Myelodysplastic Neoplasms

Slide 1 · Myelodysplastic Neoplasms

Clonal hematopoiesis · dysplasia · cytopenias · evolution

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain clonal ineffective hematopoiesis and its clinical effects.

Relate molecular abnormalities to disordered differentiation.

Identify characteristic erythroid, granulocytic and megakaryocytic dysplasia.

Integrate morphology, genetics, prognosis and treatment concepts.

MDS requires a clinicopathologic and genetic synthesis.

Slide 3 · Myeloid neoplasms: Three dominant phenotypes

Category

Primary abnormality

Typical blood consequence

Acute myeloid leukemia

Accumulation of immature myeloid blasts

Suppression of mature blood-cell production

Myelodysplastic neoplasms

Ineffective, dysplastic maturation

One or more cytopenias

Myeloproliferative neoplasms

Increased production of mature myeloid cells

Increased counts initially

Slide 4 · The defining biological lesion

Clonal stem-cell disease

The marrow is populated by progeny of an altered multipotent hematopoietic stem cell.

Differentiation is retained

Cells mature along myeloid lineages, but maturation is abnormal.

Production is ineffective

Marrow activity fails to generate adequate functional circulating cells.

Slide 5 · A clonal stem cell creates the MDS phenotype

Acquired clonal lesion

Multipotent stem cell

Abnormal maturation

Dysplastic progeny

Ineffective output

Marrow production does not yield effective circulating cells

Peripheral cytopenias

Anemia, neutropenia or thrombocytopenia

Slide 6 · Normal vs dysplastic hematopoiesis

Feature

Normal marrow

MDS

Hematopoietic clone

Regulated diverse progenitors

Expansion of neoplastic clone

Maturation

Orderly lineage progression

Disordered maturation

Output

Production meets blood-cell needs

Ineffective output despite marrow activity

Blood counts

Maintained by homeostasis

Cytopenia(s) of variable severity

Slide 7 · Why a cellular marrow can produce cytopenias

Marrow

Abundant but ineffective

Hematopoietic cells

Peripheral blood

Insufficient mature

Circulating cells

Marrow cellularity and effective blood-cell output are not synonymous.

Slide 8 · Three lineages explain the clinical syndrome

Red-cell lineage

Ineffective erythropoiesis → anemia and weakness.

Granulocytic lineage

Abnormal myeloid production → neutropenia and infection risk.

Megakaryocytic lineage

Defective platelet production → thrombocytopenia and bleeding.

Slide 9 · Primary and therapy-related MDS

Aspect

Primary MDS

Therapy-related MDS

Clinical context

De novo; No identified genotoxic antecedent

After cytotoxic drugs or irradiation

Age

Predominantly older adults

Depends on previous treatment history

Course

Variable prognostic groups

Typically more adverse; Rapid AML progression

Slide 10 · Exposure-associated disease has a latent interval

Genotoxic therapy

Chemotherapy or radiation

Latent interval

Usually 2–8 years in this source

Therapy-related MDS

Often adverse course

The latency is a population description—not a diagnostic requirement for an individual patient.

Slide 11 · MDS is a potential antecedent of AML

MDS clone

Disordered differentiation

Additional clonal changes

Additional mutations or cytogenetic changes may emerge

Progressive blast expansion

Disease aggressiveness increases

AML

Transformation in a subset of patients

Slide 12 · Three broad categories of MDS drivers

Acquired mutations perturb the regulation of myeloid differentiation.

Epigenetic regulators

DNA methylation, histone modifications and chromatin organization.

RNA splicing factors

Defects in the machinery that processes pre-mRNA.

Transcription factors

Disruption of programs needed for normal myelopoiesis.

Slide 13 · Epigenetic disturbance can alter differentiation

Epigenetic-factor mutation

DNA methylation, chromatin or histone control

Altered gene regulation

Epigenomic dysregulation

Abnormal maturation

Phenotypic dysplasia

A conceptual relation; This diagram does not specify an unverified gene-to-phenotype pathway.

Slide 14 · Epigenetic regulators overlap with AML

MDS and AML share abnormalities in epigenetic control pathways.

Affected protein classes regulate DNA methylation, histone modifications and chromatin looping.

This overlap is biologically consistent with progression of some MDS clones to AML.

Shared pathways do not imply that the same lesion predicts identical clinical behavior.

