ANATOMY AND PHYSIOLOGY OF REPRODUCTIVE SYSTEM.pptx
Myelodysplasticsyndromes
1. MYELODYSPLASTIC SYNDROME
PRESENTED BY-DR.SURENDRA GHINTALA
MODERATED BY-DR. K. BHATTACHARJEE
(Associate professor))
“We are put off by the fact that MDS is a
heterogenous vaguely defined group of
conditions with seemingly ever changing names
2. • First described in 1900 by Leube who used the term
“Leukanamie”
• Subsequently it had undergone a trial of jargon
30’s - Refractory anemia
40’s- Preleukemic anemia
50’s- Preleukemia/RARS/ Refractory normoblastic anemia
60’s-Smoldering acute leukemia
70’s –CMML/Refractory anemia with excess myeloblasts
• 1982- Myelodysplastic syndrome (Benett et al )
3. Our bone marrow is the spongy tissue inside some of
our bones, mainly flat bones. It contains immature
cells, called stem cells. The stem cells can develop into
the red blood cells that carry oxygen through our
body, the white blood cells that fight infections, and
the platelets that help with blood clotting. If we have
a myelodysplastic syndrome, the stem cells do not
mature into healthy blood cells. This leaves less room
for healthy cells, which can lead to infection,
anemia,bleeding.
4. • WHO definition 2008
• A group of clonal hematopoietic stem cell diseases
characterized by
Cytopenia
Dysplasia in one or more major myeloid cell lines
Ineffective hematopoiesis
Increased risk of development of AML
5. INCIDENCE
• Idiopathic MDS is a disease of the elderly; the mean age at
onset is older than 70 years.( in india > 45 yrs)
• There is a slight male preponderance .
• MDS is a relatively common from of bone marrow failure,
with reported incidence rates of 35 to >100 per million person
in the general population and 120 to >500 per million in the
older adult.
• MDS is a rare in children, but monocytic leukemia cab be
seen.
• Secondary or therapy-related MDS is not age related.
6. The threshold for cytopenia as recommended by the IPSS for
risk stratification are
• Hb < 10 g/dl
• Absolute neutrophil count< 1800/uL
• Platelets < 1 lakh/uL
7. • PREDISPOSING FACTORS
HEREDITARY
A) Constitutional genetic disorders
Downs Syndrome: 10-30 times more risk
Trisomy 8 : Seen in 50% cases of MDS
Monosomy 7 : Seen in 50% cases of MDS.
B) Neurofibromatosis
C) Congenital neutropenia syndrome
Kostmann Agranulocytosis
Shwachman Diamond syndrome
8. • D) DNA repair defects
Fanconi anemia,
Ataxia telangiectasia
Bloom syndrome
• E) Mutagen detoxification(GSTq1-null)
Glutathione-S-Transferase. Studies show that GST- q1null
genotype increases risk by 4 times.
.
9. • ACQUIRED
These factors play a major role in secondary MDS/ t-MDS
a)Mutagen exposure
1.Genotoxic therapy- alkylating agents
2. Beta-emitter phosphorus; Used in the treatment of
Polycythemia Vera- 10-15% increased risk.
3. Topoisomerase(Topo-II) interactive agents like
anthracycline, etoposide.
4. Autologous stem cell transplantation- long term survivors
10. b) Environmental /occupational exposures
Exposure to benzene-5-20 fold increase in risk.
