Post on 15-Oct-2021
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□ CASE REPORT □
Isolated Isochromosome 17q in Myelodysplastic Syndromeswith Pure Red Cell Aplasia and Basophilia
Yumiko Inui 1, Katsuya Yamamoto 1, Atsuo Okamura 1, Kimikazu Yakushijin 1,
Yoshitake Hayashi 2, Hiroshi Matsuoka 1 and Hironobu Minami 1
Abstract
Myelodysplastic syndromes (MDS) with pure red cell aplasia (PRCA) have been shown to be a rare form
of MDS. A 35-year-old man presented with pancytopenia: hemoglobin 59 g/L, reticulocytes 2×109/L, plate-
lets 33×109/L, and leukocytes 1.8×109/L with 1% blasts. Bone marrow was hypercellular with 50.4% myeloid
cells, 0.0% erythroblasts, 25.4% basophils, and 5.6% myeloblasts. Dysplastic changes including pseudo-
Pelger-Huët anomaly of neutrophils and mononuclear micromegakaryocytes were found. Immunohistochemis-
try with glycophorin C confirmed erythroid aplasia. Cytogenetic analysis showed 46,XY,i(17)(q10)[18]/47,
XY,+8[2]. Considering two reported cases, these findings indicate that isolated i(17q) may be implicated in
the pathogenesis of MDS with PRCA as a recurrent cytogenetic aberration.
Key words: isolated isochromosome 17q, myelodysplastic syndromes, pure red cell aplasia, basophilia
(Intern Med 51: 1579-1584, 2012)(DOI: 10.2169/internalmedicine.51.7298)
Introduction
An isochromosome of the long arm of chromosome 17,
i(17q), is frequently observed in accelerated and blast phases
of Philadelphia (Ph) chromosome-positive chronic myeloid
leukemia (1). In addition, i(17q) is occasionally detected as
a sole abnormality in Ph-negative myeloid malignancies in-
cluding myeloproliferative neoplasms (MPN), myelodysplas-
tic syndromes (MDS), MDS/MPN, and their transformation
to acute myeloid leukemia (AML) (2-8). It has been shown
that isolated i(17q) is associated with marked granulocytic
and megakaryocytic dysplasia and severe anemia in these
myeloid malignancies (3-8).
MDS associated with pure red cell aplasia (PRCA), or
with erythroid hypoplasia/aplasia, are rare forms of myelo-
dysplasia, and characterized by moderate to severe anemia,
reticulocytopenia, and profound reduction of erythroblasts in
the bone marrow (9, 10). Approximately 50 cases have been
reported in the literature, although the definitions of
erythroid hypoplasia were heterogeneous: erythroblasts were
1% or fewer, or less than 5% of bone marrow cells (9-21).
These patients were predominantly elderly males, required
regular red cell transfusions, and had poor prognoses mainly
because of acute transformation (9). Thus, MDS with PRCA
are thought to represent a distinct clinicopathological en-
tity (10, 19). However, cytogenetic findings in MDS with
PRCA have not been fully characterized. Here, we describe
a new case of MDS with PRCA, which also demonstrated
an isolated i(17q) and bone marrow basophilia.
Case Report
A 35-year-old man was admitted to another hospital be-
cause of general malaise and fever. Initial peripheral blood
examination showed severe anemia: hemoglobin 41 g/L,
platelets 138×109/L and white blood cells (WBC) 5.2×109/L.
After repeated transfusions, the patient was transferred to
our hospital for precise examination of anemia. On admis-
sion, peripheral blood values were hemoglobin 95 g/L,
platelets 138×109/L and WBC 12.3×109/L with 2% blasts
and 91% neutrophils. Serum level of C-reactive protein
(CRP) was 30.68 mg/dL (normal range, <0.3). Computed
tomography (CT) scans disclosed severe bilateral pneumonia
1Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Japan and 2Division of
Molecular Medicine and Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Japan
Received for publication January 11, 2012; Accepted for publication March 9, 2012
Correspondence to Dr. Katsuya Yamamoto, kyamamo@med.kobe-u.ac.jp
Intern Med 51: 1579-1584, 2012 DOI: 10.2169/internalmedicine.51.7298
1580
Figure 1. Bone marrow smears at the diagnosis (May-Grünwald-Giemsa staining). (A, B) Relative myeloid hyperplasia and erythroid aplasia are shown (×400). (C) Myeloblasts, (D) pseudo-Pelger-Huët anomaly and hypogranulation of neutrophils, (E, F) binuclear and mononuclear micromega-karyocytes, and (G) basophils are seen (×1,000).
