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2. Definition
Group of clonal hematopoietic stem cell diseases characterised by
• Cytopenia (atleast 1 lineage)
• Hb < 10g/dl
• Platelet count < 1 lakh/cu.mm
• ANC < 1800 cells/cu.mm
• Monocytes < 1000/cu.mm
• dysplasia in one or more of the major myeloid lineages
• Ineffective hematopoiesis
• Recurrent genetic abnormalities
• Increased risk of AML
3. Hypoplastic MDS
• 10% MDS
• Independent favourable
prognosis
• DD – Aplastic Anemia
• Exclude Acute marrow injury
MDS with Fibrosis
• 10 – 15% of MDS
• Grade 2 – 3 fibrosis
• Excess of Blasts
• Aggressive clinical course
• Bone marrow Biopsy > BMA
• IHC for CD 34
• Different from Primary
Myelofibrosis
• No splenomegaly
• No leucoerythroblastic blood
picture
• Intrasinusoidal hematopoiesis
4. Epidemiology
• Older adults
• Male preponderance
• Annual incidence = 3 – 5 caser per 1 lakh population
• At least 20 cases per 1 lakh population > 70 yrs
• Median age at presentation
• United Kingdom – 65 yrs
• India – 45 yrs
• Progression to AML – 30 – 35 %
7. Evaluation
• History
• Prior exposure to CT/RT
• Recurrent infections
• Bleeding/Bruising
• Examination
• Pallor/ bruising
• organomegaly
• Blood counts
• Hb, TLC, Platelet count
• RC
• Blood film
• BMA + BM Bx
• IHC
• CD 34
• CD 41
• CD 61
• Immunophenotyping of BM
• Bone marrow cytogenetics
• Biochemical tests
• S. Iron
• S. LDH
• TSH
• Red cell folate & S. B12
• Other tests
• Viral markers
• Autoimmune disease work up
• FLAER for PNH
8. Exclusion of reactive causes of Dysplasia
• Megaloblastic Anemia
• HIV Infection
• Recent cytotoxic therapy
• Alcoholism
• Severe intercurrent illness
9. Microscopy – Points to remember
• >2 hrs from collection –
specimen unsatisfactory
• Staining is significant
• Don’t diagnose MDS without
detailed history
• No of cells to count
• PS – 200 cells
• BM – 500 cells
• If Cytopenic - Count from buffy
coat
• PS blasts can be more than BM
blasts in 13% of MDS
• Persistent cytopenia without
dysplasia – Idiopathic cytopenia
of undetermined significane
• MDS associated clonal gene
mutations without dysplasia –
clonal hematopoiesis of
indeterminate potential
• If in doubt – observe patient for
6 months before diagnosis
10. PS Characteristics of dysplasia - RBC
• Ovalocytosis
• Macrocytosis
• Elliptocytosis
• Stomatocytes
• Tear drop cells
• Nucleated red cells
• Basophilic stippling
• Howell-Jolly bodies
11. PS Characteristics of Dysplasia - WBC
• Hypolobation
• Hyposegmentation – Pince-nez
type
• Hypogranulation
• Ring shaped nuclei
• Pseudo-Pelger Huet anomaly -
marked clumping of nuclear
chromatin – nuclear hypolobation
• Auer rod
• Irregular contour of nuclei
• Blasts
14. BMA Characteristics of dysplasia - RBC
• Megaloblastic erythropoiesis
• Nuclear budding of erythroblasts
• Multinucleation
• Karyorrhexis
• Ring sideroblasts
• > 5 iron granules
• Encircling > 1/3rd nucleus
• Cytoplasmic vacuolation – PAS
+ve
• Increased Iron stores
15. BMA Characteristics of dysplasia - WBC
• Defective granulation
• Presence of Auer Rods in myeloid
cells
