Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :782
Small font sizeDefault font sizeIncrease font size
Navigate here
Resource links
   Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
   Article in PDF (1,109 KB)
   Citation Manager
   Access Statistics
   Reader Comments
   Email Alert *
   Add to My List *
* Registration required (free)  

  In this article
   Article Figures
   Article Tables

 Article Access Statistics
    PDF Downloaded35    
    Comments [Add]    

Recommend this journal


  Table of Contents  
Year : 2021  |  Volume : 58  |  Issue : 3  |  Page : 463-468

Philadelphia-positive de novo myelodysplastic syndrome: A new entity with review of literature

1 Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Clinical Hematology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission03-Apr-2020
Date of Decision03-Jul-2020
Date of Acceptance06-Jul-2020
Date of Web Publication21-Jun-2021

Correspondence Address:
Rashmi Kushwaha
[email protected]
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_282_20

Rights and Permissions

How to cite this article:
Kushwaha R, Verma S P, Yadav G. Philadelphia-positive de novo myelodysplastic syndrome: A new entity with review of literature. Indian J Cancer 2021;58:463-8

How to cite this URL:
Kushwaha R, Verma S P, Yadav G. Philadelphia-positive de novo myelodysplastic syndrome: A new entity with review of literature. Indian J Cancer [serial online] 2021 [cited 2021 Dec 8];58:463-8. Available from: https://www.indianjcancer.com/text.asp?2021/58/3/463/318897

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by cytopenia, dysplasia in one or more of the major myeloid lineages, ineffective hematopoiesis, and recurrent genetic abnormalities.[1] Multiple genetic abnormalities have been described in the clonal evolution of MDS patients but BCR-ABL translocation has not been described as one among them.

Translocation t(9;22)(q34;q11.2) and its variants give rise to the Philadelphia chromosome (Ph). This translocation fuses the sequences of BCR gene on chromosome 22 with ABL1 on chromosome 9. BCR-ABL1 fusion gene is pathognomonic of chronic myeloid leukemia (CML) but it can also be found in 25% of de novo precursor B-cell acute lymphoblastic leukemia (ALL) in adults and 2-4% of childhood ALL. Less than 1% acute myeloid leukemia (AML) patients have BCR-ABL1 fusion.[2] The BCR-ABL1 fusion gene is rarely reported in MDS. Only a few cases have been described in literature and most of these cases have acquired it during transformation to acute leukemia. There are a very few cases of de novo Ph-positive MDS. It is so rare that this entity has not found a place in the cytogenetic abnormalities of MDS described in the World Health Organization (WHO) textbook of hematology.[1]

We hereby describe a case of MDS with the de novo occurrence of Ph chromosome.

A 30-year-old woman presented with fever, oral ulcers, and chest pain for one month. On examination she had pallor. The spleen was palpable 2 cm below the left costal margin. Biochemical parameters were serum lactate dehydrogenase (LDH) 1595 U/L, serum blood urea nitrogen (BUN) 24.2 μmol/L, and creatinine 282.8 μmol/L. A complete blood count revealed hemoglobin 52 gm/L, total leucocyte count, 7.5 × 109 cells/L, and differential counts, polymorphonuclear cells 76%, lymphocytes 12%, monocytes 8%, and blasts 04%. The peripheral smear showed anisocytic red blood cells and marked nuclear dysplasia in neutrophils in more than 90% of cells. The platelet count was 350 × 109/L. Bone marrow aspirate smear was normocellular and showed dysplasia in all the cell lineages. Erythroid precursors showed dysplasia in the form of nuclear irregularities, budding, and nuclear-cytoplasmic asynchrony. The granulocytic precursors showed dysplasia in the form of irregular nuclear lobulations and the presence of pseudo-pelger-huet cells, ringed nucleus. Seventeen percent of the blasts were also seen. Megakaryocytes showed nuclear dysplasia like nuclear hyperlobulation/hypolobulation. The Perl's stain for marrow iron did not show any ringed sideroblasts. The trephine biopsy was hypercellular for age and showed the presence of increased blasts on immunohistochemistry with CD34 [Figure 1], [Figre 2], [Figure 3].
Figure 1: Peripheral blood smear showing dysplastic neutrophils and blasts, Leishman, 100&w#215;

Click here to view
Figure 2: (a) Bone marrow imprint smears, hypercellular marrow, dysplastic cells and blasts. Leishman stain, 200×. (b) Bone marrow aspirate smears, dysplastic cells, and blasts. Leishman stain, 200×

Click here to view
Figure 3: (a) Bone marrow trephine biopsy, H and E, 100×. (b) Bone marrow trephine biopsy showing increased number of blast cells, immunohistochemistry (IHC) CD34, 400×

Click here to view

The estimated revised international prognostic scoring system (R-IPSS) score was 5.5, placing her in the high high-risk group.[1]

Based on history, clinical symptoms, and morphological features, the following two differentials were considered (a) Myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and (b) CML in accelerated phase.

The sample was evaluated for MDS-related cytogenetics. MDS fluorescence in situ hybridization (FISH) including probes for del(5q), del(7q), del(20q) and trisomy 8 were negative.

Karyotyping revealed 46 XX with t(9;22)(q34;q11.2). The qualitative reverse transcriptase polymerase chain reaction (RT-PCR) showed the BCR-ABL translocation (Major transcript, p210).

