1. Myelodysplastic Syndrome
Ahmad Sh. Silmi
Msc Haematology, FIBMS

2. What Is Myelodysplastic Syndrome?
The myelodysplastic syndromes are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction.
In MDS the bone marrow cannot produce blood cells effectively, and many of the blood cells formed are defective.
These abnormal blood cells are usually destroyed before they leave the bone marrow or shortly after entering the bloodstream.
As a result, patients have shortages of blood cells, which are reflected in their low blood

3. Characteristics
Varying degree of tri-lineage cytopenia ( red blood cells, white blood cells and platelets).
Dysplasia
Normocellular or hypercellular B.M.
May progress to acute leukaemia

4. Signs and Symptoms
Excessive tiredness, shortness of breath, and pale skin can be caused by anemia (shortage of red blood cells).
Serious infections with high fevers can be caused by leukopenia (not having enough normal white blood cells) and, in particular, by having neutropenia or granulocytopenia (too few mature granulocytes).
Excessive bruising and bleeding, for example, frequent or severe nosebleeds and/or bleeding from the gums, can be due to thrombocytopenia (not having enough of the blood platelets needed for plugging holes in damaged blood vessels).

5. Incidence
1- Disease of elderly. 2- Median age is 65 years. 3- <10% are younger than 50 years. 4- Incidence rates 1/100,000 pop./ years. 5- Incidence rise to 1/1000 / years in > 60 years old. 6- Male slightly higher than female

6. MDS Etiology Two etiologic categories of MDS:
1.) De Novo:
Associated with:
-benzene exposure (gasoline)
-cigarette smoking
-viruses Fanconi’s anemia
2.) Therapy related:
-alkylating agent chemotherapy
-radiation

7. Aetiology
This shows the tow arms of haemopoiesis

8. This shows how stem cell is affected

9. Aetiological Agents Tobacco smoke. Ionizing radiation.
Organic chemicals (such as benzene, toluene, xylene, and chloramphenicol).
Heavy metals.
Herbicides.
Pesticides.
Fertilizers.
Stone and cereal dusts.
Exhaust gases.
Nitro-organic explosives.
Petroleum and diesel derivatives.
Alkylating agents.
Marrow-damaging agents used in cancer chemotherapy.

10. Chromosomal abnormalities and MDS
Chromosomal abnormalities are present in up to 50%of de novo cases of MDS and in virtually all cases of secondary MDS. The most common are:
Abnormality q- 7q- 11q- 12q- 13q- 20q- inv3 i(17q) t(1;3) t(1;7) t(3;3)
Frequency(%)

11. Deletion of the long arm of chromosome 5 (5q- syndrome )
Strongly associated with RA.
5q- accounts for up to 70% of cytogenetic abnormalities in this subtype.
The q arm of chromosome 5 is particularly rich in genes, which encoded haemopoietic growth factors and their receptors. For example , IL-3 , IL-4 , IL-5 , GM-CSF and the M-CSF receptor are located in this region.
The potential for the loss of any or all of these genes contribute to the disruption of ordered haemopoiesis.

12. Monosmy 7 and 7q- Most strongly associated with secondary MDS.
Associated with the loss of a major surface glycoprotein (gp 130) in neutrophile and susceptibility to bacterial infection secondary to impaired granulocyte monocyte chemotatic activity.

13. Deletion of the q arm of chromosome 11 (11q-)
Account for 20% of the chromosomal abnormalities in RAS.
This abnormality is associated with raised iron stores and high ring sidroblast counts.
The presence of the gene , which encoded the H-subunit of ferritin at chromosome 11 , may explain this

14. Abnormalities of chromosome 17 (i17q)
It involves the loss or disruption of the Р53 tumor suppressor gene are seen in CML in association with transformation to the blastic phase and in up to 5% of cases of primary MDS.
This predisposes to certain dysplastic features and neutrophil vaculation.

15. Abnormalities of chromosome 3
Dysmegakaryopiesis and thombocytosis appear to be associated with Abnormalities of chromosome 3

16. The importance of indication of chromosomal abnormalities
To confirm diagnoses .
To know the stage of disease.
To know the direction of progression of disease.
Multiple genetic abnormalities indicate late events in MDS.

17. Patterns of MDS evolution
A stable group with no increase in B.M blasts and a normal karyotype .
Rapid blast transformation with acquisition of new cytogenetic changes after an initial , stable phase .
Gradually increasing blast count in the absence of new cytogenetic changes .

