚ and ❚Image 3B❚. On bone marrow
examination, 11 of 13 iatrogenic cases displayed normal or
decreased bone marrow cellularity; the remaining 2 were
CLL cases that showed increased bone marrow cellularity due to infiltration by CLL-type leukemic cells ❚Image
2F❚. Although PPHA cells or their immediate precursors
were noted ❚Image 1G❚ and ❚Image 2E❚, no significant
morphologic dysplasia other than PPHA was appreciable,
and blasts were not increased in the iatrogenic group. In
contrast, among the 9 MDS cases, 8 (89%) showed mild
to marked dysplasia other than PPHA ❚Image 3C❚, ❚Image
3D❚, and ❚Image 3E❚, 3 (33%) had increased blasts (Image
3E), and 8 (89%) demonstrated significantly increased
bone marrow cellularity ❚Image 3F❚.
Cytogenetic Studies
Cytogenetic analyses were performed on bone marrow specimens from 10 iatrogenic PPHA cases. Of these,
9 showed a normal karyotype, while 1 CLL case demonstrated a complex cytogenetic abnormality in a mitogenstimulated culture, consistent with a B-cell clone from the
underlying CLL. All 9 cases of MDS had conventional
cytogenetic analysis performed, and 7 of 9 showed clonal
cytogenetic abnormalities ❚Image 4❚ (case 7; Table 2),
while the remaining 2 cases had a normal karyotype.
Bone Marrow Engraftment Analysis
Among the iatrogenic PPHA cases, 3 of 5 bone marrow or stem cell transplant recipients had concurrent
engraftment studies performed, with 2 showing donor cell
engraftment, confirming the donor origin of PPHA cells
❚Figure 1❚ (case 1; Table 1), and 1 demonstrating recipient
origin, the latter representing an engraftment failure. Donor
origin of bone marrow hematopoietic elements was also
seen in 2 of 4 bone marrow or stem cell transplant cases by
cytogenetic studies (as determined by discordance of sex
chromosome in cases 2 and 5; Table 1).
Clinical Follow-up and Resolution of PPHA in
Peripheral Blood
All but 1 case of iatrogenic PPHA had follow-up
evaluation of peripheral blood smears. All cases evaluated
showed evidence of normalized neutrophilic segmentation based on manual WBC differential or examination
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❚Table 1❚
Evaluation of PPH Anomaly Associated With Medications*
CBC
Case No./
Sex/Age (y) History
Transplant Medications
WBC Count Neutrophils Hemoglobin Platelets Blasts PPH Cells
(× 109/L)
(× 109/L)
(g/L)
(× 109/L) (%) (%)
1/M/67
AML/MDS
Allo BM
1.4
0.74
129
112
0
94
2/M/20
MDS
Allo BM
3.5
1.8
102
31
0
21
3/M/52
4/M/68
5/F/50
6/F/68
7/M/56
8/M/24
9/M/57
10/M/71
AML/MDS
AML
AML
AI
HCC
Cirrhosis
Cardiomyopathy
CLL
Allo BM
Allo BM
Allo BM
—
Liver
Liver
Heart
—
2.0
4.6
10.6
0.5
3.5
1.4
3.3
2.3
0.81
3.13
9.33
0.25
2.37
0.77
1.2
0.92
108
111
91
112
89
93
92
118
22
62
105
0.9
170
93
320
93
0
0
0
0
0
0
0
0
33
29
17
11
90
64
19
85
11/M/75
12/M/72
13/F/41
CLL
CLL
Metastatic
breast cancer
—
—
Auto BM
13.9
0.9
22.2
4.17
ND
20.2
104
131
119
87
119
257
0
0
0
57
79
17
MMF; tacrolimus; acyclovir;
posaconazole; others
MMF; tacrolimus; ganciclovir; cotrimoxazole; itraconazole; others
MMF; tacrolimus; G-CSF; others
MMF; tacrolimus; others
MMF; tacrolimus; others
MMF; prednisone; others
MMF; tacrolimus; others
MMF; tacrolimus; ganciclovir; others
MMF; tacrolimus; others
Co-trimoxazole; ciprofloxacin;
bendamustine; acyclovir; others
Fludarabine; rituximab; others
Fludarabine; rituximab; others
GCSF; letrozole; citalopram;
lorazepam; others
AI, autoimmune disease; allo BM, allogeneic BM/hematopoietic stem cell; AML, acute myeloid leukemia; Auto, autologous hematopoietic stem cell; BM, bone marrow;
CLL, chronic lymphocytic leukemia; GCSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HCC, hepatocellular
carcinoma; Hyper, hypercellular; Hypo, hypocellular; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; NA, not applicable; ND, not done; Norm, normocellular;
PPH, pseudo–Pelger-Huët (neutrophils).
