Myeloid Neoplasms

Slide 1 · Myeloid Neoplasms

Clonal stem-cell disease • differentiation • marrow output

A pathology framework for AML, MDS, and MPN

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify myeloid tumors by the dominant defect in blood-cell production.

Link progenitor-cell mutations to differentiation, marrow morphology, and peripheral counts.

Interpret the AML–MDS–MPN spectrum, clonal evolution, and selected diagnostic pitfalls.

Apply a source-grounded approach to laboratory, marrow, and molecular findings.

Slide 3 · Three major categories arise from myeloid progenitors

Acute myeloid leukemia

Accumulating blasts; Loss of effective mature-cell production

Myelodysplastic neoplasms

Disordered maturation; Ineffective hematopoiesis

Myeloproliferative neoplasms

Growth-factor-independent expansion; Increased mature cells

The dominant biological defect is more informative than the label “myeloid.”

Slide 4 · Their common starting point is a transformed progenitor

Each family originates in a hematopoietic progenitor with acquired oncogenic alterations.

Bone marrow is usually the principal site of disease.

A neoplastic clone competes with or suppresses normal stem cells and progenitors.

Clinical manifestations follow the pattern of disturbed blood-cell production.

Clone determines output

Mutant progenitor

Clonal offspring

Altered output

Slide 5 · The marrow is both factory and disease compartment

Stem / progenitor clone

Abnormal differentiation or expansion

Marrow architecture altered

Peripheral blood phenotype

The blood count is an output signal; Marrow biology explains its cause.

Slide 6 · Secondary hematopoietic organs can become involved

The spleen and liver may support extramedullary hematopoiesis.

Lymph nodes can be involved, usually less prominently.

Organomegaly is particularly relevant to proliferative and fibrosing disorders.

The pattern depends on the neoplasm and the degree of marrow displacement.

Sites of involvement

Bone marrow

Spleen

Liver / nodes

Slide 7 · A CBC does not directly measure marrow productivity

High counts

Often reflect expanded output in myeloproliferation

Low counts

May reflect ineffective maturation or blast-mediated suppression

Mixed counts

Can occur with skewed lineages, progression, or overlap

Interpret counts alongside smear, marrow, and molecular findings.

Slide 8 · AML, MDS, and MPN: The central biological contrast

Dimension

AML

MDS

MPN

Dominant defect

Blast accumulation

Ineffective maturation

Uncontrolled expansion

Peripheral pattern

Often cytopenias

Usually cytopenias

Often increased cell counts

Marrow clue

Immature blasts

Dysplastic forms

Proliferating maturing cells

Important trajectory

Marrow failure

AML evolution

Fibrosis or acute leukemia

Slide 9 · Cell number and cell function are different variables

Neoplastic clone expands

Differentiation may fail

Output may be ineffective

Cytopenia despite active marrow

A hypercellular marrow may coexist with low circulating counts, particularly in MDS.

Slide 10 · Normal blood formation is hierarchical

Hematopoietic stem cell

Committed myeloid progenitors

Differentiating precursors

Mature RBCs, granulocytes, platelets

The transformed cell’s position in this hierarchy influences disease phenotype.

Slide 11 · Homeostasis couples demand to blood-cell output

Growth factors and cytokines regulate normal marrow proliferation and maturation.

Feedback adjusts red cell, granulocyte, and platelet production to physiologic needs.

The response requires intact signaling and an orderly differentiation program.

Myeloid tumors partially escape these controls.

Physiologic feedback

Cytokine signal

Receptor activation

Regulated output

Slide 12 · Neoplastic cells escape feedback control

Acquired driver event

Altered growth / differentiation signals

Clonal competitive advantage

Suppression of normal hematopoiesis

“Clonality” alone does not specify whether the output will be blastic, dysplastic, or proliferative.

Slide 13 · Cell of origin shapes clinical behavior

Pluripotent HSC

Can retain both myeloid and lymphoid differentiation potential

Myeloid-committed progenitor

Phenotype is generally restricted to myeloid production

Later myeloid precursor

Mutation effects depend on the maturation program available

Slide 14 · Differentiation is the second major axis

Blocked

Immature forms accumulate; AML archetype

Disordered

Abnormal maturation with ineffective output; MDS archetype

Largely preserved

Many mature elements produced; MPN archetype

The model is a teaching simplification: Actual tumors are genetically and clinically heterogeneous.

Slide 15 · Why myeloid tumors cause cytopenias

Leukemic blasts can crowd and suppress normal hematopoiesis.