19. FAB classification scheme in 1985 for MDS

20. Refractory Anemia RA Definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic therapy
Myeloblasts < 1% blood and < 5% marrow
<15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of erythroid abnormalities must be excluded. These include:
drug/toxin exposure vitamin deficiency
viral infection congenital disease

21. Refractory Anemia Epidemiology: 5-10% of MDS cases. Older patients
Morphology:
Anisopoikilocytosis on peripheral smears
Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)
< 15% ringed sideroblasts

22. Refractory Anemia Genetics: 25% may have genetic abnormalities
Prognosis:
Median survival is 66 months
6% rate of progression to acute leukemia

23. Peripheral Smear - Anisopoikilocytosis

24. Dyserythropoeisis on Bone Marrow Aspirate

25. Megaloblastoid Change on Bone Marrow Aspirate

26. Refractory Anemia with Ringed Sideroblasts
RARS definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic therapy
Myeloblasts < 5% in marrow, absent in blood
>15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of ringed sideroblasts must be excluded. These include:
Anti- tuberculosis drugs
Alcoholism

27. Refractory Anemia with Ringed Sideroblasts
Epidemiology:
10-12% of MDS cases.
Older patients
Males > females
Morphology:
Dimorphic pattern on peripheral smears
Majority RBC’s normochromic, 2nd population hypochromic
Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)

28. Refractory Anemia with Ringed Sideroblasts
Morphology (con’t.)
< 15% ringed sideroblasts (RS)
RS = Erythroid precursor with ≥ 10 siderotic granules encircling 1/3 or more of the nucleus.
If excess blasts present, this dictates diagnosis, despite percentage of RS’s.

29. Refractory Anemia with Ringed Sideroblasts
Genetics:
Clonal chromosomal abnormalities in
<10%; in fact, development of such an abnormality should prompt reassessment of diagnosis.
Prognosis:
Median survival 6 years (72 months)
1-2% rate of progression to acute leukemia

30. Dimorphic Red Cell Population

31. Ringed Sideroblasts

32. Ringed Sideroblasts

33. Megaloblastoid Change

34. Refractory Anemia with Excess Blasts
RAEB definition:
Refractory anemia with 5-19% myeloblasts in the bone marrow.
RAEB-1:
5-9% blasts in bone marrow and <5% blasts in blood.
RAEB-2:
10-19% blasts in the bone marrow
Auer rods present

35. Refractory Anemia with Excess Blasts
Epidemiology: 40% of MDS cases.
Older patients (over 50 years)
Morphology:
Dysplasia of all three cell lines often present
Neutrophil abnormalities may include:
Hypogranulation hypersegmentation
Pseudo-Pelger-huet (hyposegmentation/barbells)
Pseudo Chediak-Higashi granules
Megkaryocyte abnormalities may include
Hypolobation Micromegakaryocytes

36. Refractory Anemia with Excess Blasts
Morphology (con’t.)
Erythroid precursor abnormalities may include:
Abnormal lobulation -megaloblastoid change
Multinucleation
0-19% myeloblasts in the blood
5-19% in the marrow
Bone marrow:
Usually hypercellular (10-15% hypocellular)
Abnormal localization of immature precursors (ALIP) may be present
Immunophenotype:
Blasts express CD 13, CD33 or CD117
The only MDS with a relevant phenotype

37. Refractory Anemia with Excess Blasts
Genetics:
Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include:
– – del(5q)
– – del(7q) – Complex karyotypes
Prognosis:
Median survival, RAEB-1 = 18 months
Median survival, RAEB-2 = 10 months
RAEB-1 = 25% rate of progression to acute leukemia
RAEB-2 = 33% rate of progression to acute leukemia

38. Hypercellular Bone Marrow

39. Blasts and Hypogranulation

40. Myeloblast with Auer Rod

41. Chediak-Higashi-like Granules
Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology

42. Refractory Anemia with Excess Blasts in Transformation (RAEB-t)
21-30 percent blasts in the marrow; more than 5 percent in the bloodstream
excessive numbers of monocytes (a type of white blood cell)
normal or hypercellular (filled with cells) marrow
accounts for about 25 percent of cases

43. Chronic Myelomonocytic Leukemia (CMMOL)
5-20 percent blasts in the marrow; less than 5 percent in the bloodstream
cytopenia of at least two cell lines
normal or hypercellular (filled with cells) marrow
accounts for 15 to 20 percent of cases.

44. CMML Splenomegaly (10%) Maculopapular skin infiltration
Monocytic pleural or pericardial effusion
JMML (MPD/MDS)
Pallor, bleeding, hepatosplenomegaly, skin involvement

45. WHO Refractory anemia Refractory anemia e ringed siderblast
Refractory cytopenia e multilineage dysplasia
Refractory cytopenia e multilineage dysplasia & ringed sideroblasts
Refractory anemia e excess blast-1
Refractory anemia e excess blast-2
Myelodysplastic syndrome unclassified
MDS associated e isolated del (5q)