• Maturation arrest at myelocyte stage
• Increase in Monocytoid cells
• ALIP
• Very small/large granules
• Pseudo chediak higashi granules –
Abnormal large granular clumping
• Irregular nuclear hypersegmentation
• CD 34 +ve blasts
16. BMA Characteristics of dysplasia - Platelets
• >10% Micromegakaryocytes*
• < 15 µm - Size of promyelocyte
• Non/bi lobated nucleus
• Eosinophilic cytoplasm
• Hypogranulation of
megakaryocytes
• Mutliple small nuclei of
megakaryocytes – Pawn ball
• Nuclear Hypolobation
• CD 61 & CD 41 +ve
17. Bone Marrow Trephine Biopsy
• Cellularity of Marrow
• ALIP
• Reticulin Fibrosis – 20%
• Megakaryocyte Dysplasia
• CD 61
• CD 41
• Lymphoid aggregates
• Hypoplastic MDS
• Neovascularisation –
transformation to AML
ALIP
Blasts in cell clusters located away from
bone trabeculae & Vascular structures
CD 34 +
18. IHC
Immature, Blast cells CD 34
TdT
CD 117
Erythroblasts Glycophorin A
Megakaryoblasts CD 61
CD 41
Apoptotis Markers TNF – Alpha
Bax
19. Immunophenotype
• Flow cytometry in CD 34+ve
cells
• Aberrant maturation patterns in
granulopoiesis can predict
morphological dysplasia
• Myeloblasts, monocytoid cells &
maturing myeloid cells – typical
expression related to lineage &
stage of maturation
• In MDS
• Increased/ Decreased expression of
normal antigens
• Asynchronous maturational
expression
• Aberrant antigen expression
• Atleast 3 aberrancies +
20.
21. Genetic profile
• Isolated 5q deletion alone & 5q deletion + one additional abnormality
• Hypo/non – lobated megakaryocytes
• Macrocytic anemia
• Favourable clinical course
• Loss of 17 p
• pseudo pelget huer anomaly
• TP 53 mutation
• Therapy related
• Unfavourable clinical course
Conventional Karyotyping
Multicolour FISH
Gene sequencing
SNP Array
26. MDS - U
Name Dysplasia Cytopenia RS PS Blasts BM Blasts
With 1% Blood blasts 1 – 3 1 – 3 None or any 1%ON 2 OCC <5%
With SLD & Pancytopenia 1 3 <1% <5%
Based on defining cytogenetic
abnormality
0 1 – 3 <15%MDS-RS-SLD
27. FAB Classification
Subtype Abbreviation PS –Blasts BM
Refractory Anemia RA < 1% Blasts < 5% + RS < 15%
RA + Ringed Sideroblasts RARS < 1% Blasts < 5% + RS > 15%
RA + Excess blasts RAEB < 5% Blasts 5 – 20%
RA + Excess blasts in transformation RAEB – t >5% Blasts 20 – 30 % (Auer rods)
Chronic myelomonocytic leukemia CMML <5% + Monocytes >
1000/cu.mm
Any of the above
Acute Myeloid Leukemia AML Variable Blasts > 30 %
28. MDS – Single lineage dysplasia
• Incidence : 7 – 20% MDS
• Definition
• Unexplained cytopenia/ bicytopenia
• > 10% dysplastic cells in one myeloid lineage
• 2008 edition – Refractory cytopenia with unilineage dysplasia
• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
• Ringed sideroblasts
• < 15%
• <5% in cases with SF3B1 mutation
No correlation between
cytopenia & dysplasia
29. MDS – Multi lineage dysplasia
• 1 or >1 cytopenia
• 2 or >2 dysplasia in the myeloid lineages (> 10%)
• 200 erythroid, 200 Neutrophil precursors & 30 megakaryocytes (30 – 40%) to
be examined in the BMA or BM Bx
• Blasts
• Peripheral smear - < 1%
• Bone marrow - <5%
• Auer rods – Absent
• Monocyte count - < 1000 cells/cu.mm