Other agents like solvents, petrochemicals,Insectide
c) Tobacco
Tobacco smoke contains a number of leukemogens like
nitrosamines, benzene and polonium-210
d) Senescence
e) Aplastic anemia
13. FAB CLASSIFICATION OF MDS
• 1%BLAST
SUBTYPE BLOOD BONE MARROW
REFRACTORY
ANEMIA(RA)
<1%BLASTS DYSPLASIA;
<5%BLASTS
REFRACTORY
ANEMIA WITH
RINGED
SIDEROBLASTS(
RARS)
<1%BLASTS DYSPLASIA;
<5%BLASTS;
>15%RINGED
SIDEROBLASTS
REFRACTORY
ANEMIA WITH
EXCESS
BLASTS(RAEB)
<5%BLASTS DYSPLASIA;
5-19%BLASTS
14. contd
SUBTYPE BLOOD BONE MARROW
REFRACTORY ANEMIA
WITH EXCESS BLASTS
IN TRANSFORMATION
(RAEBt)
> 5%BLASTS DYSPLASIA;
20-29%BLASTS OR AUER
RODS
CHRONIC
MYELOMONOCYTIC
LEUKEMIA(CMML)
>1X109/L MONOCYTES DYSPLASIA;
<30%BLASTS
15. WHO CLASSIFICATION OF MDS (2008)
SUBTYPE BLOOD BONE MARROW
REFRACTORY
CYTOPENIA WITH
UNILINEAGE
DYSPLASIA (RCUD)
REFRACTORY
ANEMIA (RA),
REFRACTORY
NEUTROPENIA(RN) ,
(REFRACTORY
THROMBOCYTOPENIA
(RT)
ANEMIA;
NO OR RARE BLASTS
UNICYTOPENIA
BICYTOPENIA
UNILINEAGE
DYSPLASIA > 10%
CELLS IN ONE
MYELOID LINE WITH
< 5% BLASTS
<15%RINGED
SIDEROBLASTS
REFRACTORY
ANEMIA WITH
RINGED
SIDEROBLASTS
ANEMIA;
NO OR RARE BLASTS
>15%RINGED
SIDEROBLASTS;
ERYTHROID
DYSPLASIA;
<5%BLASTS;
16. SUBTYPE BLOOD BONE MARROW
REFRACTORY
CYTOPENIA WITH
MULTILINEAGE
DYSPLASIA (RCMD)
BI / PAN CYTOPENIAS;
NO OR RARE BLASTS;
NO AUER RODS;
<1X109/L MONOCYTES
DYSPLASIA IN >10% OF
THE CELLS >2
MYELOID LINES
<5%BLASTS IN BM
>15%RINGED
SIDEROBLAST
NO AUER RODS
REFRACTORY ANEMIA
WITH EXCESS BLASTS
1
BI / PAN CYTOPENIAS;
< 5%BLASTS;
NO AUER RODS;
<1X109/L MONOCYTES
UNI OR MULTILINEAGE
DYSPLASIA;
5-9%BLASTS;
NO AUER RODS
REFRACTORY ANEMIA
WITH EXCESS BLASTS
2
CYTOPENIAS;
5-19%BLASTS;
AUER RODS PRESENT;
<1X109/L MONOCYTES
UNI OR MULTILINEAGE
DYSPLASIA;
10-19%BLASTS;
AUER RODS PRESENT
17. SUBTYPE BLOOD BONE MARROW
MYELODYSPLASTIC
SYNDROME,
UNCLASSIFIED(MDS-u)
CYTOPENIAS;
NO OR RARE BLASTS;
NO AUER RODS;
UNILINEAGE DYSPLASIA;
<5% BLASTS;
NO AUER RODS
5q-SYNDROME ANEMIA;
NORMAL/INCREASED
PLATELET COUNT;
<5%BLASTS
NORMAL/INCREASED
MEGAKARYOCYTES;
<5%BLASTS;
NO AUER RODS
CHILDHOOD MDS < 2 % BLASTS
DYSPLASTIC CHANGES IN
>10 % NEUTROPHILS
DYSPLASTIC CHANGES IN >
10 % ERYTHROID
PRECURSORS
DYSPLASTIC CHANGES IN >
10 % GRANULOCYTE
PRECURSORS
MICROMEGAKARYOCYTES,
DYSPLASTIC CHANGES IN
MGKS
18. SUBTYPE BLOOD BONE MARROW
MYELODYSPLASTIC
SYNDROME,
UNCLASSIFIED(MDS-u)
CYTOPENIAS;
NO OR RARE BLASTS;
NO AUER RODS;
UNILINEAGE
DYSPLASIA;
<5% BLASTS;
NO AUER RODS
5q-SYNDROME ANEMIA;
NORMAL/INCREASED
PLATELET COUNT;
<5%BLASTS
NORMAL/INCREASED
MEGAKARYOCYTES;
<5%BLASTS;
NO AUER RODS
CHILDHOOD MDS < 2 % BLASTS
DYSPLASTIC CHANGES
IN >10 % NEUTROPHILS
DYSPLASTIC CHANGES
IN > 10 % ERYTHROID
PRECURSORS
DYSPLASTIC CHANGES
IN > 10 %
GRANULOCYTE
PRECURSORS
MICROMEGAKARYOCY
TES,DYSPLASTIC
CHANGES IN MGKS
19. DIFFERENCES BETWEEN WHO AND FAB
The WHO system
• Makes use of cytogenetic findings.