Slide 15 · RNA splicing is another recurrent target

Spliceosome component mutation

A subset of MDS has splicing-factor gene defects

Altered RNA processing

The precise pathogenic contribution remains incompletely established

MDS-associated clone

Molecular evidence supports clonality

Slide 16 · Clonal hematopoiesis links aging and MDS

Age-associated mutant hematopoietic clones may be present with normal blood counts.

Splicing-factor mutations in clonal hematopoiesis are associated with particularly high progression risk.

Clonal hematopoiesis alone is not equivalent to symptomatic MDS.

Transition to MDS requires evidence beyond merely detecting a mutated clone.

Slide 17 · Transcription-factor defects disturb maturation

Loss-of-function mutation

Example: RUNX1

Disrupted transcriptional program

Normal differentiation requires transcriptional control

Abnormal myelopoiesis

MDS phenotype may result

Slide 18 · RUNX1 illustrates a transcription-factor lesion

RUNX1 is required for normal myeloid development.

MDS may harbor loss-of-function lesions involving RUNX1.

The principal conceptual consequence is a defect in lineage differentiation.

Do not confuse RUNX1 loss-of-function with AML-associated balanced rearrangements.

Slide 19 · Chromosomal changes: MDS vs de novo AML

Feature

MDS

Common de novo AML patterns

Prominent genetic change

Deletions, monosomies and other unbalanced aberrations

Specific balanced rearrangements in subsets

Examples emphasized

−5, −7, del(5q), del(7q), del(20q), +8

T(8;21), inv(16), t(15;17)

Interpretation

Different predominant genetic landscape

These typical AML rearrangements are not seen in MDS in this account

Slide 20 · TP53 marks a clinically adverse subset

Approximately 10%

Loss-of-function TP53 mutations in roughly one-tenth of MDS cases.

Genetic association

Often accompanies a complex karyotype.

Clinical association

Correlates with particularly poor outcomes.

Slide 21 · Complex karyotype is a prognostic warning

Defined in the source as multiple chromosomal abnormalities.

Associated with worse clinical outcomes across risk frameworks.

Often present in TP53-mutated disease.

Prognostic significance depends on the integrated disease context.

Slide 22 · Recurrent chromosome abnormalities in MDS

Whole-chromosome loss

Partial deletion

Chromosome gain

Monosomy 5

Del(5q)

Trisomy 8

Monosomy 7

Del(7q)

Del(20q)

Slide 23 · Copy-number changes alter gene dosage

Deletion/loss

Single copy

Normal pair

Two copies

Trisomy

Three copies

Concept: Changing gene dosage can confer a growth advantage; The exact contribution of most aneuploidies remains incompletely understood.

Schematic — not a clinical/histologic specimen

Slide 24 · Deletion 5q: An illustrative mechanism

Deletion of 5q region

Chromosomal loss

One fewer RPS14 copy

RPS14 encodes a ribosomal protein

Defective erythropoiesis

Demonstrated in experimental systems

Slide 25 · Trisomy 8: A gene-dosage hypothesis

Extra chromosome 8

Aneuploidy

Increased MYC copy number

MYC resides on chromosome 8

Potential growth advantage

Model proposed in the source

Gene dosage is a proposed mechanism, not proof that MYC alone explains trisomy 8 disease.

Slide 26 · Molecular tests have complementary roles

Cytogenetics

Detects recurrent gains, losses and complex karyotypes; Contributes to prognosis.

DNA sequencing

Identifies acquired variants that can support clonal disease and classification.

Morphology

Shows abnormal maturation and lineage-specific dysplasia.

Slide 27 · A mutation alone does not establish MDS

Genetic clonality may also occur in people with normal blood counts.

The MDS diagnosis requires correlation with peripheral counts and morphologic findings.

Use cytogenetic and sequencing data to complement—not replace—clinical assessment.

Clinicopathologic interpretation prevents overcalling age-related clonal hematopoiesis.

Slide 28 · An integrated diagnostic reasoning sequence

Cytopenia detected

One or more affected lineages

Examine blood and marrow

Identify dysplasia, blast burden and cellularity

Cytogenetics / DNA

Corroborate clonality and stratify risk

Integrated interpretation

Separate MDS from mimics and related myeloid neoplasms

Slide 29 · Bone marrow cellularity varies

Pattern

Status in the source

Interpretation

Hypercellular

Most common at diagnosis

Ineffective hematopoiesis despite increased marrow cellularity

Normocellular

Sometimes encountered

Does not exclude MDS

Hypocellular

Less common

Does not exclude MDS

Slide 30 · MDS is a multilineage dysplasia

Assess erythroid, granulocytic, monocytic and megakaryocytic elements.

