Unusual Myelodysplastic Syndrome with the Initial ...

Original Paper Acta Haematol 2002;108:139–143

Received: January 3, 2002 Accepted after revision: April 18, 2002

Unusual Myelodysplastic Syndrome with the Initial Presentation Mimicking Idiopathic Thrombocytopenic Purpura Junya Kuroda a, b Shinya Kimura b Yutaka Kobayashi a Katsuya Wada a Nobuhiko Uoshima a Toshikazu Yoshikawa a a First

Department of Internal Medicine, Kyoto Prefectural University of Medicine, and of Transfusion Medicine, Kyoto University Hospital, Kyoto, Japan

b Department

Key Words Idiopathic thrombocytopenic purpura W Myelodysplastic syndrome W Refractory cytopenia W Thrombocytopenia

Abstract Idiopathic thrombocytopenic purpura (ITP) and primary myelodysplastic syndrome (MDS) are hematological disorders that are frequently associated with thrombocytopenia, and both are heterogeneous disorders of uncertain etiology. Their diagnosis requires the exclusion of other hematological or immunological disorders whose diagnosis is usually not difficult. However, in some patients presenting with thrombocytopenia, the differential diagnosis is complex. We performed a retrospective study of 47 consecutive patients treated between 1990 and 2001; in 25 patients the initial diagnosis was ITP, in 22 it was MDS; we compared their backgrounds, laboratory data and clinical outcomes. Among the 25 ITP patients, there were 5 confusing cases. Following treatment, they presented with inexplicable refractory anemia and/or neutropenia. Cytopenia, the polyploidization pattern of megakaryocytes, and chromosomal aberrations were of diagnostic relevance in these patients’

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defective hematopoiesis. Their cytopenia progressed relatively slowly and none progressed to leukemic transformation. We suggest that these 5 patients should be classified into an unusual subtype of MDS with clinical characteristics resembling ITP. Copyright © 2002 S. Karger AG, Basel

Introduction

Idiopathic thrombocytopenic purpura (ITP) and myelodysplastic syndrome (MDS) are hematological disorders whose clinical features and etiopathogenesis vary from case to case. Typically, after evaluation for trilineage myelodysplasia, refractory cytopenia, and abnormal immunoregulation, a differential diagnosis of ITP or MDS is not difficult. However, there are some confusing cases with thrombocytopenia, where it is difficult to differentiate the actual disorder from other hematological disorders such as MDS with minimal dysplasia [1–4] and impaired immune regulation in the presence of connective tissue diseases or acquired immunodeficiency syndrome [5, 6].

Yutaka Kobayashi, MD First Department of Internal Medicine Kyoto Prefectural University of Medicine 465 Kajii Kamigyo-ku, Kyoto 602 (Japan) Tel. +81 75 251 5505, Fax +81 75 252 3721, E-Mail [email protected]

Table 1. Laboratory data of cases with MDS mimicking ITP

Case

Age/sex

Normal range

WBC !109/l

Hb g/dl

MCV fl

Plt. !109/l

PAIgG ng/107 cells

3.2–8.5

10.8–16.9

86.0–104.0

104.0–348.0

9–25 812.9 6,733.0 43.2

1 2 3

69/F 77/M 65/M

4.4→4.0 7.1→2.3 9.8→3.4

10.8→8.5 10.4→7.2 10.5→8.2

97.2→113.2 95.1→100.5 94.8→95.7

23.0→98.0 24.0→37.0 3.0→67.0

4 5

82/F 47/M

4.2→2.2 3.9→3.6

12.5→10.3 15.6→12.2

NA 97.4→95.1

41.0→55.0 76.0→102.0

NA 129.6

Treatment

cepharanthin vitamin C PSL splenectomy AZP – cepharanthin

F = Female; M = male; ANC = all nucleated cell; Erb = erythroblast; PSL = prednisolone; AZP = azathioprine; NA = not available. The data of WBC, Hb, MCV, and Plt. are indicated as initial data→data at altering diagnosis to MDS.

We performed a retrospective study of 47 consecutive patients who were initially diagnosed as having ITP (n = 25) or de novo MDS (n = 22). In 5 ITP patients the initial diagnosis became questionable because they showed subsequent inexplicable, slowly progressive anemia and/or neutropenia. These patients manifested neither marrow dysplasia nor did they progress to leukemic transformation. As there is little information in the literature on such patients, we undertook a retrospective comparative study on the backgrounds, hematological data, serum levels of platelet-associated immunoglobulin G (PA-IgG), myelograms, chromosomal analysis, and clinical outcomes of the 47 patients.