* Values for WBCs, neutrophils, hemoglobin, and platelets are given in Système International units; conversions to conventional units are as follows: WBCs and neutrophils (/μL),
divide by 0.001; hemoglobin (g/dL), divide by 10.0; and platelets (× 103/μL), divide by 1.0.
† Morphologic dysplasia other than PPH anomaly.
‡ In case 8, PPH anomaly cells decreased transiently at 13 weeks, then recurred at high levels during an episode of renal failure.
§ In case 11, PPH anomaly cells persisted in the peripheral blood smear 1 week after the index BM biopsy, and the patient was then lost to follow-up.
of follow-up peripheral blood smears, including the case
with bone marrow engraftment failure (case 3; Table 1).
In 1 patient (case 8; Table 1), the decrease in PPHA cells
was transient, decreasing from 64% at the time of bone
marrow biopsy to 8% 13 weeks later, with subsequent
return of high numbers of PPHA cells. The return of PPHA
neutrophils in this patient was noted during an episode of
acute renal failure (slow increase in PPHA cells with rising
serum creatinine level). In the remaining iatrogenic PPHA
cases evaluated, neutrophilic segmentation completely
normalized ❚Image 1H❚. The time to resolution ranged from
3 to 29 weeks after the index bone marrow biopsy with a
median of 8.5 weeks.
Discussion
PPHA is an acquired alteration of neutrophils with
morphologic features resembling hereditary PHA. As in
the hereditary form, PPHA is characterized by neutrophils
with abnormally condensed chromatin and hypolobated
nuclei, which can be round, oval, peanut-shaped, coffee
bean–shaped, or symmetrically bilobed. PPHA can be seen
in 2 major categories of acquired granulocytic changes.
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First, it can occur in myeloid neoplasms such as MDS.
In these cases, PPHA is considered a component of the
malignancy,4-6 and the change persists or progresses without treatment of the underlying myeloid neoplasm. The
second category of PPHA occurs in association with various
infections18-20 or can be induced by certain medications.7-17
The changes in the latter category are reversible following
recovery from the underlying conditions or after adjustment or discontinuation of culpable medications. Because
of the conventional acceptance that PPHA is a marker for
myelodysplasia,4-6 the presence of iatrogenic PPHA in the
peripheral blood or bone marrow, particularly in patients
with anemia, neutropenia, and/or thrombocytopenia, often
causes confusion because it suggests MDS or a related
myeloid neoplasm. This diagnostic confusion becomes even
more critical in patients after bone marrow or hematopoietic stem cell transplantation for MDS or AML because
the presence of PPHA may suggest relapsed disease or a
therapy-related myeloid neoplasm.
