isolated isochromosome 17q in myelodysplastic syndromes

1579

□ 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, [email protected]

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-


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


1582

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-


1583

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).

References

1. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular

genetic evolution of chronic myeloid leukemia. Acta Haematol

107: 76-94, 2002.

2. Becher R, Carbonell F, Bartram CR. Isochromosome 17q in Ph1-

negative leukemia: a clinical, cytogenetic, and molecular study.

Blood 75: 1679-1683, 1990.

3. Weh HJ, Kuse R, Hossfeld DK. Acute nonlymphocytic leukemia

(ANLL) with isochromosome i(17q) as the sole chromosomal

anomaly: a distinct entity? Eur J Haematol 44: 312-314, 1990.

4. Solé F, Torrabadella M, Granada I, et al. Isochromosome 17q as a

sole anomaly: a distinct myelodysplastic syndrome entity? Leuk

Res 17: 717-720, 1993.

5. McClure RF, Dewald GW, Hoyer JD, Hanson CA. Isolated iso-

chromosome 17q: a distinct type of mixed myeloproliferative dis-

order/myelodysplastic syndrome with an aggressive clinical

course. Br J Haematol 106: 445-454, 1999.

6. Xiao Z, Liu S, Yu M, Xu Z, Hao Y. Isochromosome 17q in pa-

tients with myelodysplastic syndromes: six new cases. Haema-

tologica 88: 714-715, 2003.

7. Pinheiro RF, Chauffaille MLLF, Silva MRR. Isochromosome 17q

in MDS: a marker of a distinct entity. Cancer Genet Cytogenet

166: 189-190, 2006.

8. Nishida H, Ueno H, Park JW, Yano T. Isochromosome i(17q) as a

sole cytogenetic abnormality in a case of leukemic transformation

from myelodysplastic syndrome (MDS)/myeloproliferative dis-

eases (MPD). Leuk Res 32: 1325-1327, 2008.

9. Martinaud C, Pons S, Ménard G, Gisserot O, de Jaureguiberry JP,

Brisou P. Myelodysplastic syndrome with erythroblastopenia. Rev

Med Interne 32: 33-38, 2011 (in French, Abstract in English).

10. Garcia-Suárez J, Pascual T, Muñoz HA, Herrero B, Pardo A.

Myelodysplastic syndrome with erythroid hypoplasia/aplasia: a

case report and review of the literature. Am J Hematol 58: 319-

325, 1998.

11. Williamson PJ, Oscier DG, Bell AJ, Hamblin TJ. Red cell aplasia

in myelodysplastic syndrome. J Clin Pathol 44: 431-432, 1991.

12. Yokohama A, Murata N, Shimano S, et al. Myelodysplastic syn-

drome accompanied by i(17)(q10) anomaly following pure red cell

aplasia and transient myeloproliferative stage. Rinsho Ketsueki.

(Jpn J Clin Hematol.) 40: 34-39, 1999 (in Japanese, Abstract in

English).

13. Park S, Merlat A, Guesnu M, et al. Pure red cell aplasia associ-

ated with myelodysplastic syndromes. Leukemia 14: 1709-1710,

2000.

14. Shimamoto T, Iguchi T, Ando K, et al. Successful treatment with

cyclosporin A for myelodysplastic syndrome with erythroid hy-

poplasia associated with T-cell receptor gene rearrangements. Br J

Haematol 114: 358-361, 2001.

15. Takata S, Kojima K, Fujii N, et al. Successful treatment with cy-

closporin A of myelodysplastic syndrome with erythroid hypopla-

sia associated with t(6;8)(q15;q22). Cancer Genet Cytogenet 140:

167-169, 2003.

16. Goyal R, Varma N, Marwaha RK. Myelodysplastic syndrome with

erythroid hypoplasia. J Clin Pathol 58: 320-321, 2005.

17. Dinçol G, Öztürk�, Palanduz�, et al. A case of myelodysplastic

syndrome with erythroid hypoplasia associated with a familial

translocation t(3;14)(p21.1;q24.1). Am J Hematol 81: 883-887,

2006.

18. Rawat S, Thakur R. Myelodysplasia with erythroid hypoplasia.

Am J Hematol 81: 557-558, 2006.


1584

19. Wang SA, Yue G, Hutchinson L, et al. Myelodysplastic syndrome

with pure red cell aplasia shows characteristic clinicopathological

features and clonal T-cell expansion. Br J Haematol 138: 271-275,

2007.

20. Chihara D, Takeoka T, Shirase T, et al. Progressive multifocal leu-

koencephalopathy in myelodysplastic syndrome involving pure red

cell aplasia. Intern Med 49: 2347-2352, 2010.

21. Nitta H, Harada Y, Okikawa Y, et al. Good’s syndrome-associated

pure red cell aplasia with myelodysplastic syndrome. Intern Med

50: 2011-2014, 2011.

22. Bunn HF, McNeil BJ, Rosenthal DS, Krantz SB. Bone-marrow

imaging in pure red blood cell aplasia. Arch Intern Med 136:

1169-1172, 1976.

23. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent

prognostic scoring system for predicting survival and leukemic

evolution in myelodysplastic syndromes. J Clin Oncol 25: 3503-

3510, 2007.

24. Matsushima T, Hanada H, Yokohama A, et al. Prevalence and

clinical characteristics of myelodysplastic syndrome with bone

marrow eosinophilia or basophilia. Blood 101: 3386-3390, 2003.

25. Jary L, Mossafa H, Fourcade C, Genet P, Pilik M, Flandrin G.

The 17p- syndrome: a distinct myelodysplastic syndrome entity?

Leuk Lymphoma 25: 163-168, 1997.

26. Musilová J, Michalová K, Zemanová Z, B�ezinová J. Multiple un-

related clones in myelodysplastic syndrome and in acute myeloid

leukemia. Cancer Genet Cytogenet 88: 141-143, 1996.

Ⓒ 2012 The Japanese Society of Internal Medicine

http://www.naika.or.jp/imindex.html

isolated isochromosome 17q in myelodysplastic syndromes

Documents