Materials and Methods Patients We retrospectively evaluated 47 patients diagnosed between 1990 and 2001 as having ITP (n = 25) or de novo MDS (n = 22), according to a previously described diagnostic procedure [7, 8]. All patients were treated at the First Department of Internal Medicine, Kyoto Prefectural University of Medicine; their backgrounds, hematological data, myelograms, serum levels of PA-IgG, the results of chromosomal analysis, and their clinical outcomes were obtained form clinical records. Serum levels of PA-IgG were evaluated only in patients with the initial diagnosis of ITP. DNA Ploidy of Bone Marrow Megakaryocytes This examination was performed on the bone marrow of 3 patients whose initial diagnosis appeared questionable to us (cases 1–3), using the method described by Kobayashi et al. [9, 10]. Bone marrow smears were stained with the Wright-Giemsa (WG) solution to identify and to map megakaryocytes. The DNA ploidy of megaka-

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Acta Haematol 2002;108:139–143

ryocytes was examined by microcytofluorometry with DAPI staining after WG destaining. Statistical Analysis The mean values and standard deviations (SD) were calculated for age, leukocyte counts, hemoglobin concentrations (Hb), platelet counts, serum PA-IgG levels, all-nucleated cell (ANC) counts, and the ratios of marrow myeloblasts and of marrow erythroblasts. The mean B SD values were compared by the paired Student t test (p ! 0.05) for the 3 patient groups (ITP patients, MDS patients, and patients with MDS mimicking ITP).

Results

An initial diagnosis of ITP was made in 25 cases, and a diagnosis of de novo MDS was reached in 22 cases. In the former group, thrombocytopenia had resolved or was controlled by conventional ITP treatment such as splenectomy or the administration of corticosteroids, azathioprine, cepharanthin, vitamin C, danazol, or intravenous immunoglobulin. However, the initial diagnosis became questionable in 5 patients (cases 1–5); their hematological data and the serum level of PA-IgG are summarized in table 1, and the results of bone marrow analysis are summarized in table 2. Case 1 received cepharanthin instead of other conventional treatment because of severe diabetes mellitus, and her thrombocytopenia (23.0 ! 109/l) resolved. However, in the course of a 3-year follow-up she presented with anemia (8.5 g/dl of Hb) and neutropenia (1.0 ! 109/l). Case 2 rejected corticosteroid therapy, and high-dose vitamin C administration resolved his thrombocytopenia (24 !

Kuroda/Kimura/Kobayashi/Wada/ Uoshima/Yoshikawa

Table 2. Bone marrow and chromosomal analysis at initial diagnosis of cases with MDS mimicking ITP

Case

ANC !109/l

Blast %

Erb %

Normal range

100–250

0–2.0

–20.6

1 2 3

206.8 320.0 152.0

0.8 1.2 0.2

53.0 5.2 7.4

4

140.0

0.6

5

113.0

1.5

MgK !106/l

Karyotype

Treatment

165 81 124

46,XX 46,XY 46,XY

31.2

122

cepharanthin vitamin C PSL splenectomy AZP –

37.0

118

46,XX →46,XX,20q46,XY cepharanthin →46,XY,inv(9)(p11q13)

50–100

F = Female; M = male; ANC = all nucleated cell; Erb = erythroblast; MgK = megakaryocyte; PSL = prednisolone; AZP = azathioprine; NA = not available.

109/l); however, in the course of a 4-year follow-up he developed anemia (7.2 g/dl of Hb) and neutropenia (0.9 ! 109/l). In case 3, thrombocytopenia (3.0 ! 109/l) was controlled by predonisolone and splenectomy; however, over a period of 6 years, this patient experienced slowly progressive anemia (8.2 g/dl of Hb). Despite the improvement of thrombocytopenia, a consistently abnormal karyotype 46,XX,20q- was identified in case 4 2 years after the initial diagnosis, and 46,XY,inv(9)(p11q13) was identified 4 years after the first presentation of case 5 (table 1). As for DNA ploidy of megakaryocytes, a shift in the mean value toward lower ploidy, with the maximum peak at 8N, was identified in cases 1 and 2. In case 3, the maximum peak was found to be normal, at 16N (fig. 1). Because systemic examinations eliminated nutritional deficiencies, intoxication, metabolic disturbances, chronic inflammation, and nonhematological malignancies as contributing factors in all 5 confusing cases, we eventually corrected their diagnosis from ITP to MDS. All are currently alive and none progressed to leukemia. As shown in table 3, there were no statistically significant differences between patients with typical ITP and our confusing cases with respect to leukocyte count, Hb, platelet count, PA-IgG, ANC count, megakaryocyte number and the ratio of marrow myeloblasts and of marrow erythroblasts. On the other hand, there were statistical differences with respect to Hb, peripheral platelet count, and the ratio of marrow blasts and marrow erythroblasts between patients with MDS mimicking ITP and MDS cases. Megakaryocyte numbers of 5 confusing cases were

Unusual MDS Initially Presenting as ITP

Fig. 1. Megakaryocyte DNA ploidy of cases 1–3.

statistically higher than those of typical MDS. These confusing cases of uncommon MDS whose initial clinical features mimicked ITP accounted for 20% of our cases with an initial diagnosis of ITP.