Erythroid

Abnormal nuclear maturation and iron distribution.

Granulocytic

Abnormal granulation and segmentation.

Megakaryocytic

Abnormal nuclear number and lobation.

Slide 31 · Erythroid abnormalities have several forms

Ring sideroblasts: Perinuclear mitochondrial iron on Prussian blue stain.

Megaloblastoid maturation: Resemblance to B12 or folate deficiency.

Nuclear budding, multilobation and irregular polyploid nuclei.

Different abnormalities may coexist in the same marrow.

Slide 32 · Ring sideroblasts represent mitochondrial iron

Erythroblast

Ring sideroblast

Perinuclear iron is demonstrated with Prussian blue staining.

Schematic — not a clinical/histologic specimen

Slide 33 · Prussian blue demonstrates abnormal iron distribution

Ring sideroblasts are erythroid precursors, not mature circulating erythrocytes.

Iron-laden mitochondria appear as blue perinuclear granules.

The abnormal localization provides morphologic evidence of disordered erythropoiesis.

A ring pattern must be assessed in the correct cell and stain.

Slide 34 · Abnormal erythroblast nuclei show budding

Single nucleus

Nuclear budding

The schematic illustrates an irregular erythroblast nuclear contour.

Schematic — not a clinical/histologic specimen

Slide 35 · Megaloblastoid maturation is a morphologic mimic

Feature

MDS

Vitamin B12 / folate deficiency

Morphology

Can show megaloblastoid maturation

Can show megaloblastic maturation

Interpretive implication

Requires clonal/marrow context

Requires evaluation of a nutritional cause

Conclusion

Morphology by itself may overlap

Look beyond isolated nuclear appearance

Slide 36 · Granulocytic dysplasia affects granules and nuclei

Neutrophils may have reduced secondary granules.

Toxic granulation and Döhle bodies may also occur.

Abnormal nuclear segmentation is exemplified by pseudo–Pelger-Huët cells.

Evaluate the overall dysplastic pattern, not one cell in isolation.

Slide 37 · Pseudo–Pelger-Huët neutrophils are bilobed

Normally segmented neutrophil

Pseudo–Pelger-Huët form

The abnormal neutrophil has two nuclear lobes rather than the usual three to five.

Schematic — not a clinical/histologic specimen

Slide 38 · Pseudo–Pelger-Huët cells are useful smear clues

They may be visible in peripheral blood as well as marrow.

They have abnormally reduced nuclear segmentation; Some cells lack segmentation entirely.

Their recognition should prompt review of other lineages and clinical data.

A characteristic clue is not a stand-alone diagnosis.

Slide 39 · Megakaryocytic dysplasia has distinctive nuclei

Some megakaryocytes have a single nuclear lobe.

Others show multiple separate nuclei—the “pawn-ball” pattern.

These findings differ from the normal large multilobated nucleus.

Megakaryocyte morphology is an important component of multilineage assessment.

Slide 40 · Megakaryocytes may have separated nuclei

Typical multilobated nucleus

Dysplastic separate nuclei

Simplified nuclear topology; Actual cytologic diagnosis requires marrow assessment.

Schematic — not a clinical/histologic specimen

Slide 41 · Peripheral blood can reveal multilineage dysplasia

Blood element

Representative source finding

Meaning

Red cells

Macrocytes and poikilocytes

Abnormal erythropoiesis

Neutrophils

Pseudo–Pelger-Huët cells

Abnormal granulocytic maturation

Platelets

Giant platelets

Megakaryocytic dysplasia

Monocytes

Relative or absolute monocytosis

Possible accompanying pattern

Slide 42 · Macrocytosis and poikilocytosis warrant context

Macrocytes are enlarged red cells.

Poikilocytosis denotes variation in erythrocyte shape.

In MDS, these smear findings can accompany marrow erythroid dysplasia.

Peripheral morphology is supportive, not pathognomonic.

Slide 43 · Giant platelets are another peripheral clue

Oversized platelets can be seen on blood smears.

They complement marrow evidence of dysplastic megakaryocytes.

Thrombocytopenia, when present, creates bleeding risk.

Recognize both qualitative morphology and quantitative platelet count.

Slide 44 · Monocytic findings need integrated interpretation

The blood may show relative or absolute monocytosis.

MDS morphology can include abnormalities in the monocytic lineage.

Monocytosis alone cannot define the disease subtype described here.

