This document discusses Myelodysplastic Syndromes (MDS), including definitions, classification systems, predisposing factors, cytogenetic abnormalities, theories of pathophysiology, clinical manifestations, laboratory/pathology findings, and morphological abnormalities. Key points:
- MDS are clonal stem cell disorders characterized by ineffective hematopoiesis leading to cytopenias from defects in maturation. There have been many historical names and classification schemes, now defined by WHO.
- Predisposing factors include aging, genetic syndromes, chemotherapy/radiation, and environmental exposures. Cytogenetic abnormalities impact prognosis.
- Pathophysiology involves genetic/epigenetic changes, telomere dysfunction, altered micro
Hemostasis Physiology and Clinical correlations by Dr Faiza.pdf
Myelodysplastic Syndrome
1. Dr. Indranil Bhattacharya
MD & WHO Fellow (Pathology)
HOD – Dept. of Pathology
Jagjivan Ram Hospital
Mumbai
Myelodysplastic Syndromes
2. Definition:
MDSs are clonal disorders of the
hematopoietic stem cell characterized by
ineffective hematopoiesis leading to
peripheral blood cytopenias, reflecting
defects in erythroid, myeloid and
megakaryocytic maturation and by frequent
evolution to AML.
3. Different Terminology of MDS
Refractory anemia 1938 Rhoades and Barker
Preleukemic anemia 1949 Hamilton-Paterson
Preleukemia 1953 Block et al.
Refractory anemia with ringed sideroblasts 1956 Bjorkman
Refractory normoblastic anemia 1959 Dacie et al
Smoldering acute leukemia 1963 Rheingold et al
Chronic erythremic myelosis 1969 Dameshek
Preleukemic syndrome 1973 Saarni and Linman
Subacute myelomonocytic leukemia 1974 Sexauer et al
Chronic myelomonocytic leukemia 1974 Miescher and Farguet
Hypoplastic acute myelogenous leukemia 1975 Beard et al
Refractory anemia with excess myeloblasts 1976 Dreyfus
Hematopoietic dysplasia 1978 Linman and Bagby
Subacute myeloid leukemia 1979 Cohen et al
Dysmyelopoietic syndrome 1980 Streuli et al
Myelodysplastic syndromes 1982 Bennet et al
6. Cytogenetic Abnormalities in
Myelodysplastic Syndromes
Prognosis Alteration
Intermediate Trisomy 8
Favorable 5q-, 20q-, 12p-
Unfavorable i(17q ) or t(17p), inv(3),
translocation (3;3), complex (at
least 3 anomalies)
7. Theories of
Pathophysiology
involved
in MDS Development
Potential Targets/
Components
Involved
Overall Result of Abnormality
Environmental / Aging
Aging Increased BM
apoptosis
Decreased hematopoietic stem cell
pool
Environmental
Exposures
Smoking
Radiation
Benzene
Viral Infections
Chemotherapy
Direct Toxicity to hematopoietic
stem cells.
Telomere Abnormalities Potential decreased
telomerase and
subsequent
telomere shortening
•Impaired ability to renew stem cell
pool.
•Genetic Instability
8. Genetic
Alterations
Potential Targets/
Components Involved
Overall Result of Abnormality
Cytogenetic
Abnormalities
Common Abnormalities:
• 5q- , 20q-
• Y- , Trisomy 8
• 7q-/Monosomy7, 17p
Syndrome
• 11q23, 3q
• p53 mutations, Ras mutations
• Complex Cytogenetics
• Abnormalities: typically
unbalanced genetic loss
• Numerous theories of tumor
suppressor Loss
• Multi-Hit progression from low
risk MDS to AML
• Genetic Instability
Epigenetic
Modulation
•Hypermethylation
•Acetylation Alterations
Methylation and acetylation
abnormalities lead to silencing of
genes important in cell cycle,
differentiation, apoptosis,
angiogenesis
9. Altered Bone Marrow
Microenvironment
Components
Involved
Overall Result of Abnormality
Altered Bone Marrow
Microenvironment
Cytokines
Up regulation of:
TNF-, IFN-gamma,
TGF-Beta, IL-1B, IL-6,
Il-11
• Alteration of growth,
differentiation, angiogenesis
• Immune modulation
Alterations in Apoptosis
via Signalling
• Increased TNF-
levels
• FAS: Increased
Apoptosis
• BCL-2 alterations
• Increased apoptosis and
proliferation in early stage MDS
leading to hypercellular marrow
with peripheral cytopenias
• Decreased apoptosis and
increased proliferation in later
stage MDS leading to progression
to AML
Increased
Angiogenesis
• Increased VEG-F
• Possible Increase:
gFGF and EGF
Angiogenin
Increased Microvessel Density
(MVD): role in pathogenesis not
clearly elucidated but associated
with progression to AML
10. Altered Bone Marrow
Microenvironment
Components Involved Overall Result of
Abnormality
Immune Dysregulation • T cell Expansion
• B cell alterations
• Increased T cells leading to
potential attack on
hematopoietic stem cells.
