ABC of clinical haematology: The myelodysplastic syndromesBMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7084.883 (Published 22 March 1997) Cite this as: BMJ 1997;314:883
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Asmida Isa BSc (1), Nur Nadzirah binti Mohamed (2),Faridah binti Mohd Idris (2),
Khairunnajwa binti Khairuddin (2),Zulzhafi bin Abd Razak (2), Tanu Pramanik BSc.MA.DSc (3) Narazah Moh Yusoff MBBS.PhD (4),Jogenananda Pramanik MBBS.MD.DSc (5)
Affiliations: 1) Doctoral scholar, AMDI/USM, Malaysia 2) Research students, MD-UKM-AUCMS, Malaysia 3) Research Supervisor, AUCMS, 4) Head of Regenerative Medicine Cluster, AMDI/USM. Malaysia, 5) Director of Post Graduate Studies, AUCMS, Malaysia and Research Consultant to Regenerative Medicine Cluster, AMDI/USM, Malaysia.
Background: Unexplained refractory anemia associated with ring sideroblasts is regarded as a critical pre-cancerous condition that affects individuals of any age but predominantly affects geriatric population, and therefore, demands in-depth investigation including systematic chromosomal analysis. The author of the current clinical review, David G Osier, deserves sincere applause for his comprehensive review on clinico-pathological features of myelodysplastic syndrome emphasizing common diagnostic dilemmas.(1) He reported that impaired ability to metabolize and detoxify potential carcinogen or impaired DNA repair mechanisms, is currently being investigated as one of the prime background mechanism for myelodysplastic syndrome. According to his report, myelodysplastic syndrome is commonly found to be an incidental finding in elderly patients whose routine blood count shows an unexplained anemia, macrocytosis, neutropenia, monocytosis or thrombocytopenia. The author recommended that chromosomal analysis is absolutely necessary in all those cases where morphological diagnosis seems to be difficult (1).
Despite several alarming reports published in national and international journals since 1970 , the importance of rigorous laboratory investigations for unexplained refractory anemia is commonly underestimated in resource poor health care settings of developing countries.
Cytogenetic studies: With the advent of advanced analytical techniques such as multicolor fluorescence in situ hybridization (M-FISH), Spectral karyotyping (SKY), DNA microarray techniques, Array based comparative genomic hybridization (CGH), tiling microarray techniques etc., a number of chromosomal aberrations have been demonstrated in patients with refractory anemia with ring sideroblasts (RARS) and others.
In recent years, various cytogenetic aberrations causing RARS have been documented such as 5q- chromosome (20% of refractory anemia with ring sideroblasts and clonal aberrations), 11q deletion (20% of the cases), 20q deletion ( 5% of all MDS ) including 10-15% of RARS with abnormal karyotype.(2) Other chromosome aberrations in RARS include trisomy 8 in 20% of cytogenetically abnormal cases and -7/7q- or 11q- in < 5% of the abnormal cases (2).
On rare occasions, trisomy 11 in myelodysplastic syndrome has been reported that revealed a unique group of aggressive clinico-pathologic features (3). In the International Prognostic Scoring System (IPSS), it is assigned under the intermediate-risk group with undefined clinical significance and is not associated with any French-American-British (FAB) classification. It is observed that, MDS patients with trisomy 11 have a shorter overall survival rate and represent an early evolving stage of acute myeloid leukemia (AML). (4) Most of these patients die due to cytopenias, while many of them transform to acute myeloid leukemia and therefore, this form of refractory anemia with myelodysplasia is often referred to as pre-leukemic state (5).
Refractory anemia, myelodysplastic syndrome and acute myeloid leukemia are no more considered as a disease of geriatric population exclusively. MDS or pre-leukemia was reported in 17% of childhood AMLs (2.9% of all children with leukemia).(6) Other studies confirmed that a pre-leukemic phase precedes AML in about 12-20% of children with AML.(7)
Although MDS is a clonal, neoplastic stem cell disorder associated with several well-recognized unbalanced cytogenetic abnormalities, the initial DNA damage (that permits the emergence of a hematopoietic clone) is believed to precede the induction of these common abnormalities (8). As such, a model of stepwise genetic progression has emerged to explain the development and evolution of MDS (9).In this model, a primary event—inherited or acquired—incites the initial DNA damage and subsequently increases the susceptibility of the cell to further injury. Subsequent events then may promote acquisition of the cytogenetic abnormalities common to MDS and may precipitate additional abnormalities that may be submicroscopic and, therefore, beyond traditional karyotypic detection but that profoundly affect cell cycle regulation, survival, and proliferation.(10)
Collaborative research project: Till recently, few cases of unexplained refractory anemia have been reported from Malaysian Research Institutes after systematic chromosomal analysis (11-14). At present, researchers from Allianze University College of Medical Sciences, Malaysia, are screening patients at different teaching hospitals to identify refractory anemia cases in collaboration with researchers at AMDI/USM, Malaysia, who are analyzing chromosomal anomalies in unexplained refractory anemia cases using advanced molecular techniques.