D
E F G
A
B
C
but not thymoma. After treatment with antibiotics and anti-
fungal agents for one month, pneumonia was relieved and
CRP decreased to 0.02 mg/dL. At this time, peripheral
blood values were hemoglobin 59 g/L, reticulocytes 2×109/
L, platelets 33×109/L and WBC 1.8×109/L with 1% blasts,
1% metamyelocytes, 1% band forms, 23% segmented neu-
trophils, 1% eosinophils, 27% basophils, 1% monocytes, and
45% lymphocytes. Serum levels of ferritin and erythro-
poietin were markedly elevated to 6,826 ng/mL (25-280)
and 4,062 mIU/mL (0-29), respectively. Serum IgM anti-
body for parvovirus B19 was negative.
Bone marrow examination showed relative myeloid hy-
perplasia, erythroid aplasia and an increased number of
megakaryocytes (Fig. 1A, B). Differential counts were 0.0%
erythroblasts, 5.6% myeloblasts, 1.4% promyelocytes, 8.6%
myelocytes, 22.2% metamyelocytes, 3.6% band forms,
14.6% segmented neutrophils, 2.8% monocytes, 4.6%
eosinophils, 25.4% basophils, and 10.4% lymphocytes. Bi-
lineal dysplastic changes, such as pseudo-Pelger-Huët anom-
aly of neutrophils and mononuclear micromegakaryocytes,
were observed (Fig. 1C-G). Bone marrow biopsy revealed
hypercellular marrow with myeloid hyperplasia and myelofi-
brosis (Fig. 2A, B). Immunohistochemistry showed that only
a few cells were positive for glycophorin C, confirming
erythroid aplasia, whereas almost all cells were positive for
myeloperoxidase (Fig. 2C, D).
Immunophenotyping by three-color flow cytometry dem-
onstrated that blasts were positive for CD13, CD16, CD33,
CD41, and HLA-DR. The CD4/CD8 ratio in the T-cell
population of bone marrow was inverted (0.49). G-banding
analysis showed unrelated clones as follows: 46,XX,i(17)
(q10)[18]/47,XX,+8[2] (Fig. 3A). Fluorescence in situ hy-
bridization (FISH) with TP53/CEP 17 probes showed that
one TP53 signal was deleted in 84 of 100 interphase nuclei
(Fig. 3B). FISH with CEP 8 probe confirmed three CEP 8
signals in 6 of 100 cells (Fig. 3C). We next performed bone
marrow scintigraphy with indium chloride (111In), because111In is selectively incorporated into erythroid precursors af-
ter binding to transferrin (22). The scintigraphy exhibited a
marked decrease of activity in the central bone marrow
(Fig. 4).
We made a diagnosis of MDS, refractory anemia with ex-
cess of blasts (RAEB)-1, according to the World Health Or-
ganization (WHO) classification. There was no effect of
pneumonia when the diagnosis of MDS was made. The as-
sociation with PRCA was also confirmed by these labora-
tory findings. The disease was classified as intermediate-2 in
the International Prognostic Scoring System (IPSS), and
high in the WHO classification-based prognostic scoring
system (WPSS) (23). Then, two months later after admis-
sion, the patient underwent myeloablative cord blood trans-
plantation (CBT) from an human leukocyte antigen (HLA)
one locus mismatched unrelated female donor. Before CBT,
there was no significant change of hematological data: he-
moglobin 64 g/L, reticulocytes 2×109/L, platelets 58×109/L
and WBC 1.4×109/L with 2% blasts, 10% segmented neutro-
Intern Med 51: 1579-1584, 2012 DOI: 10.2169/internalmedicine.51.7298
1581
Figure 2. Pathological findings of the bone marrow at the diagnosis. (A) Bone marrow is markedly hypercellular (Hematoxylin and Eosin staining, ×20). (B) Bone marrow fibrosis is revealed by silver staining (×40). (C) Immunohistochemistry shows that only a few cells are positive for glycophorin C (×40). (D) Almost all cells are positive for myeloperoxidase (×40).
