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Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 173-176

De novo Philadelphia chromosome positive myelodysplastic syndrome: Report of two cases with brief literature review

1 Department of Hematology, SGPGI, Lucknow, Uttar Pradesh, India
2 Molecular Biology and R&D, Oncquest Laboratory, New Delhi, India

Date of Submission10-Apr-2016
Date of Decision03-Jun-2016
Date of Acceptance11-Jun-2016
Date of Web Publication16-Aug-2016

Correspondence Address:
Khaliqur Rahman
Type 4/98, New Campus, SGPGI, Raebareli Road, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.188428

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 > Abstract 

Myelodysplastic syndromes (MDSs) are characteristically defined by the presence of specific karyotypic abnormalities, based on which they have been prognosticated. Translocation t(9;22)(q34;q11.2) (Philadelphia positive [Ph +ve]) and corresponding BCR-ABL fusion transcript is the defining parameter of chronic myeloid leukemia. It is also seen in a fair proportion of adult acute lymphoblastic leukemia. Occurrence of a Ph +ve MDS is very uncommon, and that too is seen mostly on progression to higher stage/acute leukemia. Even rarer is the de novo presence of Ph positivity in an MDS. A literature search through PubMed has shown only about forty cases of Ph +ve MDS among which less than half had shown Ph positivity at the time of initial diagnosis. Due to its rarity, this entity has not yet found its space in current WHO 2008 classification and is still under “yet to be validated phase” in current practice of hematological malignancies. The benefit of using a tyrosine kinase inhibitor in such a situation is also debatable. We report here two such cases of de novo Ph +ve MDS, diagnosed in last 1½ year at our institute along with brief literature review.

Keywords: Genetic abnormalities, myelodysplastic syndrome, Philadelphia chromosome

How to cite this article:
Rahman K, Singh MK, Gupta R, Dutta S, Nityanand S. De novo Philadelphia chromosome positive myelodysplastic syndrome: Report of two cases with brief literature review. J Can Res Ther 2020;16:173-6

How to cite this URL:
Rahman K, Singh MK, Gupta R, Dutta S, Nityanand S. De novo Philadelphia chromosome positive myelodysplastic syndrome: Report of two cases with brief literature review. J Can Res Ther [serial online] 2020 [cited 2023 Jan 27];16:173-6. Available from: https://www.cancerjournal.net/text.asp?2020/16/1/173/188428

 > Introduction Top

Translocation t(9;22)(q34;q11.2) (Philadelphia chromosome positive [Ph +ve]) and corresponding BCR/ABL1 fusion transcript is the defining parameter to differentiate between chronic myeloid leukemia (CML) and non-CML myeloproliferative neoplasm. Besides CML, Ph positivity has frequently been reported with adult acute lymphoblastic lymphoma (Ph+ ALL). On the contrary, Ph+ myelodysplastic syndrome (MDS) is rare with only handful cases reported.[1] Most of these cases reported in the literature have acquired the Ph positivity during their progression to a higher stage or acute leukemia transformation. It has not yet been certain whether this is just an incidental finding or the Ph positivity has any prognostic significance. We report here two de novo Ph +ve cases of MDS along with brief literature review.

 > Case Reports Top

Case 1

A 55–year-old female presented with complaints of weakness and easy fatigability for 10 months. She was referred as a suspected case of aplastic anemia, having pancytopenia and a hypoplastic marrow. Physical examination showed only pallor, without organomegaly or lymphadenopathy. Hematological and biochemical workup revealed anemia, thrombocytopenia, and mild leukocytosis showing shift to left with the presence of prominent cytoplasmic granulations (probably, a growth factor-induced changes) and increased serum lactate dehydrogenase levels [Table 1]. Bone marrow (BM) examination showed hypocellular particles with the presence of a few dysplastic, hypolobated megakaryocytes. Erythroid series cells showed a megaloblastic maturation. Approximately, 6% blasts with fine nuclear chromatin, prominent nucleoli, and variable amount of cytoplasm were noted along with mild dyspoiesis in myeloid series cells [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d Perl's staining did not reveal any ringed sideroblasts. A morphological diagnosis of hypoplastic MDS-RAEB 1 (refractory anemia with excess blast) was rendered. Conventional karyotyping showed the presence of t(9;22)(q34;q11.2) along with monosomy 4. Supportive therapy was initiated with a plan to start hypomethylating agent. Due to lack of financial support, the patient remained on supportive care. Meanwhile, she developed high-grade fever and succumbed to disease within month of diagnosis.
Table 1: Patient characteristics

