MYELODYSPLASTIC NEOPLASM
Historically was known as refractory anemia, smoldering leukemia, oligoblastic
leukemia, or preleukemia
1982: FAB proposed terminology and specific set of morphologic criteria
WHO
1997: includes molecular, cytogenetic, and immunologic criteria in addition to morphologic
features
2008, 2016, 2022: renamed MDS as myelodysplastic neoplasm
MDS are group of acquired clonal hematologic disorders characterized by progressive
cytopenia in the PBS. Reflecting defects in erythroid, myeloid, and/or megakaryocytic
maturation
77: median age of diagnosis
rare in age 40: unless preceded by chemotherapy, radiation, or germline mutation
ETIOLOGY
cell of origin of MDS is the phenotypically normal HSC
mutations in the affected HSC drives clonal expansion
as humans age somatic mutations are acquired by hematopoietic cells
competitive survival is an advantage to mutated cell leading to clonal hematopoiesis
CCUS (Clonal cytopenia of unknown significance) and CHIP (clonal hematopoiesis of
intermediate potential) – clonal disorders that does not meet the criteria for diagnosis
of MDS since they lack:
CCUS – dysplasia and MDS-related mutation
CHIP – dysplasia and peripheral cytoplasm
HSC that lead to mutations
o primary MDS – de novo mutations, most of the cases
o myeloid neoplasm post cytotoxic therapy
o secondary exposure to chemicals/radiation (no prior disease treatment)
o inherited-myeloid neoplasms associated with:
- germline predisposition – inherited
- associated with down syndrome
MN-pCT (myeloid neoplasm post-cytotoxic therapy) previously known as “Therapy
Related MDS)
- develops after treatment history of exposure to cytotoxic chemotherapy and/or
large-field radiation therapy
- median onset: 4 years after therapy was initiated
- patients who received cytokines
MDS is characterized by:
progressive cytopenia despite cellular bone marrow
ineffective hematopoiesis
dysplasia in one/more cell lines
clonal hematopoiesis (evidence by presence of cytogenetic abnormalities)
* characteristic cytopenia found in MDS is caused by ineffective hematopoiesis. We can now
understand that this process is characterized by inflammatory pathway known as pyroptosis.
DYS – abnormality (could be morphology and/or function)
MYELO – myeloid cell lineage (immature/mature cells)
POIETIC – formation
Simultaneous proliferation and apoptosis of hematopoietic cells (Turgeon)
Cytopenias due to ineffective hematopoiesis and increased apoptosis, showing
morphologic dysplasia of at least one and usually more lineages, and have varied
cytogenetic findings (but not typically those associated with myeloproliferative
neoplasms), and many have a propensity to progress to acute leukemias (Henry's)
No cytogenetic abnormality is specific to a subtype of MDS except del(5q)
Myeloid Neoplasms with Germline Predisposition
○ Inherited BM failure syndromes
○ Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome.
Inflammasome activation leading to pyroptosis
PBS AND BM FINDINGS
WHO: threshold of at least 10% of cells within a lineage
MORPHOLOGIC ABNORMALITIES IN PERIPHERAL BLOOD AND BONE MARROW
Dyserythropoiesis
PBS: oval macrocytes (most common), hypochromic microcytes, dimorphic RBC
population
BM: RBC precursors with >1 nucleus, abnormal nuclear shapes, intranuclear
sideroblasts, basophilic stippling
Oval macrocytes – most common
- if seen in the presence of normal vitamin B12 (D. latum, Megaloblastic anemia) and folate =
suspect MDS
- hypochromic microcytes (in adequate iron stores)
Dimorphic RBCs
Ring sideroblasts – common finding
Megaloblastoid – development in the presence of vitamin B12
Inclusions: poikilocytosis, basophilic stippling, Howell-jolly bodies, siderocytes
Abnormal cytoplasmic features: basophilic stippling and heterogenous staining
Dysmyelopoiesis
PBS: persistence of basophilia in an otherwise mature WBC, hypo/hypersegmentation,
anomaly, nuclear rings abnormal granulation, pseudo-Pelger Hüet
BM: nuclear cytoplasmic asynchrony, uneven staining, abnormal granulation
suspected when there is presence of basophilia in the cytoplasm indicating nuclear
cytoplasmic asynchrony
abnormal granulation of cytoplasm of neutrophils in the form of larger than normal
granules = hypogranulation and absence of granules
agranular bands can be mistaken as monocytes
Abnormal nuclear features:
o hypo/hypersegmentation
o pseudo-pelger-huet anomaly
o nuclear rings
bone marrow = nuclear cytoplasmic asynchrony
cytoplasmic changes = uneven staining (dense ring of basophilia around the
periphery)
abnormal granulation of the cytoplasm = promyelocytes or myelocytes or both are
devoid of primary granules
bone marrow – may exhibit granulocytic hypo/hyperplasia
- monocytic hyperplasia (common finding in dysplastic marrows)
- abnormal localization of immature precursors = BM biopsy
Normally myeloblast and promyelocytes reside along the endosteal surface of the
bone marrow. In some cases of MDS, these cells tend to cluster centrally in the marrow
sections.
Dysmegakaryopoiesis
PBS: giant platelets, abnormal granulation, micromegakaryocytes
BM: large mononuclear megakaryocytes with multiple nuclei
common changes
giant platelets
abnormal platelet granulation (hypo/hyper granulation)
some platelets have large fused cells
circulating micromegakaryocytes – in PB
megakaryocytic component (bone marrow)
large mononuclear megakaryocytes
micromegakaryocytes
micromegakaryoblasts
The nuclei in these cells are:
bilobed
multiple, small, separated nuclei
Do you think these morphologically bizarre cells have normal functions?
The cells produced by abnormal maturation not only have an abnormal appearance
but also have abnormal functions.
CLASSIFICATION OF MDS
FAB
Five classes
Morphology, amount of dysplasia, number of blasts
WHO
Threshold for dysplasia: 10% dysplastic cells in any hematopoietic lineage
International Consensus Classification (2022)
Preserved the name Myelodysplastic Syndromes
MDS/AML category (10-19% blasts)
MDS-5q = Best prognosis, lenalidomide works!
MDS-SF3B1 = Ring sideroblasts, stable disease.
MDS-biTP53 = Post-chemo, high leukemia risk.
MDS-LB = Classic MDS, low blasts.
MDS-h = Looks like aplastic anemia.
MDS-IB = Increased blasts, urgent treatment needed.
MDS-F = Fibrosis, poor outcome.
Childhood MDS-LB = Rare, but needs monitoring.
Childhood MDS-IB = High leukemia risk.
MDS WITH DEFINING GENETIC ABNORMALITIES
MDS, MORPHOLOGICALLY DEFINED
CHILDHOOD MDS
MDS/MPN
FAB CLASSIFICATION