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Table 3. Comparative analysis of clinical data

Patients’ background

ITP

Age, years Sex (male:female)

53.9B20.7 12:8

n.s. n.s.

68.0B13.5 3:2

n.s. n.s.

63.8B13.7 14:4

Blood examination Leukocyte count, !109/l Hemoglobin concentration, g/dl Mean capsular volume, fl Platelet count, !109/l

7.28B3.13 13.2B2.6 93.7B2.9 24.5B24.3

n.s. n.s. n.s. n.s.

5.88B2.54 12.0B2.2 96.1B1.4 33.4B27.4

n.s. p = 0.042 n.s. p = 0.046

3.01B1.23 9.1B1.7 97.7B7.1 77.3B95.1

Serological data Pa-IgG, ng/107 cells

191.0B218.6

n.s.

1,929.8B3,220.8

Bone marrow analysis All nucleated cell count, !109/l Megakaryocyte, !106/l Myeloblasts, % Erythroblasts, %

123.7B86.0 116.0B42.1 0.93B0.56 27.1B6.8

n.s. n.s. n.s. n.s.

186.4B82.1 122.0B34.4 0.86B0.51 26.8B20.3

Karyotype Normal:abnormal (n)

20:0

MDS mimicking ITP

3:2

MDS

NA n.s. p = 0.012 p = 0.005 p = 0.028

110.0B97.1 56.9B34.4 7.31B9.13 33.9B16.7 12:9

n.s. = Statistically nonsignificant difference.

Discussion

In our series, 5 of 25 patients whose initial diagnosis was ITP manifested slowly progressive cytopenias and in 2 of the 5 patients, consistent chromosomal aberrations were noted throughout their clinical course. In addition, the DNA ploidy of the megakaryocytes in 2 of 3 cases analyzed (cases 2 and 3) became low (fig. 1). These findings are characteristic of MDS and show that a defect in the hematopoietic process affects megakaryocytic polyploidization [9–11], whereas megakaryocyte ploidy has been reported to be normal in classical ITP patients [11]. Because the diagnosis of ITP was unlikely in the presence of the defect in our patients’ hematopoiesis, we finally corrected their diagnosis from ITP to MDS. For a definitive diagnosis of MDS, the presence of marrow dysplasia must be confirmed and other disorders similar to MDS in their clinical manifestations must be eliminated [2–4]. Although MDS with minimal dysplasia seemed to be similar to the conditions noted in our 5 confusing cases among a number of MDS subtypes with respect to slowly progressive cytopenia attributable to defective hematopoiesis, rare progression to leukemia, and a relatively favorable prognosis [1–4, 12–14], we con-

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sidered that this was not an appropriate diagnosis for our 5 confusing cases in the absence of prominent dyserythropoiesis [15]. We suggest that in confusing cases such as ours, a temporary, working diagnosis of so-called ‘not quite MDS’ or ‘not yet MDS’ with initial presentation of immune thrombocytopenia may be appropriate until further clinical developments help to establish a definitive diagnosis [2]. Initially, it may be difficult to differentiate such an equivocal condition from ITP because there are no significant differences with respect to the backgrounds, blood counts, serum PA-IgG levels, and bone marrow analysis. Simultaneously, it would be difficult to regard such patients as having typical MDS, since their laboratory data show statistically significant differences in several points (table 3). Considering the possible existence of impaired hematopoiesis, patients should be carefully monitored after an initial diagnosis of ITP. In establishing a correct differential diagnosis, a clonality assay such as conventional chromosomal analysis or, more precisely for female patients, the polymorphic short tandem repeat on the human androgen-receptor gene will be of help [16]. Actually, chromosomal aberration involving 20q-, as seen in 8.0% of MDS [1], and inv(9)p11q13), also reported to be

Kuroda/Kimura/Kobayashi/Wada/ Uoshima/Yoshikawa

seen in MDS [17], was diagnostically relevant in our series. In addition, the analysis for megakaryocyte ploidy would be informative not only to know the aspects of the mode of proliferation of megakaryocytes in each case but also to suggest underlying hematological disorders in cases of thrombocytopenia. In contrast, although the mac-

rocytic change in red blood cells has been one of the characteristics of early MDS, it was seen only in case 1. In conclusion, we report so-called ‘not yet’ or ‘not quite’ MDS mimicking ITP in patients with defective hematopoiesis without prominent marrow dysplasia later.

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Unusual MDS Initially Presenting as ITP

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