Dysplastic progenitors may fail to generate effective mature cells.

Fibrotic replacement displaces functional marrow late in some MPNs.

The same low count can therefore arise through very different mechanisms.

Different roads to low counts

Blasts / dysplasia

Ineffective output

Cytopenias

Slide 16 · Why some myeloid tumors cause cytoses

Constitutively active signaling can bypass normal growth-factor requirements.

When maturation remains largely intact, mature blood elements accumulate.

The dominant expanded lineage helps distinguish MPN phenotypes.

High cell counts do not imply that blood cells function normally.

Differentiation persists

Constitutive signal

Mature cell excess

Cytosis

Slide 17 · Blood counts are a phenotype, not a lineage diagnosis

Finding

Possible mechanism

Context needed

Anemia

Ineffective erythropoiesis / crowding / fibrosis

Smear + marrow

Neutropenia

Production failure or blast expansion

Differential + marrow

Leukocytosis

Mature-cell proliferation or leukemic cells

Cell identification + molecular

Thrombocytosis

Clonal MPN or reactive change

Marrow + clinical exclusions

Thrombocytopenia

Marrow failure or advanced fibrosis

Marrow and disease course

Slide 18 · Categorical boundaries can overlap

Mutations influence both proliferative capacity and differentiation.

Some myeloid disorders display mixed myelodysplastic and myeloproliferative features.

Morphology and molecular findings may place a case between familiar patterns.

A single count should not override the integrated clinicopathologic picture.

Axes are not exclusive

Proliferation

Dysmaturation

Mixed phenotype

Slide 19 · A clonal disorder can evolve over time

Founding mutant clone

Additional acquired alterations

Changing marrow / blood pattern

More aggressive disease

Progression commonly involves the emergence or expansion of genetically altered subclones.

Slide 20 · AML is a frequent endpoint of progression

Both MDS and several MPNs can transform to acute myeloid leukemia.

Progression is accompanied by increasing blast production and loss of effective hematopoiesis.

The risk and tempo vary substantially among underlying diseases.

A change in counts, symptoms, or blast burden may signal biological evolution.

Clonal progression

Stable clone

Subclone expands

AML transformation

Slide 21 · CML demonstrates pluripotent stem-cell origin

BCR::ABL1-positive HSC

Chronic myeloid expansion

Clonal progression

Myeloid or lymphoid blast crisis

Lymphoid blast crisis supports origin upstream of myeloid / lymphoid lineage commitment.

Slide 22 · Clonal hematopoiesis may precede overt malignancy

Acquired cancer-gene mutations can create a detectable blood-cell clone before cytopenias appear.

This state in people whose blood counts remain normal.

It is a precursor state, not itself equivalent to AML, MDS, or MPN.

Additional biological context determines whether progression occurs.

CH ≠ leukemia

Mutation positive

Normal counts

Follow clinically

Slide 23 · Age expands the opportunity for selected clones

Somatic mutations accumulate

Some alter stem-cell fitness

A clone gradually expands

Detection becomes more common with age

Frequent involvement of DNMT3A and TET2 in clonal hematopoiesis.

Slide 24 · Clonal hematopoiesis: What the definition requires

Acquired mutation

At least one pathogenic alteration in a cancer-associated gene

Detectable clone

The chapter discusses a conventional sequence-read fraction threshold

Normal counts

No overt count abnormality defining a myeloid malignancy

Mutation detection must be interpreted in clinical context, not as an automatic cancer diagnosis.

Slide 25 · The biology of clonal hematopoiesis is selective

Most mutations arising over life do not confer an advantage.

Occasional changes in oncogenes or tumor suppressors promote stem-cell survival or growth.

TET2 and DNMT3A regulate epigenetic programs that influence differentiation.

Expanded clone size can increase the likelihood of later neoplasia.

Selective advantage

Mutant HSC

Selection

Expanded clone

Slide 26 · Clonal hematopoiesis has consequences beyond cancer

The chapter associates clonal hematopoiesis with systemic proinflammatory effects.

Clones carrying TET2 alterations are especially linked to monocyte/macrophage reprogramming.

Reported associations include greater severity of atherosclerosis and other inflammatory disease.

Association is not synonymous with inevitable malignant transformation.