Conclusion: Medical News Today of American Cancer Society reported that 14,000 people are diagnosed with myelodysplastic syndrome each year in the US (15). We sincerely hope that routine application of genomic and proteomic microarray analyses in the study of refractory anemia may offer new insights into the pathogenesis and may reveal unique submicroscopic features of chromosomal aberrations to detect these pre-leukemic conditions at an early stage with promising prognostic outcome.
1. Clinical Review: ABC of clinical haematology: The myelodysplastic syndromes:BMJ 1997; 314
2. Cuneo A, Castoldi GL . Refractory anemia with ringed sideroblasts (RARS). Atlas Genet Cytogenet Oncol Haematol. November2003.
3. Wang SA, Jabbar K, Lu G, Chen SS,et al. Trisomy 11 in myelodysplastic syndromes defines a unique group of disease with aggressive clinicopathologic features. Leukemia. 2010 Apr;24(4):740-7. Epub 2010 Jan 14.
4. Mufti GJ, Stevens JR, Oscier DG,et al.: Myclodysplastic syndromes: a scoring system with prognostic significance. BrJ Haematol 1985;59:425-33.
5. D A G GALTON: Research Article: The myelodysplastic syndrome:BMJ1989;299doi:http://dx.doi.org/10.1136/bmj.299.6699.582 : BMJ 1989;299:582.
6. Blank J, Lange B. Preleukemia in children. J Pediatr. Apr 1981;98(4):565-8. [Medline].
7. Greenberg PL, Mara B. The preleukemic syndrome: correlation of in vitro parameters of granulopoiesis with clinical features. Am J Med. Jun 1979;66(6):951-8. [Medline].
8. Emanuel PD. Myelodysplasia and myeloproliferative disorders in childhood: an update. Br J Haematol. 1999;105:852-863.
9. Hellstrom-Lindberg E, Willman C, Barrett AJ, et al.:Achievements in understanding and treatment of myelodysplastic syndromes. Hematology 2000: American Society of Hematology Education Program Book.Washington,
DC: American Society of Hematology; 2000:110-132.
10. Jo-Anne Vergilio, MD, and Adam Bagg, MD:Myelodysplastic Syndromes:Contemporary Biologic Concepts and Emerging Diagnostic Approaches: Am J Clin Pathol 2003;119(Suppl 1):S58-S77 DOI: 10.1309/T8DFXEXMYLHW51DG
11. Marini R, W. Zaidah W.A, Suhair A et al.: Sideroblastic Anaemia- In A Malay Family Med J Vol 4 No 2 December 2005
12. Yin Yin Lee, Ping Chong Bee, Chew Kek Lee et al., Bullous Pemphigoid in an Elderly Patient with Myelodysplastic Syndrome and Refractory Anemia Coupled with Excess of Blast: Ann Dermatol. 2011 December; 23(Suppl 3): S390–S392. doi: 10.5021/ad.2011.23.S3.S390
13. Zainina S, Cheong SK. Myelodysplastic syndrome transformed into Acute Lymphoblastic Leukaemia (FAB:L3): Clin Lab Haematol. 2006 Aug;28(4):282-3.
14. Mohadese Hashem Broojerdi, Rajesh Ramasamy, Sabariah Md Noor et al. :Qualitative Flow Cytometric Analysis of Malaysian Myelodysplastic Syndromes (MDS) Patients: Med J Malaysia Vol 67 No 1 February 2012
15. Statistics by Country for Myelodysplastic syndromes: http://www.rightdiagnosis.com/m/myelodysplastic_syndromes/stats-country.....
Competing interests: No competing interests