In this case series, all patients with medication-related
(iatrogenic) PPHA underwent bone marrow biopsies owing
to anemia, neutropenia and/or thrombocytopenia, or pancytopenia. In all of these cases, except for the 3 CLL cases,
MDS or a related myeloid neoplasm was initially considered
© American Society for Clinical Pathology
Hematopathology / Original Article
BM
Blasts
CytoCellularity (%) Dysplasia† genetics
Resolution/ Time
Engraftment to Resolution (wk)
Hypo
<5
No
46,XY
Donor
Yes/29
Hypo
<5
No
46,XX
Donor
Yes/4
Hypo
Hypo
Norm
Norm
Norm
Norm
Hypo
Hyper
<5
<5
<5
<5
<5
<5
<5
<5
No
No
No
No
No
No
No
No
ND
46,XY
46,XY
ND
46,XY
46,XY
47,XX
ND
Recipient
ND
Donor
NA
NA
NA
NA
NA
Yes/6
Yes/10.5
Yes/10
Yes/3
Yes/22
Yes/13‡
Yes/9
Yes/9
Hyper
Norm
Norm
<5
<5
<5
No
No
No
Complex NA
46,XY
NA
46,XX
NA
A
C
ND§
Yes/4.5
Yes/8
in the differential diagnosis for the cytopenias. Furthermore,
a diagnosis of MDS or related myeloid neoplasm was made
or suggested in the diagnostic comment when PPHA was
identified in peripheral blood and bone marrow aspirate
smears. A typical diagnostic error is exemplified by case 7
in the series (Table 1). Briefly, this 56-year-old man developed chronic anemia 2 years after liver transplantation for
hepatocellular carcinoma. Routine peripheral blood smear
review revealed numerous PPHA cells, which were also
noted in the subsequent bone marrow biopsy. Considering
the concomitant peripheral monocytosis and clinical history, a diagnosis of “chronic myelomonocytic leukemia,
probably therapy-related” was suggested in the pathology
report, even though neither additional dysplastic changes
nor increased blasts were identified and conventional
cytogenetic analysis showed a normal male karyotype.
Fortunately, the treatment was held owing to other medical
issues. A follow-up peripheral blood smear demonstrated
B
❚Image 1❚ (Case 1, Table 1) Reversible pseudo–Pelger-Huët
anomaly (PPHA) in a hematopoietic stem cell transplant
recipient. Note the hypolobated neutrophils with abnormally
clumped chromatin and round (A), oval (B), and coffee
bean–like (C).
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D
E
F
G
H
❚Image 1❚ (cont) Peanut-like (D), and bilobed (E) nuclear
contours in peripheral blood; an eosinophil with normal
segmentation in peripheral blood (F); PPHA cell precursors
(G, right field); and a few normal-appearing erythroid
normoblasts (G, left field) on the bone marrow touch imprint
and eventually normalized neutrophilic segmentations in
peripheral blood (H) (A-F and H, Wright, ×1,000; G, WrightGiemsa, ×1,000).
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A
B
C
D
E
F
❚Image 2❚ (Case 10, Table 1) Reversible pseudo–Pelger-Huët anomaly (PPHA) in a patient with chronic lymphocytic leukemia (CLL).
Note the hypolobated neutrophils with abnormally clumped chromatin and unilobed nuclear contours in peripheral blood (A, B, C,
and D, round, oval, coffee bean–like, and peanut-like nuclear shapes, respectively); 1 unilobed neutrophil or PPHA cell precursor
near the center of the image in a background of CLL cells on marrow aspirate smear (E); and CLL cell infiltrate (lower field) in bone
marrow on bone marrow biopsy section (F) (A-D, Wright, ×1,000; E, Wright-Giemsa, ×1,000; F, H&E, ×200).
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A
B
C
D
E
F
Image 3 (Case 1, Table 2) Pseudo–Pelger-Huët anomaly (PPHA) and associated other pathologic abnormalities in a patient with
myelodysplastic syndrome (MDS). A and B, Note the hypolobated neutrophils with abnormally clumped chromatin and twisted
or irregular nuclear contours in peripheral blood (A and B, Wright, ×1,000). C, D, and E, Many PPHA cells in the marrow aspirate
smear (C-E), markedly dysplastic erythroid normoblasts (C-E, arrows), 1 dysplastic megakaryocyte (micromegakaryocyte) (D,
arrowhead), and increased blasts (E, arrowheads) in aspirate smear (C-E, Wright-Giemsa, ×1,000). F, Hypercellular bone marrow
with increased immature cells on bone marrow biopsy section (H&E, ×200).
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Hematopathology / Original Article
normalized neutrophilic segmentation a few months later,
and, thus, the diagnosis was corrected to “reversible PPHA,
probably related to transplant medications.” Clearly, recognition of the benign nature of iatrogenic PPHA in these
cases is crucial to avoid unnecessary diagnostic intervention
and medical treatment.