46. WHO Bone Marrow Blood Subtype Anemia RA RARS RCMD RCMD-RS
Erythroid dysplasia only
Anemia RA
Erythroid dys
>15% ringed
RARS
>10%Dysp in 2 or more cell lineage
Bi- pancytopenia
RCMD
>10%Dys 2 or more cell lineage
Bi-pancytopenia
RCMD-RS

47. WHO Bone Marrow Blood subtype RAEB-1 RAEB-2 MDS-U MDS with 5q
Uni-multilineage dys, 5-9%blast
Cytopenia
<5% blast
RAEB-1
Uni-multi dys
10-19%blast
Or Auer rods
Cytopenia,
5-19%blast or Auer rods
RAEB-2
Myeloid or megakaryocte dys
cytopenia
MDS-U
Mega e hypolobated nuclei, <5%blast
Anemia,nor or increased PLT
MDS with 5q

48. Relation FAB & WHO WHO FAB RA RARS RAEB RAEBt CMML RA(unilineage) RCMD
5q-syndrome RA
RARS(unilineage)
RCMD-RS
RARS
RAEB-1
RAEB-2
RAEB
AML e multilieage dys
AML & MDS-TR
RAEBt
Myelodysplastic/ myeloproliferative disease
CMML

49. Prognostic Groups
Two groups based on survival and evolution to acute leukemia
1.) “Good” group
Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)
5q - syndrome
2.) “Bad” group
Refractory anemia with excess blasts (RAEB)
Refractory anemia with excess blasts in transformation (RAEB-t)
CMML
MDS unclassified can be either

50. International Prognostic Scoring System (IPSS) Factors
the percentage of blasts in the bone marrow.
whether chromosome abnormalities are present and, if so, which ones.
how low the patient's blood counts are. These are given a score; the lowest scores have the best outlook for survival.

51. Prognostic Scoring 0.5 1.0 1.5 2.0 <5 5-10 -- 11-20 20-30 0-1 2-3
The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables:
0.5
1.0
1.5
2.0
% Blasts
<5
5-10 --
11-20
20-30
Karyotype
Normal, -Y, del(5q), del(20q)
Abnormal-ities
NOS
≥ 3 abnormalities, chr 7 abnormalities
Cytopenia
0-1
2-3

52. Differential Diagnosis
Several common diagnostic considerations given these findings including:
Causes of bone marrow failure(idiopathic or drug-induced aplasia)
Hypersplenism
Vitamin B12 or folate deficiency
(PNH)– can have similar BM findings and MDS.

54. Pathophysiology
The initial hematopoietic stem cell injury can be from cytotoxic chemotherapy, radiation, virus, chemical exposure, or genetic predisposition.
A clonal mutation predominates over bone marrow, suppressing healthy stem cells.

55. Laboratory Finding Peripheral blood : Bone Marrow:
Red blood cells : ovalmacrocytosis , hypochromia.
WBCs: promyelocyte and hyposegmentation.
Platelet: large , dysplastic forms.
Bone Marrow:
RBCs : erythroid hyperplasia , megaloblastic appearance and dyserythropoiesis with excess sidroblasts.
WBCs: abnormal monocyte maturation and granulocyte maturation bulge.
Platelet: megakaryocytosis and dysthrombopoiesis.

56. Erythrodysplasia
Major changes are found in the peripheral blood counts and morphology, and bone marrow abnormalities also are present.
The peripheral blood counts, (CBC) and blood film :
Premature red cell death .
Anemia will vary in degree from mild to severe
Macro - ovalocytosis
Basophilic stippling .
Decreased reticulocyte count .
Nucleated RBC,s .
blood indices:
(Increased MCV, decreased MCHC, decreased MCH )

57. Leucodysplasia Number of WBC,s is Variable . Neutropenia .
Monocytosis .
Increased Promyelocyte .
Hyposegmented Neutrophil .
Hypogranular PMNs .
Circulating metamylocytes .
Decreased myeloperoxidase and alkaline phosphatase activity

58. Thrombodysplasia
Thrombocytopenia and Large , atypical platelets

59. Bone Marrow Erythrodysplasia : Leucodysplasia: Thrombodysplasia:
- Ringed sideroblast, Hyponucleated RBC,s and
condensed chromatin pattern .
Leucodysplasia:
Myeloid hyperplasia .
Partial maturation arrest at myelocyte stage .
Thrombodysplasia:
Increased number of bizarre megakaryocytes
Micromegakaryocytes
Mononucleas

61. Survival Time
Refractory anemia : Survival time varies from 2 to 5 years in most series
Refractory anemia with ringed sideroblasts : The same like RA.
Refractory anemia with excess blasts : Median survival for RAEB-2 is approximately 10 months.
Refractory anemia with excess blasts in transformation: median survival time is 6 months or less.

62. Median Survival – Myelodysplastic Syndromes

63. Treatment Chemotherapy.
Supportive therapy, such as WBCs, RBCs, Platelets transfusions.
B.M transplantation in young patients.