• Marrow fibrosis – 16%
Incidence
30% of all cases
48% of cases without excess blasts
65% along with MDS – RS – MLD
30. MDS with Ringed sideroblasts
• Incidence: 3 – 11 %
• >15% ringed sideroblasts in the bone marrow
• >5% in case of SF3B1 mutation
• Other subtypes to be excluded
• MDS – RS – SLD – Usually anemia + Erythroid Dysplasia (9982/3)
• MDS – RS – MLD – any number of cytopenias / dysplasias (9993/3)
31. MDS with Excess Blasts
• < 20% in both Bone Marrow (5 – 19%) & Blood ( 2 – 19%)
• Incidence – 40%
• Hypercellular marrow
• 30 – 50% have clonal genetic abnormalities
EB 1 EB 2
PS Blasts 2 – 4 % 5 – 19%
BM Blasts 5 – 9 % 10 – 19 %
Auer rods Absent Present
Progression to AML 25% 33%
Median Survival 16 months 9 months
32. Variants
MDS EB & Erythroid Predominance
• Maturing Erythroblasts > 50% of
marrow cells
• Myeloblasts > 20% of non
erythroid nucleated cells
MDS EB & Fibrosis
• 15% show significant degree of
fibrosis
• Therapy related MDS
• Presence of excess blasts
confirmed by IHC – CD 34
• Increased dysplastic
megakaryocytes
• FCM – CD 34 & C-KIT +ve
33. MDS with isolated del 5q
• Anemia + other cytopenia + Thrombocytosis
• Thrombocytosis in 1/3rd – ½ of cases
• Loss of tumour suppressor genes in the minimally deleted region (q31 –
q33)
• Erythroid hypoplasia
• Dysplastic Megakaryocytic hyperplasia
• Del 5q demonstrated by FISH analysis
• Cases with addl monosomy 7/ Del 7q is included in this category
• Subsets show JAK2 V617F mutation & SF3B1 mutation
• Median survival – 66 – 145 months
• AML transformation < 10 %
34. MDS - Unclassifiable
• Diagnosed by Exclusion
• Incidence : 6.3% of cases with <5% blasts
• 1% blasts in the blood on 2 separate occasions
• Persistent cytopenia
• < 2% Blasts in blood
• < 5% blast in BM
• < 10% Dysplasia
• Prognosis in cases with 1% blasts
• Median survival – 30 months
• AML Progression – 14%
35. Childhood MDS
• < 5% of all hematopoietic neoplasms in less than 14 yrs
• Subtypes
• Refractory Cytopenia of childhood (Blasts <5% in BM & <2% in PS)
• Conventional MDS
• MDS – EB
• MDS – RS
• T - MDS
• GATA2 germline mutation is present in 7% primary MDS
• Criteria for diagnosis - MDS (atleast 2)
• Sustained unexplained cytopenia
• Bilineage morphologic dysplasia
• Acquired clonal cytogenetic morphology
• Increased blasts (>5%)
36. Therapy related MDS
• Late complication of Chemotherapy/ radiotherapy administered for
prior neoplastic or non neoplastic disorder
• Incidence: 10 – 20% of all cases of AML, MDS & MDS/MPN
• Prior history
• 70% for solid tumours (Breast Cancer)
• 30% Hematopoietic neoplasms (Non Hodgkin’s lymphoma)
• Poor Prognosis
40. Very low Low Intermediate High Very High
Patients % 19% 38% 20% 13% 10%
Survival 8.8 5.3 3.0 1.6 0.8
AML transformation Not reported 10.8 3.2 1.4 0.7
42. References
• Atlas & textbook of hematology, Tejinder Singh
• WHO Classification of Tumours of Hematopoietic & Lymphoid
tissues
• American Association of Pathology Atlas of Bone Marrow Pathology
• Wintrobe’s Clinical Hematology
• Williams Hematology Malignant Lymphoid Diseases