Clinicopathologic studies comparing the peripheral
blood and bone marrow findings in benign vs neoplastic
PPHA are lacking in the literature. We investigated the
features of 13 cases of iatrogenic PPHA and compared
them with 9 cases of MDS-related PPHA. In contrast with
MDS, we found that iatrogenic PPHA tends to have a higher
proportion of circulating PPHA neutrophils (median, 33%
vs 9%; mean, 47.4% vs 12.3%; P < .01), which show more
homogeneous unilobed nuclei. The proportion of PPHA
cells in the iatrogenic group is within the ranges previously reported in the literature,7,8,11 while that for the MDS
group seems to be higher than what has been described in
the literature,6,23 likely owing to a selection bias in this
subset of MDS. However, the quantitative differences in
PPHA cells between the iatrogenic and MDS groups is
not as obvious in the bone marrow aspirate smear as in
peripheral blood, which may be explained by intramedullary destruction (apoptosis) of neoplastic myeloid elements
in MDS.23-25 As the timing of peripheral blood and bone
marrow analyses can be quite variable in iatrogenic PPHA
cases, a subset of these cases might be evaluated at periods
beyond the peak of PPHA cell formation, eg, due to waning
drug effects, and, thus, the proportion of circulating PPHA
cells could be relatively low, as was seen in cases 2, 5, 6,
and 13 of the iatrogenic group (Table 1). In these cases, the
number of PPHA cells overlapped with those in the MDS
group. Therefore, the proportion of circulating PPHA cells
❚Image 4❚ (Case 7, Table 2) Clonal cytogenetic abnormality
detected by chromosomal karyotyping. Representative
karyotype showing an apparently balanced translocation
between the X chromosome and chromosome 5. The
International System for Human Cytogenetic Nomenclature
describing this clonal abnormality is as follows: 46,X,t(X;5)
(q13;q32)[10]/46,XX[11]. In this case, mild dysplasia and
hypercellularity were noted by morphologic examination of
the bone marrow biopsy specimen, and the presence of a
clonal cytogenetic abnormality confirmed the diagnosis of
myelodysplastic syndrome.
should be used with caution when distinguishing between
iatrogenic PPHA and MDS.
Of interest, the MDS cases in this study displayed highgrade features with increased blasts (3/9) or a high frequency
of clonal cytogenetic abnormalities (7/9). In particular, all 6
❚Table 2❚
Evaluation of MDS With Component of PPH Anomaly*
CBC
Marrow
Case No./
Sex/Age (y) History
WBCs Neutrophils Hemoglobin Platelets Blasts PPH
Blasts
(× 109/L) (× 109/L)
(g/L)
(× 109/L) (%) Cells (%) Cellularity (%) Dysplasia†
Cytogenetics Classification
1/M/75
2/F/61
3/M/53
4/M/67
5/M/63
6/F/61
7/F/80
8/M/82
Cytopenia
Anemia
Anemia
FL
Cytopenia
Anemia
Anemia
Anemia
2.5
6.0
3.5
5.6
4.8
6.0
8.3
8.5
0.52
NA
2.24
2.62
2.1
ND
ND
5.36
100
69
116
126
106
99
78
90
59
143
229
88
71
210
145
291
—
—
—
—
—
1
—
—
24
3
4
9
18
5
2
18
Hyper
Hyper
Norm
Hyper
Hyper
Hyper
Hyper
Hyper
7
8
<5
<5
<5
12
<5
<5
46,XY
Complex
del(5q),+21
Complex
del(3p)
46,XX
t(X;5)
del(11q)
RAEB
RAEB
RCMD
T-MDS
RA
RAEB
RA
RARS
9/M/81
CA
4.7
2.63
85
137
1
28
Hyper
<5
Complex
T-MDS
Marked
Marked
Moderate
Moderate
No
Mild
Mild
Mild/
moderate
Marked
CA, prostatic carcinoma; FL, follicular lymphoma; Hyper, hypercellular; MDS, myelodysplastic syndrome; Norm, normocellular; PPH, pseudo–Pelger-Huët; RA, refractory
anemia; RAEB, RA with excess blasts; RARS, RA with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; T-MDS, therapy-related MDS.
* Values for WBCs, neutrophils, hemoglobin, and platelets are given in Système International units; conversions to conventional units are as follows: WBCs and neutrophils
(/μL), divide by 0.001; hemoglobin (g/dL), divide by 10.0; and platelets (× 103/μL), divide by 1.0.
† Morphologic dysplasia other than PPH anomaly.