Beyond malignancy

TET2 clone

Myeloid immune cells

Inflammation

Slide 27 · Clonal precursor, dysplasia, and leukemia differ

State

Peripheral counts

Dominant marrow event

Clonal hematopoiesis

Normal by definition

Selected mutation-bearing clone

MDS

Cytopenias common

Dysmaturation / ineffective hematopoiesis

AML

Cytopenias common

Expansion of immature blasts

Slide 28 · Acute myeloid leukemia arrests differentiation

Oncogenic alteration(s)

Impaired myeloid maturation

Blast accumulation in marrow

Suppressed normal cell formation

AML is defined by immature myeloid progenitors, not merely by a high circulating leukocyte count.

Slide 29 · Marrow failure drives many AML symptoms

Anemia contributes to fatigue and weakness.

Neutropenia or dysfunctional granulocytes increase infection susceptibility.

Thrombocytopenia produces mucosal bleeding, petechiae, and ecchymoses.

Symptoms may develop over weeks to months as marrow replacement advances.

Loss of normal production

Blasts

Marrow failure

Infection / bleeding

Slide 30 · AML morphology centers on immature myeloid cells

Myeloblasts often show delicate nuclear chromatin and prominent nucleoli.

Azurophilic cytoplasmic granules may be visible.

Auer rods support myeloid differentiation when identified.

Blood blast counts vary widely; Marrow evaluation may be decisive.

Morphology → workup

Immature cells

Granules ± Auer rods

Lineage confirmation

Slide 31 · Auer rods are a useful diagnostic clue

Appearance

Needle-like azurophilic cytoplasmic inclusions

Interpretation

Strongly support myeloid differentiation in a blast

Context

Especially conspicuous in acute promyelocytic leukemia

Morphologic description only; No synthetic specimen is presented.

Slide 32 · Lineage confirmation combines morphology and markers

Blasts can be difficult to classify as myeloid versus lymphoid by appearance alone.

Myeloperoxidase and myeloid surface antigens contribute to identification.

Flow cytometry defines populations and degrees of maturation.

Genetic findings then refine the disease category and clinical implications.

Integrated lineage workup

Immature population

Myeloid markers

Genetic subtyping

Slide 33 · Molecular lesions in AML are functionally diverse

Altered program

Examples in Robbins

Biological effect

Transcription factors

RUNX1::RUNX1T1, CBFB::MYH11

Impaired differentiation

Signaling

FLT3, RAS alterations

Growth / survival drive

Epigenetic regulation

IDH1, IDH2; chromatin regulators

Altered gene-expression state

Genome surveillance

TP53 dysfunction

High-risk biology

Slide 34 · Acute promyelocytic leukemia is mechanistically distinctive

PML::RARA fusion

Promyelocyte maturation blocked

Abnormal promyelocytes accumulate

Targeting fusion releases block

All-trans-retinoic acid and arsenic trioxide as therapies that counter this lesion.

Slide 35 · APL carries a particular bleeding danger

Promyelocytic leukemia can produce prominent coagulation abnormalities.

Disseminated intravascular coagulation is a major early risk.

Promyelocytes may contain numerous Auer rods, sometimes in bundles.

Recognizing the subtype has immediate clinicopathologic significance.

Early recognition matters

APL clone

Procoagulant effects

Bleeding / DIC

Slide 36 · AML is classified increasingly by genetics

AML into genetically defined and differentiation-defined groups.

Recurrent fusions and gene mutations can define biologically distinct entities.

Cytogenetic and molecular results can also inform prognosis and targeted treatment.

Morphology remains necessary but is not sufficient for comprehensive classification.

Complementary evidence

Morphology

Cytogenetics

Molecular profile

Slide 37 · Clinical setting adds information in AML

De novo disease

Some younger patients have recurrent balanced rearrangements

After genotoxic therapy

Chromosome 5 / 7 abnormalities and TP53 lesions may occur

Older adulthood

Mutations overlapping clonal hematopoiesis or MDS are common

Slide 38 · Myelodysplastic neoplasms produce cells inefficiently

Mutant multipotent clone

Abnormal maturation

Ineffective cell output

Peripheral cytopenias

A marrow rich in precursors can coexist with anemia, neutropenia, and thrombocytopenia.

Slide 39 · MDS is clonal and may affect several lineages

Erythroid, granulocytic, monocytic, and megakaryocytic maturation may be disordered.

The pattern and severity of dysplasia vary by patient.

Marrow is usually hypercellular but may be normocellular or hypocellular.

Cytopenias are often the clinical consequence of ineffective hematopoiesis.