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Figure 1: (a) Bone marrow aspiration smears from case 1 showing hypoplastic marrow particles (b) with the trails showing significant dyspoiesis in megakaryocytes, (c) erythroid precursors and (d) myelomonocytic lineage cells. (e) Images from case 2 showing cellular marrow particles, (f) with the trails showing an increase in number of blasts, (g) dyspoietic myeloid, erythroid series cells and (h) megakaryocytes

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Case 2

A 31–year-old male presented with a history of recurrent episodes of petechial rashes all over the body for last 7 months. There was a history of multiple random donor platelet transfusions in the recent past. Examination revealed pallor along with multiple petechial spots and ecchymotic patches all over the body. There was no organomegaly or lymphadenopathy. Hemogram showed severe pancytopenia [Table 1]. He was administered transfusion support along with hematinics. BM aspirate smears were cellular, with presence of 14% myeloid blasts and dysplasia in all the three hematopoietic lineages [Figure 1]e-h] A morphological diagnosis of MDS-RAEB II was rendered. Conventional karyotyping showed presence of a complex karyotype, 44–45, XY,+X, der(4),-5, der(7),-7,-8, t(9;22)(q34;q11.2),-15,+22,+mar1 [Figure 2] in all the 20 metaphases counted. A week after his first visit to the hospital, patient developed severe headache followed by loss of consciousness and died on the way to hospital.
Figure 2: Karyogram of case 2: 44–45,XY,+X,der(4),add(4)(q31.3),-7, del(7)(q22),-8,t(9;22)(q34.q11.2),-13,-15,-18,-20,+22,+mar1[cp20]

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 > Discussion Top

Philadelphia chromosome, discovered by Nowell and Hungerford in patients with CMLs, got its name after the place where it was discovered.[2] This is the truncated chromosome 22, of the characteristic reciprocal translation t(9;22)(q34;q11.2) seen in patients of CML. This translocation results in the formation of BCR-ABL1 fusion protein with an enhanced tyrosine kinase activity, which further activates several signaling pathways such as Myc, Ras, c-Raf, MAPK/ERK, SAPK/JNK, Stat, NFKB, PI-3 kinase, and c-Jun. Because of all these possible mechanisms, this translocation may be an important event in the initiation or progression of diseases in addition to CML.

The genetic profile of MDS is heterogeneous. Clonal chromosomal abnormalities occur in ~50% of successfully karyotyped cases of de novo MDS and in ~80% of secondary and therapy-related MDS.[3] These cytogenetic abnormalities form one of the cornerstones for prognostication of MDS according to International Prognostic Scoring System score. However, about 14% of the cytogenetic abnormalities seen in MDS have unknown prognostic significance.[3] In addition to the well-described karyotypic abnormalities, a number of molecular changes associated with genes such as Ras, NF1, Core binding factor complex, WT1, and cell cycle-related genes have been encountered in variable proportions of cases. It is also a well-known fact that neither all molecular genetic changes are reflected in cytogenetic abnormalities, nor all the cytogenetic abnormalities are translated into defined molecular genetic events. With the advent of newer molecular modalities, a number of gene expression profiles have been also published.[2],[4] In spite of all these, Ph/BCR-ABL1 positivity has rarely been reported in the literature and its significance is still poorly understood. A thorough literature search on PubMed could find no more than 40 cases of Ph+ MDS and less than half belonging to de novo category. All these cases from the recent to oldest are enlisted in [Table 2].
Table 2: Overview of literature of de novo Philadelphia + myelodysplastic syndrome cases

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Overall analysis of these reported cases has pointed toward a poor prognosis in Ph +ve MDS. In series described by Keung et al .,[1] all three cases progressed to more aggressive diseases such as granulocytic sarcoma and acute myeloid leukemia (AML). Similarly, the case described by Dutta et al .[6] showed basophilia in the peripheral blood, progressed in spite of imatinib administration and died soon of fungal pneumonia. Manabe et al .[7] also reported a case of MDS unclassifiable with late appearing Philadelphia chromosome along der(5;12)(q10;q10) which showed fatal outcome. Similar to these described cases, both the patients in the present report also died within a month of their initial diagnosis.

As of current understanding, presence of this translocation points toward hyperproliferation in the marrow because of increased tyrosine kinase activity. However, Ph +ve MDS cases present with peripheral cytopenia, and interestingly one of our cases had hypoplastic marrow as well. Another important and probably difficult issue is upfront administration of tyrosine kinase inhibitors in these cases. The literature does not provide convincing results. In series by Keung et al ., one case was treated with imatinib 400 mg/day. However, the cytopenias worsened, and patient progressed to AML. On the other hand, Drummond et al .[8] reported a case of Ph +ve MDS in a 67-year-old female with 10% blasts in the BM and bilineage dysplasia, who showed a complete cytogenetic response to imatinib 600 mg/day within 3 months and complete molecular remission after 14 months.