© American Society for Clinical Pathology
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A
AM… vWA
100
1,000
800
600
400
200
0
X
D8S1179
140
14
180
TPOX
220
18
FGA
260
14
300
8
340
12
20
22
Y
B
AM… vWA
100
1,000
800
600
400
200
0
X
D8S1179
140
180
18
TPOX
220
260
14
Y
FGA
300
340
8
16
22
25
10
C
AM… vWA
100
1,000
800
600
400
200
0
X
D8S1179
140
180
TPOX
220
18
260
14
Y
8
16
FGA
300
340
22
10
25
❚Figure 1❚ (Case 1, Table 1) Bone marrow engraftment study
demonstrating donor cell engraftment in a hematopoietic
stem cell recipient when 94% pseudo–Pelger-Huët anomaly
cells were identified in the peripheral blood. Short tandem
repeat (STR) genotype profile of pretransplantation/recipient
(A), donor (B), and posttransplantation CD15+ cells (C).
The letters and numbers in the boxes above each block
indicate the names of STR markers, and the numbers below
indicate the numbers of repeats for each STR marker. Note
a complete match of 4 STR loci between donor’s (B) and
posttransplant recipient’s CD15+ cells (C). AM indicates the
amelogenin gene, which is used here for sex determination
and DNA quality control. The X chromosome gene, AMELX,
gives rise to a 106 base pair amplicon (indicated by “X” in the
box) and the Y chromosome gene, AMELY, a 112 base pair
amplicon (indicated by “Y” in the box).
cases with morphologically low- to intermediate-risk MDS
(cases 3, 4, 5, 7, 8, and 9; Table 2) had clonal cytogenetic
abnormalities detected. Of 7 cases with clonal cytogenetic
abnormalities, 3 were in a poor prognostic category and 4
were in an intermediate category according to the International
Prognostic Scoring System for MDS.21 All but 1 case showed
300
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morphologic dysplasia other than PPHA. All cases demonstrated at least 2 additional bone marrow abnormalities that
were diagnostic or suggestive of MDS (Table 2), whereas
none of these additional pathologic features were present
in the iatrogenic PPHAs except for 2 CLL cases (hypercellularity in case 10 and hypercellularity/complex cytogenetic
abnormality in case 11; Table 1) in which the abnormalities
were apparently related to the underlying CLL. Thus, our
analysis shows a tendency for clustered pathologic abnormalities in MDS-related PPHA, which can aid in the distinction
from iatrogenic PPHA. Nevertheless, our selective subset of
MDS cases shows pathologic abnormalities more frequent
than those in MDS in general.26,27 This selection bias may be
explained by the fact that PPHA represents a severe degree
of dysplasia in cases of MDS, and, thus, its presence tends to
be associated with other pathologic abnormalities related to
MDS. Based on this comparative study, we propose a diagnostic algorithm for workup of cases in which PPHA cells
are identified in peripheral blood or bone marrow aspirate
smears ❚Figure 2❚. In this algorithm, acquired or pseudo-PHA
(PPHA) is suggested if the patient had normal neutrophilic
segmentation in the past. PPHA with normal peripheral blood
cell counts would suggest a reversible (benign) change, particularly in organ and bone marrow transplant recipients, or in
patients currently taking medications known to induce PPHA
and with a high proportion of PPHA cells. Otherwise, MDS or
a related myeloid neoplasm should be considered and should
be excluded by additional tests. In cases of bone marrow or
hematopoietic stem cell transplantation, donor engraftment
would suggest a donor origin of PPHA, which is likely to
be reversible or benign but still needs to be confirmed by
the absence of other pathologic abnormalities diagnostic or
suggestive of a myeloid neoplasm. The optimal evidence of
the benign nature of iatrogenic PPHA would be spontaneous
resolution of PPHA cells, normalization of neutrophilic segmentation, or altered proportions of PPHA cells in correlation
with dose adjustment of relevant medications.
An isolated PPHA (without other pathologic abnormalities related to MDS or other myeloid neoplasms), particularly
with high proportions of PPHA cells (typically >30%) escalating within a short time, is indicative of benign or reversible
PPHA unless proven otherwise.