A B
C D
phils, and 22% basophils. CBT was performed after condi-
tioning regimen with total body irradiation and high-dose
cyclophosphamide. Tacrolimus and mycophenolate mofetil
were used for graft-versus-host disease prophylaxis. He ob-
tained hematological and cytogenetic complete remission
(CR) and complete chimerism on day 28 after CBT. At the
time of writing, he has been in CR for more than 21
months.
Discussion
We have presented an unusual case of MDS with PRCA,
isolated i(17q), and basophilia. PRCA was characterized by
bone marrow biopsy, immunohistochemistry, high levels of
ferritin and erythropoietin, and a decrease of activity in the
bone marrow scintigraphy as well as bone marrow smear.
Granulocytic and megakaryocytic dysplasia and basophilia
possibly due to i(17)(q10) were also found in the bone mar-
row. In spite of poor prognostic factors, the patient remains
in CR after receiving CBT.
Isolated i(17q) is observed in approximately 1% of pa-
tients with MDS (4, 6). MDS with i(17q) appear to have
several common clinical features: male predominance, ad-
vanced age, severe anemia, hypercellular bone marrow,
eosinophilia/basophilia, increased micromegakaryocytes, hy-
posegmentation and hypogranularity of neutrophils, and
poor prognosis (4). Among these, bone marrow eosinophilia
and basophilia were shown to be specifically and most fre-
quently associated with i(17q) (24). Thus, similar to MDS
with PRCA, MDS with i(17q) also represent a unique sub-
set.
With regard to cytogenetic findings in MDS with PRCA,
results from a total of 37 cases are available (9-21). Twenty-
six cases showed normal karyotypes, whereas 11 cases had
acquired clonal abnormalities: add(1)(q42),-2,-18,-19,+2mar
(1 case), del(5)(q13q33) (2 cases), del(5)(q14q34) (2 cases),
t(6;8)(p15;q22) (1 case), +8 (1 case), i(17)(q10)/i(17q) (2
cases), and del(20)(q11q13) (2 cases). Together with the pre-
sent case, i(17q) was found in 3 of 12 cases with cytoge-
netic abnormalities (4, 12), indicating that i(17q) as well as
del(5q) are recurrent cytogenetic aberrations in MDS with
PRCA (13).
Clinical information of MDS with PRCA and i(17q) is
summarized in Table 1. The subtypes were classified as
RAEB in all cases. Bone marrow erythroblasts ranged from
0% to 2%. All cases showed marked anemia, granulocytic
and megakaryocytic dysplasia, and basophilia and/or eosino-
philia. Cytogenetically, i(17q) was found as a sole abnor-
mality in all stem lines, and trisomy 8 was found to accom-
pany as an unrelated clone in two cases. These common
findings suggest that MDS harboring isolated i(17q) and
PRCA might constitute a novel clinical entity. Interestingly,
in spite of severe anemia, dysplastic erythropoiesis has been
hardly described in MDS with i(17q) (2-8). Thus, PRCA
Intern Med 51: 1579-1584, 2012 DOI: 10.2169/internalmedicine.51.7298
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Figure 3. Cytogenetic findings of the bone marrow cells at the diagnosis. (A) G-banded karyotype is 46,XY,i(17)(q10). An arrow indicates the i(17)(q10). (B) FISH with TP53/CEP 17 probe on inter-phase nuclei. One TP53 signal (red) and two CEP 17 signals (blue) are observed. (C) FISH with CEP 8 probe. Three CEP 8 signals (green) are confirmed.
A
B C
Figure 4. Bone marrow scintigraphy with 111In shows a marked decrease of activity in the central bone marrow. Only intense renal activity is observed.
may be one of the mechanisms responsible for severe ane-
mia in MDS with i(17q).
Isolated i(17q) results in monosomy 17p and trisomy 17q.
We performed FISH with TP53 and confirmed the loss of
17p, which could be associated with pseudo-Pelger-Huët
anomaly of neutrophils as reported in 17p- syndrome (25).