• Etiology: Possible chronic
antigenic stimulation
Abnormal Differentiation • Cell Cycle Maturation
arrest.
• Altered Proliferation.
• Transcription Factors
alterations
• Impaired maturation
• Cytopenias
• Progression to leukaemia
11.
12.
13. FAB Classification of MDS
FAB Subtype Peripheral smear Bone Marrow
Refractory anemia
(RA)
Anaemia, Blasts< 1%,
Monocytes <1x109 /L
Blasts< 5%, ringed siderblasts
< 15% of erythroblasts
Refractory anemia
with Ringed
sideroblasts
(RARS)
Anaemia, Blasts< 1%,
Monocytes <1x109 /L
Blasts< 5%, ringed siderblasts
> than 15% of erythroblasts
Refractory anemia
with excess blasts
(RAEB)
Anaemia, Blasts>1%,
Monocytes <1x109 /L
OR
Blasts <5%
Blasts 5%
BUT
Blasts20%
14. FAB Subtype Peripheral
smear
Bone Marrow
Refractory Anemia with
Excess Blasts in
Transformation (RAEB-T)
Anaemia, Blasts 5%
OR present Auer rods
Blasts 20-29%
OR present Auer rods
CMML Monocytes>1x109 /L,
Granulocytes often
increased, Blasts
<5%.
Blasts upto 20%,
Promonocytes often
increased.
16. Subtype Blood Bone Marrow
Refractory
Anaemia (RA, RN,
RT)/RCUD
Single or bicytopenia,
no blasts
Unilineage dysplasia 10% of
the cells in one myeloid lineage,
< 5% blasts, <15% ringed
sideroblasts
Refractory
Anaemia with
Ring Sideroblasts
(RARS)
Anaemia, no blasts Erythroid dysplasia only, < 5%
blasts, 15% ringed
sideroblasts
Refractory
Cytopenia with
Multilineage
Dysplasia
(RCMD)
Cytopenia(s), no or
rare blasts (<1%), no
Auer rods, < 1 x 109/L
monocytes
Dysplasia in 10% of cells in 2
or more hematopoietic lineages,
<15% ring sideroblasts, < 5%
blasts, no Auer rods.
RCMD and
Ringed
Sideroblasts
(RCMD-RS)
Cytopenias (bi or
pancytopenia), No or
rare blasts, No Auer
rods, < 1 x 109/L
monocytes
Dysplasia in 10% of cells in 2
or more myeloid cell lines, < 5%
blasts, 15% ringed
sideroblasts, No Auer rods
17. Subtype Blood Bone Marrow
Refractory anemia
with excess blasts-1
(RAEB-1)
Cytopenias,< 5%
blasts
No Auer rods, < 1 x
109/L monocytes
Unilineage or multilineage
dysplasia, no Auer rods,
5-9% blasts
Refractory anemia
with excess blasts-2
(RAEB-2)
Cytopenias, 5-19%
blasts, Auer rods ±, <
1 x 109/L monocytes
Unilineage or multilineage
dysplasia, Auer rods ±, 10-
19% blasts
MDS, unclassified
(MDS-U)
Cytopenia(s), No or
rare blasts (<1%), No
Auer rods
Unilineage dysplasia in
granulocytes or
Megakaryocytes, < 5%
blasts, No Auer rods
MDS associated with
isolated del(5q)
Anemia, < 1% blasts,
platelets normal or
increased
Normal to increased
megakaryocytes with
hypolobated nuclei, < 5%
blasts, No Auer rods Isolated
del(5q)
19. Myelodysplastic/Myeloprolifierative Neoplasms
(MDS/MPN) WHO Classification
Subtype Blood Bone Marrow
CMML-1 > 1 x 10/L monocytes, < 5%
blasts 9
Dysplasia in 1 hematopoietic
line, < 10% blasts
CMML-2 > 1 x 10 /L monocytes, 5%-
19% blasts or Auer rods
Dysplasia in 1 hematopoietic
line, 10%-19% blasts, or Auer
rods
Atypical chronic
myeloid leukemia
(CML), Bcr-Abl 1
negative
WBC 13 x 10 /L, neutrophil
precursors > 10%, < 20%
blasts
Hypercellular, < 20% blasts
Juvenile
myelomonocytic
leukemia (JMML)
> 1 x 10/L monocytes, <
20% blasts
> 1 x 10 /L monocytes, < 20%
blasts
MDS/MPN,
unclassifiable
('Overlap syndrome')
Dysplasia +
myeloproliferative features,
no prior MDS or MPN
Dysplasia + myeloproliferative
features
20. Changes made by WHO classification
The criteria for the diagnosis of AML was altered
(20% blasts).