A fairly extensive number of drugs has been associated
with the occurrence of PPHA ❚Table 3❚. Of note, along with
the rise in organ and hematopoietic stem cell transplantation
in the past decade, cases of iatrogenic PPHA have become
more frequent in hematology clinics and/or clinical laboratories, with some resulting in bone marrow biopsies to exclude
MDS or related myeloid neoplasms. PPHA in transplant
recipients has been related to 2 immunosuppressive drugs,
mycophenolate mofetil7-9 and tacrolimus.7,10 Indeed, of the
13 iatrogenic PPHA cases in our series, 9 (69%) were treated
© American Society for Clinical Pathology
Hematopathology / Original Article
with mycophenolate mofetil, and 8 of these patients received
tacrolimus as well.
Concomitant use of the antiviral drug gancyclovir9 or
antifungal drug fluconazole10 has also been suggested to have
a role in development of PPHA in transplant recipients, probably via drug-drug interactions or altered enzymatic activities
involving the metabolic pathway of transplant medications.
In all reported cases, the morphologic changes in neutrophils
appear reversible because PPHA cells are decreased following dose adjustment of transplant medications or disappear
after discontinuation of the relevant drugs.7-10 Generally, in
transplant recipients, a resolution of neutrophilic abnormality occurs 2 to 6 weeks after adjustment or cessation of the
relevant medications.7,10
In our series, 2 of 9 patients treated with transplant
medications (cases 1 and 7 among cases 1-9, including case
6 of autoimmune disease treated with mycophenolate mofetil)
resumed normal neutrophilic segmentation following dose
adjustment of immunosuppressive drugs. The remaining 7
cases showed spontaneous resolution of PPHA cells without
change of relevant medications, which may be explained by
a drug desensitization or tolerance. This desensitization might
not be permanent, as illustrated in case 8, in which following
a transient and spontaneous decrease in PPHA cells, a recurrence of these cells to high numbers was noted during an episode of renal failure, perhaps related to increased serum drug
levels due to lack of renal excretion. Why the 2 cases with
changes of PPHA related to dose adjustment of medications
had longer intervals for the resolution is unclear, but it may
be due to failure to desensitize and the persistence of PPHA
until adjustment of medications for other medical issues. Of 3
CLL cases, 1 patient (case 10) was receiving co-trimoxazole
PHA
No
Prior normal
segmentation?
Work up for
hereditary PHA
Yes
Acquired/
PPHA
Cytopenia?
No
Yes
No
Transplant/other
relevant medications?
Possible MDS
Yes
No
Yes
BMT?
Cytogenetics?
No
Yes
No
Engraftment?
Yes
Possible
reversible
PPHA
Increased
blasts?
Needs
confirming
Yes
No
Other
dysplasia?
Yes
No
Confirmed
Spontaneous
decrease
in PHA
No
❚Figure 2❚ Diagnostic algorithm for pseudo–Pelger-Huët
anomaly (PPHA) identified in a peripheral blood smear or/
and bone marrow aspirate smear. BMT, bone marrow
transplantation; MDS, myelodysplastic syndrome; PPHA,
Pelger-Huët anomaly.
❚Table 3❚
Medications Associated With Pseudo–Pelger-Huët Anomaly as Reported in the Literature
Drug
Trade or Other Name
Pharmacologic Action
Indication
Effect Reference
Mycophenolate
mofetil
Tacrolimus
CellCept
Immunosuppression
Organ transplantation
D
Prograf; FK-506
Immunosuppression
Organ transplantation
D/I
Valproate
Depakote, Depacon
or Stavzor
Gantrisin; sulfafurazole
Cytovene; Cymevene
Diflucan; Trican
Advil; Motrin; Nurofen
Taxol
Taxotere
Neupogen
Sargramostim; Leukine;
Leucomax
Colcrys
Cuprimine; Depen
Inhibition of GABA
transaminase
Antibiotic
Antiviral DNA polymerase
Antifungal cytochrome P450
Inhibition of cyclooxygenase
Antimitosis
Antimitosis
Growth factor
Growth factor
Bipolar disorders,
seizures
Bacterial infection
Viral infection
Fungal infection
Rheumatoid conditions; pain
Cancer
Cancer
Neutropenia
Leukopenia
D
Etzell and Wang,7 Asmis
et al,8 Kennedy et al9
Etzell and Wang,7
Gondo et al10
May and Sunder15
D
I
I
D
D
D
D
D
Kaplan and Barrett14
Kennedy et al9
Gondo et al10
Moreira et al13
Juneja et al11
Juneja et al11
Teshima et al12
Teshima et al12
Antimitosis
Immunosuppression
Gout
Rheumatoid conditions
D
D
Clevenger et al17
Levin16
Sulfisoxazole
Ganciclovir
Fluconazole
Ibuprofen
Paclitaxel
Docetaxel
G-CSF (filgrastim)
GM-CSF
(molgramostim)
Colchicine
D-penicillamine
D, direct; GABA, γ-aminobutyric acid; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; I, indirect or via drug-drug
interaction.