Robbins does not provide detailed monocytosis-based classification criteria in this section.

Slide 45 · Blasts indicate disease burden—not all MDS is AML

Compartment

MDS statement in the source

Interpretive caution

Bone marrow

Myeloid blasts may increase, but are less than 20% of cellularity

Apply genetic exceptions and current classification carefully

Peripheral blood

Blasts usually comprise less than 10% of leukocytes

Peripheral percentages alone are insufficient

Slide 46 · MDS and AML differ in dominant maturation phenotype

MDS: Dysplastic but partially differentiated myeloid cells and ineffective production.

AML: Accumulation of immature blasts that suppress normal hematopoiesis.

The two share mutations and can be linked by clonal evolution.

A single blast cut-off is not a complete modern classification algorithm.

Slide 47 · Morphology helps link a lineage to its output

Morphologic abnormality

Likely lineage affected

Potential clinical correlate

Megaloblastoid erythroblasts

Erythroid

Anemia / fatigue

Pseudo–Pelger-Huët cells

Granulocytic

Neutropenia / infection

Dysplastic megakaryocytes

Megakaryocytic

Thrombocytopenia / bleeding

Slide 48 · MDS may be identified incidentally

Up to half

The source states that MDS may first be discovered during routine blood testing.

An abnormal complete blood count can precede overt symptoms.

Slide 49 · Age distribution is strongly weighted to older adults

Mean age ≈ 70 years

Primary MDS predominantly presents in older adulthood.

Clinical implication

Persistent unexplained cytopenias in older adults warrant careful assessment.

Slide 50 · Pancytopenia explains the symptom triad

Anemia

Weakness

Neutropenia

Infections

Thrombocytopenia

Hemorrhages

Each symptom is linked to deficiency of a specific functional blood-cell compartment.

Slide 51 · Anemia produces symptomatic weakness

Ineffective erythropoiesis reduces functional circulating red cells.

The resulting anemia contributes to weakness and fatigue.

Erythroid dysplastic changes provide the marrow correlate.

Marrow erythroid activity cannot be equated with adequate red-cell output.

Slide 52 · Neutropenia drives infectious complications

Granulocytic maturation is dysplastic and may be ineffective.

Reduced neutrophil availability predisposes to infections.

Infection is a major source of morbidity and mortality in MDS.

Morphologic abnormalities and cell counts address different aspects of risk.

Slide 53 · Thrombocytopenia drives hemorrhagic complications

Dysplastic megakaryocytes may fail to support adequate platelet production.

Thrombocytopenia increases bleeding risk.

Bleeding contributes substantially to adverse outcomes.

Platelet size abnormalities do not substitute for a measured count.

Slide 54 · Application: Unexplained multilineage cytopenia

An older adult has persistent cytopenias. The peripheral smear shows macrocytes and bilobed neutrophils; Marrow aspirate shows dysplastic megakaryocytes.

What unifying disease process should be considered?

MDS: Dysplasia across several lineages with ineffective hematopoiesis.

Slide 55 · Three recurring prognostic dimensions

Risk estimation combines measurable disease burden and genetic complexity.

Blast burden

Increasing myeloid blasts suggests more advanced disease.

Cytopenia severity

More severe blood-cell deficits worsen clinical outlook.

Cytogenetic complexity

Multiple chromosomal abnormalities predict adverse outcomes.

Slide 56 · Primary MDS has a broad survival spectrum

<6 months to >5 years

This median-survival range across prognostic groups of primary MDS.

Why this spread matters

MDS is biologically heterogeneous; Aggregate survival figures cannot describe one individual.

Slide 57 · Therapy-related MDS has particularly poor outcomes

Median 4–8 months

A very unfavorable prognosis for therapy-related MDS.

Rapid transformation

In the source, progression to AML often occurs within 2–3 months of t-MDS diagnosis.

Slide 58 · Clonal evolution underlies progression

Founding MDS clone

Earlier drivers

Additional genetic changes

New cytogenetic or driver lesions

More aggressive disease

Higher-risk phenotypes

AML transformation

May occur in a subset

Slide 59 · Treatment choice reflects biology and fitness

Approach

Goal / rationale

Source context

Allogeneic HSC transplantation

Reconstitute normal hematopoiesis; Possible cure

Relatively young and fit patients

Supportive treatment

Manage infection and cytopenia complications

Older or medically frail patients

Hypomethylating agents

Improve effectiveness of hematopoiesis / counts

Responses in a subset

Thalidomide-like drugs

Genotype-correlated therapeutic response

Isolated del(5q)

Slide 60 · Allogeneic transplantation targets the clone

Conditioning / graft

Treatment selection requires patient fitness

New donor hematopoiesis

Reconstitution of blood production

Potential cure

A curative possibility, not a universal outcome

Slide 61 · Supportive treatment addresses immediate risks

Antibiotics may be needed to manage infectious complications.

Blood-product transfusions support patients with severe cytopenias.

Supportive approaches are especially important when curative therapy is not feasible.

Supportive care treats consequences of marrow failure, not necessarily the founding clone.

Slide 62 · Hypomethylating agents address abnormal epigenetic control

DNA hypomethylation

Pharmacologic epigenetic effect

Improved marrow effectiveness

Clinical improvement in a subset

Improved blood counts in some

No universal response implied

Slide 63 · Isolated del(5q) can inform treatment response

The 5q chromosomal region contains RPS14, implicated in ineffective erythropoiesis.

An isolated 5q deletion correlates with response to thalidomide-like drugs.

The cytogenetic finding has both mechanistic and predictive clinical value.

Association with drug response is a predictive—not merely diagnostic—observation.

Slide 64 · Genetic markers serve different purposes

Role

Question answered

MDS example in source

Diagnostic / classificatory

Is there a clonal pattern useful for classification?

Cytogenetic and molecular abnormalities

Prognostic

What predicts an adverse course?

Complex karyotype; TP53 association

Predictive

Who may respond to a treatment?

Isolated del(5q) and thalidomide-like drugs

Slide 65 · Distinguishing MDS from selected alternatives

Feature

MDS

Comparator

Ineffective maturation

Central lesion

MPN: Often increased mature cell production

Multilineage dysplasia

Characteristic

Nutritional megaloblastosis may mimic erythroid change

Blast excess

Variable, below threshold in this account

AML: Accumulation of myeloid blasts

Molecular context

Overlapping drivers and chromosomal abnormalities

Clonal hematopoiesis can show mutations without cytopenia

Slide 66 · Application: Therapy-related risk

A patient develops cytopenias several years after cytotoxic therapy. Marrow examination shows dysplasia and a complex karyotype.

What major clinical concern follows from this setting?

Therapy-related MDS may have rapid progression and poor prognosis.

Slide 67 · Application: Monosomy versus translocation

A patient with morphologic MDS has monosomy 7. Another patient with a myeloid neoplasm has t(15;17).

Which finding is emphasized as recurrent in MDS?

Monosomy 7; T(15;17) is a characteristic rearrangement of an AML subtype.

Slide 68 · Application: Prognostic reasoning

Two individuals have MDS. One has severe pancytopenia, increased blasts and several cytogenetic abnormalities; The other has milder blood abnormalities.

Which profile is associated with greater risk?

The patient with higher blast burden, worse cytopenias and complex cytogenetics.

Slide 69 · Integrated diagnostic synthesis

A robust diagnosis combines the marrow phenotype with blood and genetic data.

Counts + symptoms

Define clinically significant marrow dysfunction.

Blood / marrow morphology

Identify dysplastic maturation and estimate blast burden.

Cytogenetics + DNA

Establish clonality and refine classification / prognosis.

Slide 70 · Key concepts: Mechanism to morphology

MDS is a clonal neoplasm with ineffective myeloid differentiation.

Altered epigenetic regulation, RNA splicing and transcription are major pathogenetic themes.

Dysplasia may involve erythroid, granulocytic, monocytic and megakaryocytic lineages.

Characteristic blood findings include cytopenias and abnormal cell morphology.

The bone marrow phenotype must be interpreted with molecular and clinical context.

Slide 71 · Key concepts: Prognosis and management

The probability of AML evolution varies substantially by disease risk.

More blasts, more severe cytopenias and complex cytogenetics are adverse features.

Allogeneic transplant may be curative in selected fit patients.

Supportive care and disease-modifying agents have distinct roles.

Management should not be inferred from morphology alone.

Slide 72 · References and source boundaries

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026). Chapter 13: Myeloid Neoplasms; Myelodysplastic Neoplasms, pp. 560–566.

Primary slide facts were derived from the supplied robbins.md text and the indexed teaching unit; no chapter PDF was supplied for figure verification.

Microscopic concepts are shown with native editable schematics, not clinical micrographs. Subtype criteria and updated treatment guidelines were not independently reviewed.