RAEB -T------ RAEB-II category.
Problem relating to the classification of CMML/a
CML was resolved by creation of MDS/MPD
category to which both were assigned together with
other cases with features overlapping between
MDS/MPD.
21. Drawback of WHO classification
They incorporate very little cytogenetic and molecular
genetic information.
Only the 5q- syndrome is defined.
22. Clinical manifestations
The symptoms experienced by patients with MDS
are related to the type and severity of the peripheral
blood cytopenias.
Symptoms:
o Fatigue,
o decreased exercise tolerance,
o bleeding,
o easy bruisability, or recurrent bacterial infections.
23. Physical examination
• Pallor
• Peripheral oedema
• Evidence of heart failure (severe anaemia).
• Petechiae on the lower extremities or on the buccal mucosa
(if severe thrombocytopenia is present).
• Splenomegaly may be present, especially in patients with
chronic myelomonocytic leukemia (CMML).
24. Laboratory tests
Decrease of one peripheral blood count or multiple
cytopenias.
Anaemia- Microcytic/normocytic/macrocytic.
Reticulocytopenic (corrected reticulocyte count <1%).
Leukopenia due to a decrease in the absolute neutrophil
count
Leukoerythroblastic picture.
An absolute monocytosis (monocytes >1000/μL) is present
in CMML.
Thrombocytopenia may be present
Thrombocytosis {Refractory Anaemia (RA) and an isolated
5q− abnormality, or in some cases of RARS}.
25. Bone marrow
Essential to diagnose MDS.
The BM trephine biopsy provides better assessment of
marrow cellularity and is required to evaluate the
existence of fibrosis. Abnormal distribution of cells is
detectable.
The bone marrow biopsy usually is hypercellular for the
age of the patient.
However, approx 15% of patients have a hypocellular
marrow (cellularity <25%).
26. Bone marrow..…
Granulocytic precurosrs may be clustered centrally
rather than showing their normal paratrabecular
distribution.
This phenomenon has been designated as abnormal
localization of immature precurors (ALIP).
ALIPs are diagnostically important if they are detected
in since their presence confirms MDS rather than a
secondary anaemia.
Use of antiglycophorin antibody highlights the presence
of clusters of immature erythroid cells and helps to
distinguish from ALIPs.
27. Bone marrow ..…
Abnormal megakaryocytes are readily assessed.
Megakaryocytes may be clustered or found in
paratrabecular position.
Apoptosis is increased.
Nonspecific abnormalities - increased macrophages,
prominent mast cells, lymphoid follicles and plasma cell
aggregates.
28. BM trephine biopsy section, RAEB-T, showing increased numbers of blasts
forming a small cluster (centre) (an abnormal localization of immature
precursors or ALIP).
29. Cytochemical Reactions
Most important and essential - Perl’s stain for iron.
Sudan Black B and MPO - Ensure that all cases
with Auer rods are recognized and classified as
RAEB-T (FAB) or RAEB-2 (WHO).
In CMML - Non Specific Estarage (NSE) is
necessary to identify monocyte component in bone
marrow.
PAS - Erythroblasts
33. Megakaryocyte
PS Bone marrow
Giant platelets Micromegakaryocytes
Hypogranular or agranular Hypogranulation
Platelets Multiple small nuclei
34. PB film, MDS, showing anisocytosis, poikilocytosis and two pseudo-Pelger–
Huët neutrophils, one of which is also hypogranular.
35. Refractory cytopenia with multilineage dysplasia (RCMD). Bone marrow aspirate
(Wright–Giemsa stain – 100x). Erythroid precursors with nuclear irregularity and
myeloid precursors with hypogranulation and hyposegmentation
38. A) Leishman Stain (×100 magnification). Showing dyserythropoiesis.
B) May–Grunwald Giemsa Stain (×100 magnification). Arrow showing
binucleate erythroblast. C) Leishman Stain (×200 magnification).
Showing multinucleate erythroblast and erythroid dysplasia
39. REFRACTORY CYTOPENIA WITH MULTILINEAGE DYSPLASIA: Dysplastic
erythroid precursor with multi-nucleation and nuclear fragments (arrow) and
dysplastic myeloid precursor with both eosinophilic and basophilic granulation
(arrowhead)
40. Bone marrow biopsy shows
uniformly small and monolobated
megakaryocytes (arrows).