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bendamustine, ciprofloxacin, and other drugs, while the other
2 patients (cases 11 and 12) were treated with fludarabine and
rituximab, in addition to several other drugs. While the sulfonamide component sulfamethoxazole in Bactrim may have
a role in the formation of PPHA in the former (case 10), concomitant use of other medications complicates the analysis of
the causative factors. No drug listed in Table 3 was noted to be
used in the other 2 cases of CLL (cases 11 and 12). Although
both patients were taking fludarabine and rituximab, suggesting possible causality, PPHA has been described historically
in CLL, even before these 2 drugs were introduced.28,29
Clinical observations of change in neutrophilic segmentation in correlation with dose adjustment of certain drugs should
be able to identify the causative regimens in these cases. Case
13 was a patient who was administered granulocyte colonystimulating factor (a drug listed in Table 3) at the time when
circulating PPHA was noted in peripheral blood and aspirate
smears. Owing to the complexity of numerous medications in
each case (ranging from 10 to 26 drugs when PPHA was identified in the peripheral blood), it is difficult to ascertain the
exact role of individual drug(s) or which one might be essential for the development of PPHA in our cases. Actually, in a
clinical setting, it would not be practical to allow a complete
cessation or even a dose reduction of relevant medications
to test the causative effect strictly for investigative purposes
owing to the risk of losing grafts or other potential complications. Therefore, pathologic exclusion of MDS or related
myeloid neoplasms has a central role in defining the benign
nature of iatrogenic PPHA in these cases.
The underlying mechanism of PPHA induced by medications is unclear. Hoffmann et al30 discovered the linkage of
hereditary PHA to the lamin B-receptor (LBR) gene located
on the long arm of chromosome 1 (1q41-43) by using microsatellite-based genetic linkage analysis. They also found a
gene dose-dependent reduction of LBR protein, the quantity
of which is inversely correlated with severity of neutrophilic
hypolobation or hyposegmentation. LBR is an integral protein
component of the inner nuclear membrane and seems to interact with lamin B and heterochromatin to affect nuclear lobation. While the reversible nature of PPHA induced by medications does not suggest a permanent change or mutation of the
LBR gene, certain drugs may have a role in down-regulation of
LBR gene expression or may interact directly with LBR protein
to block its function. In addition, future investigations regarding the mutation status of the LBR gene in cases of PPHA secondary to MDS or related myeloid neoplasms might provide
an additional genetic marker for diagnosis of these neoplasms,
which may also enable a more definitive distinction between
myeloid neoplasia–related and iatrogenic PPHA.
From the Departments of 1Pathology, Duke University Medical
Center, Durham, NC; 2Pathology, University of Southern
302
302
Am J Clin Pathol 2011;135:291-303
DOI: 10.1309/AJCPVFY95MAOBKRS
California Keck School of Medicine, Los Angeles; 3Laboratory
Medicine, UCSF/VA Medical Center, San Francisco, CA; and
4Pathology, City of Hope National Medical Center, Duarte, CA.
Presented in part at the 99th Annual Meeting of the United
States and Canadian Academy of Pathology; Washington, DC;
March 20-26, 2010.
Address reprint requests to Dr Wang: Dept of Pathology,
DUMC Box 3712, M-345 Davison Bldg (Green Zone), Duke
Hospital South, Durham, NC 27710.
Acknowledgment: We thank Steven R. Conlon, Department
of Pathology, Duke University School of Medicine, for technical
assistance with the photo images.
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