• The category of RAEB-t was eliminated as it got included
within AML(>20%blasts).
• CMML was removed and put in a new category of
myelodysplastic/myeloproliferative diseases.
• Adds the subtypes 5q syndrome and unclassifiable MDS.
• Recognizes the prognostic importance of % of bone marrow
blasts
20. PATHOGENESIS
MDS : a stem cell disorder
• It represents manifestation of the malignant transformation of
myeloid stem cell
• The abnormal cells in MDS are clones derived from an
abnormal stem cell
Apoptosis in MDS
• Mechanism appears to be one of increased apoptosis of
haemopoietic precursors in the marrow,
• Presence of cytopenias despite a typically hypercellular bone
marrow.
• For those patients undergoing leukaemic transformation,the
cytopenias arise due to maturation block of the malignant cells
• Apoptosis is more prominent in early MDS, such as RA and
RARS, than in advanced MDS with excess myeloblasts
21. Ineffective Hematopoiesis
• Colony forming capacities of pleuripotent stem cells and their
progeny are low or absent
• Lower level of GM-CSF, M-CSF,IL 6 .IL 3,
• CFU- GM less responsive to both G-CSF & GM-CSF
• More dramatic in pts with RAEB or RAEB –t
Immunological abnormalities in MDS
• Commonly encountered in MDS, suggesting that they may
play a role in the aetiology and pathogenesis of the disease.
22. • Particularly apparent in cases of hypoplastic MDS that share a
number of features in common with aplastic anaemia, notably
clinical presentation with macrocytosis and varying levels of
dyserythropoiesis
• Acquired mutations in the PIG-A gene characteristic of
paroxysmal nocturnal haemoglobinuria (PNH) are also
encountered
Angiogenesis
• Autocrine production of angiogenic molecules promotes
expansion of leukemic clone
• Vascular endothelial growth factor(VEGF) and its receptor
VEGFR-1 And VEGFR-2 is overexpressed
23. Molecular basis of MDS
• MDS is a preleukaemic disorder characterized by impaired
cellular differentiation that has the potential to transform to
AML if this abnormality is coupled to enhanced survival and
proliferation.
• The common chromosomal abnormalities found in MDS
include loss of Y, monosomy 5, monosomy 7,trisomy 8, 20q – ,
abnormalities of 11q23, and deletions of 17p, 12p, 13q and 11q
among others.
25. Clinical features
• Asymptomatic - Many patients are diagnosed on routine
laboratory screening
• Fatigue, weakness, angina - as a result of anemia.
• Infections most commonly bacterial, predominate with skin
being the most common site. This is the most common cause
of mortality and morbidity in MDS.
26. • Autoimmune abnormalities (uncommon) - Seen in 14 %
of the patients. Most common is cutaneous vasculitis.
• Cutaneous manifestations of MDS
Sweet syndrome
Granulocytic sarcoma
28. • OTHER ERYTHROCYTE CHANGES
• Increase in fetal hemoglobin
• Altered A,B, antigens on the surface.
29. • LEUKOCYTES
Neutropenia - 2nd most common cytopenia
Dysgranulopoiesis is seen by agranular or hypogranular
neutrophils
Persistent basophilia of cytoplasm
Hyposegmentation (pseudo Pelger-Huet) of the nucleus
Hypersegmentation of the nucleus is seen sometimes
30. • OTHER DEFECTS
Enzyme defects such as
Decreased myeloperoxidase,
Decreased leukocyte alkaline phosphatase .
Causes functional impairment of the neutrophils like defective
bactericidal, phagocytic and chemotactic properties.
31. PLATELETS
• Varying degree of thrombocytopenia
• Platelets may show agranular/hypogranular cytoplasm
• Giant platelets are seen
• Micromegakarocytes are seen. They have a single lobe nucleus
with cytoplasmic tags. Nucleus shows densely clumped
chromatin.
32. BONE MARROW ASPIRATE
• Well stained BM aspirate smears
• At least 500 cells are to be counted
• At least 30 megakaryocyte to be evaluated
• Dysplastic features should be present in > 10 % cells
CELLULARITY
In most cases it is hypercellular
But is hypocellular in Hypoplastic MDS
33. Erythropoeisis
• Usually megaloblastic erythropoeisis
• Feature of dyserthropoiesis
• Some precursors may show Howell Jolly bodies
• Vacoulization , basophilia and poor hemoglobinisation
• Ring sideroblasts
• PAS stain – may show granular positivity of normoblasts
• Advanced cases – erythroid hypoplasia seen
34. Granulopoiesis
• Usually myeloid hyperplasia
• Hypogranulrity and hyposegmentation
• Maturation arrest in myelocyte stage may be seen
• Abnormal staining of primary granules seen in myelocyte &
promyelocytes. Granules may be larger than normal or
completely absent.
• Irregular cytoplasmic basophilia seen
35. • Thrombopoiesis
• Usually normal or megakaryocytic hyperplasia
• Micromegakaryocytes, multinucleated megakaryocytes , &
hypolobated megakaryocytes
• Presence of > 10 % Micromegakaryocytes in a population
suggests MDS
• CD 61 staining
36. TREPHINE BIOPSY IN MDS
Useful for determining
• Cellularity of marrow
• Abnormal localization of immature precursors (ALIP)
• Reticulin fibrosis, Megakaryocytic dysplasia, Lymphoid
aggregate
• Hypoplastic MDS
• Increases the diagnostic accuracy & helps in refining the
IPSS score
37. EVALUATION OF SUSPECTED MDS
• HISTORY
Prior exposure to CT/RT
Recurrent infections, bleeding gums
• EXAMINATION
Pallor/ bruising
Splenomegaly
• BLOOD COUNTS
Hb, TLC, platelet count reticulocyte count
• BLOOD FILM
Macrocytosis, cytopenia, neytrophilia, monocytosis pseudo
pelger huet anomaly,hypogranular neutrophils
38. • BONE MARROW ASPIRATE
• BONE MARROW TREPHINE BIOPSY
• BONE MARROW CYTOGENETICS ANALYSIS
• EXCLUSION OF REACTIVE CAUSES OF DYSPLASIA
Megaloblastic anaemia
HIV infection
Recent cytotoxic therapy
Alcoholism
Recurrent intercurrent infection
39. MINIMAL DIAGNOSTIC CRITERIA FOR MDS IN
CHILDREN
• At least two of the following
Sustained unexplained cytopenia( neutropenia,
thrombocytopenia , anemia)
At least bilineage morphological myelodysplasia
Acquired clonal cytogenetic abmormality in hematopoietic
cells
Increased blasts > 5%
40. DIFFERENTIAL DIAGNOSIS
1. Vitamin B 12 and folic acid deficiency
2. AML M6
3. HIV infection
4. Parvo virus B 19 infection
5. Exposure to arsenic and other heavy metals
6. Congenital Dyserythropoietic anemia
7. Paroxysmal nocturnal hemoglobinemia
8. G- CSF Therapy
41. IPSS risk-based classification system
Marrow blast percentage:
< 5 0
5-10 0.5
11-20 1.5
21-30 2.0
Cytogentic features
Good prognosis 0
(–Y, 5q- , 20q-)
Intermediate prognosis 0.5
(+8, miscellaneous single abnormality,
double abnormalities)
Poor prognosis 1.0
(abnor. 7, complex- >3 abnor.)
Cytopenias
None or one type 0
2 or 3 type 0.5
42. INTERNATIONAL PROGNOSTIC SCORING SYSTEM(IPSS)
RISK SCORE AML
TRANSFOR
MATION %
MEDIAN
SURVIVAL
(YEARS)
LOW 0 19 5.7
INTERMEDIATE -1 0.5- 1.0 30 3.5
INTERMEDIATE -2 1.5 -2.0 33 1.2
HIGH 2.5 45 0.4
43.
44. Applying WHO to Indian settings
• Indian MDS differs from MDS of West
Younger age at presentation
Cytopenias more severe at presentation
Patients opted for less aggressive treatment
Poorer treatment outcomes
Infections, nutritional disorders: commoner
Follow-up: Not always available
Majority of pts had MDS-RA, MDS RAEB 1 & 2
45. Treatment strategy
(lower risk MDS)
★Improve blood cytopenias
★ Improve quality of life
★ Delay disease progression
★ Prolong survival
The therapeutic strategy remains largely based on the IPSS(R).
47. Treatment of patients with MDS: goals and options
Clinically
significant
cytopenia(s)
Supportive care
Goals
● To reduce morbidity/mortality
due to cytopenias
● To improve QoL
Active therapy
Goals
● To alter the natural history
of MDS
● To improve survival
● To improve QoL
● To alleviate complications
Transfusions (+ iron chelation)
Growth factors
Treatment of infections
HSCT
Chemotherapy
• Intensive
• Low-dose
Hypomethylating agents
Azacitidine/decitabine
Lenalidomide,
immunosuppressive Rx
HSCT = haemopoietic stem cell
transplantation; QoL = quality of life.
48. CONCLUSION
• MDS can be effectively diagnosed and classified as per WHO
2008 classification
• MDS diagnosis and classification is currently in a transitional
phase from reliance almost entirely on cell morphology
supplemented by cytochemistry and G-banded karyotyping,
towards a new era in which molecular and perhaps
immunophenotypic findings will be fully incorporated
• But in developing countries it is essential to rule out
infections/ nutritional deficiencies especially among the
elderly before considering MDS
49. 1 .Which ONE of these is the most common
finding in myelodysplastic syndromes
(MDS)?
A Hypocellular bone marrow and reduced blood cell
counts
B Hypocellular bone marrow and increased blood cell
counts
C Hypercellular bone marrow and reduced blood cell
counts
D Hypercellular bone marrow and increased blood cell
counts
50. 2.Which ONE of these is NOT a feature of peripheral blood
cells in myelodysplastic syndromes?
A Increased haemoglobin concentration in red cells
B Macrocytic red cells
C Hypogranular neutrophils
D Bilobed nucleus in neutrophils
51. 3. What percentage of blast cells in the bone marrow would
indicate a diagnosis of acute myeloid leukaemia rather than
myelodysplasia?
A 5
B 10
C 20
D 30
52. 4. Which ONE of these is NOT a diagnostic subtype
of myelodysplasia?
A Refractory anaemia with ring sideroblasts
B Refractory anaemia with excess blasts
C Refractory cytopenia with unilineage dysplasia
D X‐linked sideroblastic anaemia
53. 5. What is the most likely treatment for a 75-year-old patient
with refractory anaemia and haemoglobin 9 g/dL?
A Azacytidine
B Stem cell transplantation
C Lenolidamide
D Trial of erythropoietin
54. 6. Which ONE of these is the most powerful predictive factor
in patients with myelodysplastic syndrome?
A Serum β2‐microglobulin
B Gender
C The number of blasts in the bone marrow
D The level of anaemia
55. 7.Which ONE of these is the most likely clinical picture in a
patient with myelodysplastic syndrome associated with
isolated del(5q)?
A A man with Hb < 13 g/dL and a platelet count of 600 × 109/L
B A woman with Hb <10 g/dL and platelet count of 600 × 109/L
C A woman with Hb <13 g/dL and platelet count 100 × 109/L
D A man with Hb <10 g/dL and platelet count 100 x 109/L
56. 8.In which patients with myelodysplastic syndrome is
ciclosporin most likely to be effective?
A Low risk disease with hypocellular bone marrow
B Low risk disease with hypercellular bone marrow
C High risk disease with hypocellular bone marrow
D High risk disease with hypercellular bone marrow
57. 1.>15% ringed sideroblasts
2.>30% ringed sideroblasts
3.dyshematopoiesis in all three cell lineages
4.pancytopenia
9.In addition to the number of blasts, what other criterion is
essential for a diagnosis of RARS?
58. A. lymphocytosis in the
peripheral blood
B.mature granulocytosis in
the peripheral blood
C.hypocellular bone
marrow
D. monocytopenia
9.CMML differs from the other subgroups of MDS because it has?
62. RA
RARS
RAEB
RAEB-t
USE THE FOLLOWING INFORMATION TO ANSWER QUESTIONS 12-14:
A patient presents with the following laboratory data:
RBC 2.30 x 1012/L
HGB 78 g/L
HCT 0.24 L/L
MCV 104 fL
RDW 20
WBC 8.5 x 109/L
PLT 140 x 109/L
The differential was normal except for 2% metamyelocytes. Oval macrocytes, a
few abnormal NRBC, and a few siderocytes were seen. The bone marrow
contained 3% blasts and exhibited hypercellularity with megaloblastoid
development in erythroid cells.
63. 12.What is the most probable MDS subgroup?
1.RA
2.RARS
3.RAEB
4.RAEB-t
65. 1.serum lysozyme
2.serum ferritin
3.serum folate
and vitamin B12
4.combined
esterase stain
14.In reference to question #13, what laboratory test(s)
would be helpful to distinguish the two disorders?