CML with accelerated phase was ruled out as our patient had only mild splenomegaly and no peripheral or marrow basophilia. There was an absence of significant myeloproliferation in the bone marrow and the marrow showed severe trilineage dyshemopoesis in more than 90% of cells. The lack of myeloproliferation, absence of basophilia, and presence of significant dyspoiesis favored clonal disorder unrelated to myeloproliferative neoplasm. The final diagnosis of Ph-positive MDS-EB-2 was made.

The patient was started on tyrosine kinase inhibitor, imatinib, 400 mg once a day as a single agent. However, she developed fatal pneumonia during the hospital stay and expired.

The t(9;22)(q34;q11.2) translocation gives rise to the Philadelphia chromosome. This translocation fuses the sequences of the BCR gene on chromosome 22 with ABL1 on chromosome 9 leading to the the formation of BCR-ABL1 fusion protein. This fusion protein leads to enhanced tyrosine kinase activity which contributes to cell proliferation, inhibition of differentiation, and resistance to apoptosis by the activation of various downstream signalling pathways like JAK-STAT, PI3-kinase, c-MYC, PI3K-AKT-mTOR pathway, RAS/RAF/MEK/ERK pathway, and c-Jun pathway. Based on the breakpoint site of the BCR gene, three different kinds of the fusion protein are produced: p190, p210, and p230. The BCR-ABL1 fusion gene is pathognomonic of CML. It can also be found in 25% of de novo B precursor ALL in adults, less than 1% patients with AML, and 17–35% adults with mixed phenotypic acute leukemia.[2],[3],[4]

Various chromosomal abnormalities have been detected in 50% of cases of de novo MDS and 80% of secondary MDS cases. These cytogenetic abnormalities form the basis of the comprehensive cytogenetic scoring system (CCSS) and R-IPSS.[1]

Ph chromosome is extremely rare in MDS patients and usually is seen in the leukemic transformation of MDS.

On literature review using PubMed, we found around 30 cases of Ph-positive MDS and 20 cases are de novo Ph-positive. All these cases are briefly described in [Table 1].
Table 1: Characteristics of MDS Patients with de novo Philadelphia Chromosome

Click here to view

Recognition of this entity is important as clear guidelines do not exist for the treatment of these patients. These patients usually show poor response to conventional chemotherapy.

Most of the cases of de novo Ph-positive MDS have associated chromosomal abnormalities like del(5q), del(20q), del(7q), del(13q), loss of Y chromosome, gain of chromosome 8, or certain other balanced translocation. Contrary to this, our case did not show any other associated chromosomal abnormality.

Approximately 50% of de novo Ph-positive MDS cases reported in literature also did not have any other associated chromosomal abnormality.[5],[9],[10],[13],[14],[16],[18],[19]

BCR-ABL along with other complex karyotypic abnormalities is associated with poor survival.[5]

Both conventional cytogenetics and FISH can be used to find the cytogenetic abnormality. Conventional karyotyping analyzes only 20 metaphase cells and FISH analysis is limited to regions with predetermined probes but it can detect chromosomal abnormality with high resolution. Hence, it is judicious to use both techniques in conjunction. Literature review of de novo Ph-positive MDS shows many cases that had normal conventional karyotyping and the Ph chromosome was detected by FISH or RT-PCR.

The literature review showed that most cases of de novo Ph-positive MDS had increased blasts in marrow at the time of diagnosis and showed poor survival, highlighting the fact that the Ph chromosome has bad prognostic significance in MDS.

Although retrospective analysis shows only 20 cases of de novo Ph-positive MDS, this does not reflect the true incidence because of a lack of careful examination of BCR-ABL fusion in all the MDS cases diagnosed. Even if the karyotyping is normal in these MDS patients, BCR-ABL fusion should be checked by other techniques like FISH or RT-PCR. More studies need to be done to justify the role of imatinib in these cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Hasserjian RP, Orazi A, Brunnibg RD, Germing U, Le Beau MM, Baumaann I, et al. Myelodysplastic syndromes: Overview. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al, editors. WHO Classification of Tumours of Hematopoetic and Lymphoid Tissues. Lyon, France: IARC press; 2017. p. 98-120.  Back to cited text no. 1
Borowitz MJ, Chan JKC, Downing JR, Le Beau MM, Arber DA. B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al, editors. WHO Classification of Tumours of Hematopoetic and Lymphoid Tissues. Lyon, France: IARC press; 2017. P. 203-9.  Back to cited text no. 2
Kang Z-J, Liu Y-F, Xu L-Z, Long Z-J, Huang D, Yang Y, et al. The Philadelphia chromosome in leukemogenesis. Chin J Cancer 2016;35:48.  Back to cited text no. 3
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.  Back to cited text no. 4
[PUBMED]  [Full text]  
Armas A, Chen C, Mims M, Rivero G. Uncovering clinical features of de novo Philadelphia positive myelodysplastic syndrome. Case Rep Hematol 2017;2017:5404131.  Back to cited text no. 5
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. 6
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. 7
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. 8
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. 9
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. 10
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. 11
Lesesve JF, Troussard X, Bastard C, Hurst JP, Nouet D, Callat MP, et al. p190(bcr/abl) rearrangement in myelodysplastic syndromes: Two reports and review of the literature. Bri J Haematol 1996;95:372-5.  Back to cited text no. 12
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. 13
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. 14
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. 15
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. 16
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. 17
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. 18
Roth DG, Richman CM, Rowley JD. Chronic myelodysplastic syndrome (preleukemia) with the Philadelphia chromosome. Blood 1980;56:262-4.  Back to cited text no. 19


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


Print this article  Email this article


  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow