Myelodysplastic Syndrome

1. PRESENTOR: DR. SUNANDINI DAS
JR2, DEPARTMENT OF PATHOLOGY
MODERATOR: DR. BHARAT SONWANE
ASSOCIATE PROFESSOR, DEPARTMENT OF PATHOLOGY
GMC,AURANGABAD
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2. INTRODUCTION
 Dysplasia: Greek word- Dys-Abnormal, Plasia- Formation
 FAB-1982-Introduced the word “Myelodysplasia”
 To describe the morphologic abnormalities of the myeloid cell lines of
hematopoesis in preleukemic conditions.
 WHO: Revised FAB classification.
 WHO classification of MDS- Useful in clinical decision making, revised twice,
in 2016
 Restratification of MDS done in 2022
 IPSS: The International Prognostic Scoring System(IPSS) for MDS-1977
 IPSS-R : revised in the year 2002
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3. DEFINITION
 The MDS are group of clonal hematopoietic
stem cell disorders characterised by:
 Cytopenias
 Dysplasia in one or more of the major myeloid
lineages
 Ineffective hematopoiesis
 Recurrent genetic abnormalities
 Increased risk of developing Acute Myeloid
Leukaemia(AML)
Normal Hematopoiesis
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4. WHO CLASSIFICATION OF MDS
4

5. Dysplastic
Lineage
Cytopenias RS as %age
of erythroid
BM and PB
blasts
Cytogenetic
s
MDS-SLD 1 1 or 2 < 15%/ <5% <5% BM,
<1% PB
Any
MDS-MLD 2 or 3 1-3 < 15%/ <5% <5% BM,
<1% PB
Any
MDS-RS with
SLD
1 1 or 2 > 15%/ >5% <5% BM,
<1% PB
Any
MDS-RS with
MLD
2 or 3 1-3 > 15%/ >5% <5% BM,
<1% PB
Any
MDS with
isolated
del(5q)
1-3 1 or 2 None or any <5% BM,
<1% PB
Del(5q)
Alone or with
one other
abnormality
WHO CLASSIFICATION OF MDS 2016
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6. Dysplastic
Lineage
Cytopenias RS as %age
of erythroid
BM and PB
blasts
Cytogenetics
MDS-EB1 0-3 1-3 None or any 5-9% BM,
2-4% PB
Any
MDS-EB2 0-3 1-3 None or any 10-19% BM,
5-19% PB or
Auer Rods
Any
MDS-
Unclassifiable
with 1% PB
blasts
1-3 1-3 None or any <5% BM,
=1% PB
Any
MDS-
Unclassifiable
with SLD &
Pancytopenia
1 3 None or any <5% BM,
<1% PB
Any
MDS-
Unclassifiable
based on
karyotype
0 1-3 <15% <5% BM,
<1% PB
MDS-
defining
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7. WHO 2022 CLASSIFICATION
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8. Blasts Cytogenetics Mutations
MDS WITH DEFINING
GENETIC ABNORMALITIES
MDS with low blasts and isolated
5q deletion (MDS-5q)
<5% BM and <2% PB
5q deletion alone, or with 1 other
abnormality other than monosomy 7
or 7q deletion
MDS with low blasts
and SF3B1 mutationa
(MDS-SF3B1)
Absence of 5q deletion, monosomy
7, or complex karyotype
SF3B1
MDS with
biallelic TP53 inactivation (MDS-
biTP53)
<20% BM and PB Usually complex
Two or more TP53 mutations, or 1
mutation with evidence of TP53 copy
number loss or cnLOH
MDS, MORPHOLOGICALLY
DEFINED
MDS with low blasts (MDS-LB)
<5% BM and <2% PB
MDS, hypoplasticb
(MDS-h)
MDS with increased blasts (MDS-
IB)
MDS-IB1 5–9% BM or 2–4% PB
MDS-IB2
10-19% BM or 5–19% PB or Auer
rods
MDS with fibrosis (MDS-
f)
5–19% BM; 2–19% PB
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9. DEFINITIONS
 CLONAL HEMATOPOIESIS(CH): Presence of a population of cells derived
from a mutated multipotent stem/progenitor cells harbouring a selective
growth advantage in absence of cytopenias, hematological cancers or other
clonal disorders. These are associated with increased overall mortality,
cardiovascular disease and myeloid malignancy.
 CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL(CHIP):
Defined in classification as a term referring specifically to CH harbouring
somatic mutations of myeloid malignancy associated genes detected in the
blood or bone marrow at a variant allele fraction(VAF) of > or equal to 2% in
individuals without a diagnosed hematological disorders or unexplained
cytopenias.
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10.  CLONAL CYTOPENIAS OF UNDETERMINED SIGNIFICANCE(CCUS):
CHIP detected in presence of one or more of the cytopenias that are otherwise
unexplained by hematological or non-hematological conditions and that donot
meet the diagnosed criteria for defined myeloid neoplasms.
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11. WHO MDS DEFINING MORPHOLOGY
DYSERYTHROPOIESIS:PB BONE MARROW
 Normocytic/Macrocytic/Normochromic/
Dimorphic with high RDW
 Hyperplasia
 Megaloblastoid changes
 Multinuclearity
 Internuclear and intercytoplasmic
bridging
 Ring sideroblast
 Irregular hemoglobinisation/ragged
cytoplasm.
Dysplasia > 10%
BMA-500 cells
PB- 200 cells. 11

12. Peripheral blood showing Macrocytes,
Hypolobated neutrophils and Agranular
Neutrophils
12

13. DYSERYTHROPOIESIS
13

14. DYSGRANULOPOESIS: PB BONE MARROW
 Neutropenia in 50% cases
 Monocytosis
 Hypogranularity and/or agranularity of the
myeloid line
 Abnormal nuclear morphology
 Pseudo-pelger huet body
 Hypercellularity
 Monocytosis
 Hypogranularity and/ or agranularity of
the myeloid line.
 Increased blasts +/- Auer rods
 Lack of mature forms,
 Giant metamyelocytes
14

15. Blood film from a MDS
patient showing. (A) A
hypogranular neutrophil.
(B) Hypergranular
neutrophils. (C) Pseudo-
Pelger–Huët cells. (D) A
giant (‘balloon-like’)
platelet.
DYSGRANULOPOIESIS
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16. 16

17. 17

18. DYSMEGAKARYOPOIESIS:PB BONE MARROW
 Mild thrombocytopenia in about 25%
cases
 Platelet anisocytosis with giant forms and
raised MPV/PDW
 Abnormal granulation
 Megakaryocytic fragments
 Mild thrombocytopenia in about 25%
cases
 Hypolobulated micromegakaryocytes
 Non lobulated nuclei in megakaryocytes of
all sizes
 Megakaryocytes displaing nuclear
separation
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19. DYSMEGAKARYOPOIESIS
19

20. 20

21. 71 years female with history of
anaemia and
thrombocytopenia
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22. EPIDEMIOLOGY
 Median age- 70 years.
 Incidence: Non age corrected 4-5 cases per 100,000 persons per year
 Atleast 20 cases per 100,000 individuals aged >70 years
 MDS affecting children is rare with unique characteristics and diagnostic criteria
 Therapy related myeloid neoplasm which can occur as a late complication of
cytotoxic chemotherapy and/or radiation therapy administered for a prior
neoplastic or non-neoplastic disorders:
 Therapy related cases of acute myeloid leukemia(t-AML)
 Myelodyaplastic syndromes (t-MDS)
 Myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN)
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23. ETIOLOGY
 Primary or de novo MDS occurs without history of chemotherapy or radiation
exposure.
 Possible etiology for primary MDs includes:
 Benzene exposure
 Cigarette smoking
 Exposure to agricultural chemicals and solvents
 Family history of hematopoetic neoplasms
 Inherited bone marrow failure syndromes
 Acquired apalstic anemia
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24. PATHOGENESIS
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25. CLINICAL FEATURES
 Clinical features are highly variable
 Depends on MDS subtypes
 Majority have symptoms related to cytopenias
 Most patients are anemic – 80%
 Neutropenia- 40%
 Thrombocytopenia- 30-45%
 High risk MDS: Frequent unexplained infections, bleeding and circulating
immature myeloid cells or blasts.
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26. MUTATIONS IN MDS
 More than 100 gene muations
 Most common: SF3B1, TET2, SRSF2, ASXL1, DNMT3A
 In comparison of MDS with AML
 A similar number of genes are mutated in AML, some with higher frequencies of
20-30%
 Some mutations are seen equally in both entities
 In comparison to other non-hematopoietic malignancies, MDS- fewer somatic
mutations
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27. The SF3B1 MUTATION
 The SF3B1 mutation identifies a distinct subtype of MDS that is characterised by
Ring sideroblasts, ineffective hematopoiesis and macrocytic anemias
 Can lead to transfusion dependency
 Relatively good prognosis
 Luspatercept( TGF B family)- promotes erthyroid maturation and late
differentiation- FDA approved.
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28. CYTOGENETICS
 Cytogenetic abnormalities are present in 50-60% cases.
 Diverse mechanisms- chromosomal loss, gain, amplification, balanced
translocation.
 Techniques used: Conventional karyotyping, single-nucleotide
polymorphism microarrays
 Flouroscent insitu hybridisation (FISH)
 t-MDS- chromosomal abnormalities more.
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29. CYTOGENIC ABNORMALITIES
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30. PROGNOSTICATION IN MDS
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31. IPSS-R CYTOGENETICS RISK GROUPS
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32. IPSS-R Prognostic risk Categories/Scores
RISK CATEGORIES RISK SCORES
Very Low < or equal to 1.5
Low >1.5-3
Intermediate >3-4.5
High >4.5-6
Very High >6
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33. TREATMENT
 Low risk MDS: 1. Erythropoietin along with G-CSF & GM-CSF
 2. Immunosuppreressive therapy
 3. Antiangiogenic therapy
 4. Lenalidomide
 5. Azacitidine & Decatabine
 High risk MDS: 1. Allogenic Stem cell Transplant
 2. New therapy including 5-Azacytidine.
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34. MORPHOLOGICAL FEATURES OF SUBTYPES OF
MDS (WHO-2016)
1. MDS with single lineage dysplasia (MDS-SLD)
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35. 35

36. 2. MDS with Ring Sideroblasts(MDS-RS)
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37. 3. MDS with Multilineage Dysplasia ( MDS-MLD)
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38. 4. MDS with excess blast (MDS-EB 1)
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39. 5. MDS with excess blast 2 ( MDS-EB 2)
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40. 6. MDS with isolated 5 q deletion
 WHO has categorically stated that cases with increased
blasts in peripheral blood or bone marrow should be
excluded from diagnosis of 5q deletion.
 Blasts are <1% in blood and < 5% in bone marrow.
 Anemia- Macrocytic
 Thrombocytopenia- 40%
40

41. 7.MDS-Unclassifiable( MDS-U)
 Fails to meet the criteria appropriate for classification.
 It includes:
 A) Cases of unilineage Dysplasia with pancytopenia.
 B) Patients with cytopenias with unilineage/multilineage dysplasia with blasts 1%
in peripheral blood.
 C) Blasts <1% in peripheral blood but have MDS defining cytogenetic
abnormality.
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42. 8. CHILDHOOD MDS
 Rare
 Most become symptomatic rather
early and transform to AML in very
short span
 Divided into 2 types( WHO 2022):
 A. Childhood MDS with low blast
 B. Childhood MDS with increased
blasts
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43. HYPOCELLULAR MDS
 10-15% cases.
 Severe cytopenias and cellularity of marrow is < 30%
in adults who are < 70 years or < 20% in those who
are > 70 years.
 Majority of the patients have refractory anemia with
lower platelets and lower TLC.
 Hypoplastic MDS needs to be differentiated from
hypocellular AML and Aplastic anemia.
 In MDS cases fibrosis is more and megakaryocytes
are seen ( Unlike aplastic anemia)
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44.  MDS-h is associated with a T-cell mediated immune attack on hematopoietic
stem cells and progenitor cells, along with oligoclonal expansion of CD8+
cytotoxic T cells overproducing IFN-gama and/or TNF alfa.
 Several feastures overlap across the triad of MDS-h, paroxysmal nocturnal
hemoglobinuria (PNH) and aplastic anemia including CH
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45. SECONDARY/THERAPY RELATED MDS
 Alkylating agents, radiation, benzene, toxins, HIV infections
 Mean age is 10 years younger than primary MDS
 Pronounced cytopenia.
 Most cases are MDS-EB type.
 Trephine biopsy helps in differentiating primary MDS from t-MDS
 Increased Reticulin( Grade 2-3), stromal edema, gelatinous marrow
transformation
 Bone marrow necrosis.
 Presence of plasma cells, reactive lymphoid nodule, granuloma in trephine
biopsy
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46. MDS WITH MARROW FIBROSIS
 Majority have excess blasts (MDS-EB-f)
 More frequent cytogenetic abnormalities
 Aggressive clinical course
 Increased in number of megakaryocytes with abnormalities in size
(micromegakaryocytes)
 The current working classification of MDS-f requires diffuse coarse reticulin
fibrosis with/without collaginisation associated with dysplasia in atleast 2 of the
cell lineages.
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47. FAMILIAL MDS
 Families with more than 2 cases of MDS/ Acute leukemias/ Unexplained
cytopenias/Category of hereditary myeloid malignancy syndrome(HMMS) should
be screened for familial MDS
 Testing include:
 Germline Biallelic CEBPA( 7-11% cases are germline)
 Germline GATA 2 mutation
 Germline RUNX1 mutation, ANKRD26 and ETV6 mutations
 Germline DDX41 mutation in older patients.
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48. REFERENCES
 Atlas and Text of Hematology Volume II by Dr. Tejinder singh
 WHO classification of Myeloid Neoplasms, 5th Edition
 . Cree I. The WHO Classification of Haematolymphoid Tumours. Leukemia.
2022;36:in press (same issue).
 The 5th edition of the World Health Organization Classification of
Haematolymphoid Tumours: Myeloid and Histiocytic/ Dendritic Neoplasms
Joseph D. Khoury 1✉, Eric Solary 2✉
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49. THANK YOU
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