41. BM aspirate, RA, showing a binucleate micromegakaryocyte which is budding
platelets
42. Dysplasia in myeloid precursors can be manifested by dysplastic
granulation with granules of eosinophilic type and basophilic type (arrow)
43. Abnormal nuclear lobation such as seen in this myelocyte with two nuclei (long
arrow), abnormal distribution of granules causing granular polarity (arrowhead),
and mixed eosinophilic and basophilic granulation (top arrow)
44. Neutrophils with ring-like nuclei (ringed-neutrophil, arrow), A megaloblastoid
erythroid precursor is also seen (arrowhead)
45. Refractory anaemia, RCUD, RN, RT (WHO)
10-20% of MDS.
Older adults, median age- 65-70years.
PS-
Anaemia, marked anisocytosis, poikilocytosis.
Normochromic, normocytic/macrocytic,
occasional hypochromia.
Blasts are uncommon, less than 1%.
46. Refractory anaemia with ring sideroblasts
(WHO)………
Bone marrow shows erythroid hyperplasia.
Myeloblasts are <5% of BM nucleated cells.
15% or more of red cell precursors are ring
sideroblasts.
Iron laden macrophages may be prominent.
Very low rate of evolution to AML.
47. BM aspirate, RARS, showing numerous ring sideroblasts, several of which
can be seen to have defectively haemoglobinized cytoplasm. Perls’ stain
48. Refractory anaemia with excess of
blasts-2
It is categorized as RAEB-2 if bone marrow blasts
are 10-19%, if the peripheral blood blasts are 5-
19% (regardless of bone marrow blast count) or if
Auer rods are present.
Dysplasia in at least 10% of cells of one or more
myeloid lineages.
More than a third patient suffered transformation
to AML.
Median survival poor than RAEB-1.
49. BM trephine biopsy section from a patient with hypoplastic MDS (RAEB)
showing: (a) a disorganized marrow of low cellularity
50. Evolution of MDS
Patients with MDS may die of marrow failure as a direct
consequence of MDS or may die following
transformation to acute leukemia.
Myelodysplastic syndromes may evolve into other
MDS.
Change is usually into a worse prognostic category and
very rarely into favorable.
Thus RA and RARS may evolve into either CMML.
51. Evolution of MDS…..
Variation in number of monocytes can alter
classification, mainly between CMML and RAEB and
rarely ring sideroblasts disappear so that RARS
converts to RA.
When acute leukemia supervenes it may develop
within a brief period or there may be stepwise
evolution over weeks and months.
Acute leukemia that occurs in MDS is always AML,
but rare cases of ALL and bilineage/ biphenotypic
leukemia have been reported.
53. Has there been exposure to cytotoxic drugs or
radiation
No
Are there 5-19% blast cells in the blood or 10-19%
blast cells in the bone marrow or Auer rods
Are there no more than 5% blasts cells in the
blood and 5-9% in the bone marrow
No
No
Is there an isloated 5q-
No
Is there multilineage dysplasia
No
RA or RARS
Yes
Therapy related MDS
Yes
RAEB-II
Yes
RAEB-I
Yes
5q- syndrome
Yes
RCMD
Notas del editor
Dysfunction of enzymes required for detoxification, DNA mismatch repair, or differentiation
Degree of elevation of blast count
Although the FAB group classified MDS as CMML, atypical chronic myeloid leukemia, a condition characterized by equal if not more dysplasia, was characterized as a type of chronic myeloid leukemia.
Megakaryocytes- Megakaryocytes- Normal/increased and cytologically abnormal. They have non-lobed or bilobed nuclei but are mainly more than 30-40um in diameter.
Thus they differ from the mononuclear and binuclear micromegakaryocytes associated with other forms of MDS.
Myelodysplastic syndrome with isolated del (5q). A, B) Bone marrow aspirate (40x and 100x). Hypolobated megakaryocyte seen. C, D) Bone marrow biopsy – (10x and 40x – H&E stain). Hypercellular bone marrow with myeloid proliferation associated with hypolobated or nonlobated megakaryocytes
;
PB, aCML (Ph-negative), showing a myelocyte, a bizarre macropolycyte, an abnormal monocyte, an unidentifiable cell and a lymphocyte.
BM aspirate, aCML showing granulocytic and monocytic hyperplasia
PB, JMML, showing a monocyte, a basophil, dysplastic neutrophils, neutrophil precursors and thrombocytopenia
BM aspirate, JMML, showing granulocyte precursors and a dysplastic binucleated micromegakaryoc
Good indicates normal, 2Y,del(5q); poor, complex ($3 abnormalities), chromosome 7 anomalies; and intermediate, other abnormalities.
‡ Neutropenia indicates neutrophil level less than 1800/mL; anemia, hemoglobin level less than 10 g/dL (,6.21 mmol/L); and thrombocytopenia,
platelet level less than 100 000/mL.