On the other hand, trisomy 17q leads to the gain of
myeloid-associated genes such as CSF3 (GCSF) and MPOlocated at 17q11.2-12 and 17q21.3-23, respectively (2). Mo-
lecular mechanisms of i(17q) in myeloid malignancies re-
main to be elucidated, but the existence of unrelated minor
clones with trisomy 8 in two cases suggests that cytogeneti-
cally undetectable primary genetic events may precede iso-
lated i(17q) (26).
MDS with PRCA seem to be divided into two subtypes:
one with an increasing percentage of blasts in the bone mar-
row, and the other with no evidence of proliferative or blas-
Intern Med 51: 1579-1584, 2012 DOI: 10.2169/internalmedicine.51.7298
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Table 1. Reported Cases of MDS Associated with PRCA and Isochromosome 17q
Case No.
Age/ Sex
Dx (WHO)
WBC(×109
/L)
Hb (g/L)
Plt (×109
/L)
EPO (mIU/mL)
Mbl in BM (%)
Ebl in BM (%)
Bas in BM (%)
Eos in BM (%)
dys- myelo in BM
dys- mgk
in BM
Karyotypes OS (mo)
References
1 70/M RAEB-2* 6.1 46 349 NA 14 2
13 7 pP, hy mi, mon
eloS 6 )q71(i,YX,64 et al., 1993 (4)
2
71/M RAEB-2* 2.7 77 12 2570 16.6 0.0 1.2 21.6 pP, va ms 46,XY,i(17)(q10)[14]/46,sl,del(6)(q?)[1]/46,sl,add(21)(q11)[1]/47,XY,+8[4]
12 Yokohama et al., 1999 (12)
3
35/M RAEB-1 1.8
59 33 4062 5.6 0.0 25.4 4.6 pP, hy mi, ms,mon
46,XY,i(17)(q10)[18]/47,XY,+8[2] 21+ present case
Abbreviations: MDS, myelodysplastic syndromes; PRCA, pure red cell aplasia; M, male; Dx, diagnosis; WHO, WHO classification; RAEB, refractory anemia with excess of blasts; WBC, white blood cells; Hb, hemoglobin; Plt, platelets; EPO, erythropoietin; NA, not available; BM, bone marrow; Mbl, myeloblasts; Ebl, erythroblasts; Bas, basophils; Eos, eosinophils; dys-myelo, dysmyelopoiesis; pP, pseudo-Pelger-Huet anomaly; hy, hypogranulation; va, vacuoles; dys-mgk, dysmegakaryopoiesis; mon, mononuclear; mi, micromegakaryocytes; ms, multi-separated nuclei; OS, overall survival; mo, months. *The subtypes of MDS were reclassified according to WHO classification (2008).
tic change (11). The former is presumably due to an intrin-
sic defect of maturation and proliferation of erythroid pre-
cursors as a part of MDS, whereas the latter may have a
possibly autoimmune etiology and a favorable response to
immunosuppressive therapy. In fact, MDS patients success-
fully treated with cyclosporine were classified as RA, and T-
cell receptor gene rearrangements with an inverted CD4/
CD8 ratio were demonstrated (14, 19). In contrast, MDS
with PRCA and i(17q)/del(5q) may belong to the former
type because these cases were correlated with high percent-
ages of blasts (4, 12, 13).
Treatment regimens for MDS with PRCA were varied:
prednisolone, erythropoietin, cyclosporine, G-CSF, and
azacitidine (9-21). Only one patient underwent allogeneic
bone marrow transplantation after transformation to AML,
and died at 57 months after the diagnosis (19). The low fre-
quency of allogeneic stem cell transplantation (allo-SCT) in
the treatment for MDS with PRCA may be due to an older
age and a low proportion of high-risk groups: Wang et al.
reported that all 16 patients with MDS and PRCA had low
or intermediate-1 IPSS score at the time of diagnosis (19).
However, our results suggest that allo-SCT at an early time
could be beneficial for MDS with PRCA in spite of unfa-
vorable cytogenetic abnormalities. Accumulation of more
cases will be necessary to clarify the appropriate treatment
for MDS with PRCA.
The authors state that they have no Conflict of Interest (COI).
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