To summarize, though Ph+ MDS have not found their place as that of Ph+ ALLs, they are definitely a distinct rare entity. The presence of Philadelphia chromosome is not only an incidental finding but also probably points toward a poor prognostic group of MDS. Additional studies are required to ascertain their exact role in the biology and prognosis of MDS.


We would like to thank Dr. Sumaira Qayoom, Assistant Professor, Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


 > References Top

Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. Leuk Res 2004;28:579-86.  Back to cited text no. 1
Nowell PC, Hungerford DA. A minute chromosome in human granulocytic leukemia. Science 1960;132:1497.  Back to cited text no. 2
Chen G, Zeng W, Miyazato A, Billings E, Maciejewski JP, Kajigaya S, et al. Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood 2004;104:4210-8.  Back to cited text no. 3
Miyazato A, Ueno S, Ohmine K, Ueda M, Yoshida K, Yamashita Y, et al. Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction. Blood 2001;98:422-7.  Back to cited text no. 4
Seo BY, Lee JH, Kang MG, Choi SY, Kim SH, Shin JH, et al. Cryptic e1a2 BCR-ABL1 fusion with complex chromosomal abnormality in de novo myelodysplastic syndrome. Ann Lab Med 2015;35:643-6.  Back to cited text no. 5
Dutta S, Kumari P, Natraj KS, Mandal PK, Saha S, Bagchi B, et al . Philadelphia chromosome-positive myelodysplastic syndrome: Is it a distinct entity? Acta Haematol 2013;129:215-7.  Back to cited text no. 6
Manabe M, Yoshii Y, Mukai S, Sakamoto E, Kanashima H, Nakao T, et al. Late appearing Philadelphia chromosome as another clone in a patient with myelodysplastic syndrome harboring der(5;12)(q10;q10) at diagnosis. Rinsho Ketsueki 2012;53:618-22.  Back to cited text no. 7
Drummond MW, Lush CJ, Vickers MA, Reid FM, Kaeda J, Holyoake TL. Imatinib mesylate-induced molecular remission of Philadelphia chromosome-positive myelodysplastic syndrome. Leukemia 2003;17:463-5.  Back to cited text no. 8
Onozawa M, Fukuhara T, Takahata M, Yamamoto Y, Miyake T, Maekawa I. A case of myelodysplastic syndrome developed blastic crisis of chronic myelogenous leukemia with acquisition of major BCR/ABL. Ann Hematol 2003;82:593-5.  Back to cited text no. 9
Wakayama T, Maniwa Y, Ago H, Kakazu N, Abe T. A variant form of myelodysplastic syndrome with Ph- minor-BCR/ABL transcript. Int J Hematol 2001;74:58-63.  Back to cited text no. 10
Lesesve JF, Troussard X, Bastard C, Hurst JP, Nouet D, Callat MP, et al. p190bcr/abl rearrangement in myelodysplastic syndromes: Two reports and review of the literature. Br J Haematol 1996;95:372-5.  Back to cited text no. 11
Xue Y, Zhang R, Guo Y, Gu J, Lin B. Acquired amegakaryocytic thrombocytopenic purpura with a Philadelphia chromosome. Cancer Genet Cytogenet 1993;69:51-6.  Back to cited text no. 12
Mori H, Takahashi N, Tada J, Higuchi T, Shimizu T, Harada H, et al. RAEB transformed into AML (M0) showing Ph 1 chromosome and rearrangement of major cluster region. Rinsho Ketsueki 1993;34:1458-63.  Back to cited text no. 13
Verhoef G, Meeus P, Stul M, Mecucci C, Cassiman JJ, Van Den Berghe H, et al. Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes. Report of two cases and review of the literature. Cancer Genet Cytogenet 1992;59:161-6.  Back to cited text no. 14
Smadja N, Krulik M, Hagemeijer A, van der Plas DC, Gonzalez Canali G, de Gramont A. Cytogenetic and molecular studies of the Philadelphia translocation t(9;22) observed in a patient with myelodysplastic syndrome. Leukemia 1989;3:236-8.  Back to cited text no. 15
Toyama K, Ohyashiki K, Ohyashiki JH. Molecular implications of Ph (+) myelodysplastic syndrome. Adv Exp Med Biol 1988;241:67-71.  Back to cited text no. 16
Berrebi A, Bruck R, Shtalrid M, Chemke J. Philadelphia chromosome in idiopathic acquired sideroblastic anemia. Acta Haematol 1984;72:343-5.  Back to cited text no. 17
Roth DG, Richman CM, Rowley JD. Chronic myelodysplastic syndrome (preleukemia) with the Philadelphia chromosome. Blood 1980;56:262-4.  Back to cited text no. 18


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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