Marrow–blood discordance

Dysplastic precursor

Ineffective output

Cytopenias

Slide 40 · Erythroid dysplasia has specific morphologic patterns

Erythroblasts may have irregular or budding nuclei.

Megaloblastoid change reflects disordered nuclear/cytoplasmic maturation.

Ring sideroblasts reflect perinuclear iron-laden mitochondria on iron staining.

These features must be interpreted with the overall workup, not in isolation.

Erythroid dysmaturation

Abnormal nuclei

Ring sideroblasts

Anemia

Slide 41 · Granulocytic dysplasia can be recognized in blood

Hypogranulation reflects abnormal granulocyte maturation.

Pseudo–Pelger-Huët neutrophils show markedly reduced nuclear segmentation.

Abnormal granulation and other cytoplasmic changes may occur.

Peripheral smear abnormalities can direct attention to marrow dysplasia.

Granulocyte dysmaturation

Hyposegmentation

Hypogranulation

Dysplasia

Slide 42 · Megakaryocytic dysplasia alters nuclear architecture

Some megakaryocytes have a single, poorly lobated nucleus.

Others show multiple separate nuclei rather than one multilobated nucleus.

Platelet abnormalities can accompany dysplastic megakaryopoiesis.

Dysplasia in multiple lineages strengthens a coherent MDS interpretation.

Megakaryocytic dysplasia

Abnormal nuclei

Faulty maturation

Platelet changes

Slide 43 · MDS is associated with several molecular programs

Epigenetic regulators

DNA methylation, histone and chromatin regulation

Splicing factors

RNA-processing abnormalities; Significance varies

Transcription factors

Disordered lineage maturation; RUNX1 example

No single listed mutation is by itself a substitute for integrated diagnosis.

Slide 44 · Genotoxic exposure changes the MDS context

MDS can arise without known prior therapy or after cytotoxic treatment / radiation.

Therapy-related cases tend to have adverse cytogenetic or molecular features.

The source identifies recurrent chromosome 5 and 7 abnormalities.

Previous treatment history is integral to marrow evaluation.

Clinical context matters

Prior genotoxicity

Acquired clonal injury

MDS risk

Slide 45 · MDS prognosis reflects severity and clonal genetics

Blast burden

Higher blasts indicate more advanced biology

Cytopenias

More severe deficits increase clinical consequences

Cytogenetics

Complex abnormalities often indicate worse outcomes

Substantial heterogeneity in progression to AML.

Slide 46 · Myeloproliferative neoplasms escape growth control

Constitutive kinase / signaling lesion

Growth-factor independence

Progenitor proliferation

Increased mature blood output

Unlike classic AML, differentiation is generally preserved in chronic-phase MPNs.

Slide 47 · The main MPNs differ by dominant lineage

Disorder

Driver context

Dominant clinical / pathologic pattern

CML

BCR::ABL1

Granulocytic proliferation

Polycythemia vera

Usually JAK2

Red-cell excess / panmyelosis

Essential thrombocythemia

JAK2, CALR, or MPL

Platelet excess

Primary myelofibrosis

JAK2, CALR, or MPL often

Atypical megakaryocytes / fibrosis

Slide 48 · Ligand-independent signaling explains proliferative output

Activated BCR-ABL or JAK-STAT axis

Persistent growth / survival signals

Expansion of maturing progeny

Cytosis and clonal dominance

The figure abstracts several kinase-driven pathways; Individual lesions are not interchangeable.

Slide 49 · BCR::ABL1 is the defining CML lesion

A fusion of sequences from BCR and ABL1 encodes an active tyrosine kinase.

The classic Philadelphia rearrangement is t(9;22).

Cryptic rearrangements may require molecular testing.

The kinase promotes pathways supporting progenitor proliferation and survival.

CML-defining fusion

T(9;22)

BCR::ABL1

Active kinase

Slide 50 · CML marrow and blood show granulocytic expansion

Marrow contains abundant maturing granulocytic precursors.

Circulating granulocytes appear at several stages of maturation.

Basophilia and frequently thrombocytosis accompany the pattern.

Splenic enlargement may follow extramedullary hematopoiesis.

Chronic phenotype

Myeloid expansion

Left shift / basophilia

Splenomegaly

Slide 51 · CML can progress from chronic disease to blast crisis

Chronic phase

Additional clonal abnormalities

Accelerated biology (sometimes)

Blast crisis

Blast crisis can be myeloid or lymphoid, reflecting an early stem-cell origin.

Slide 52 · Polycythemia vera is more than isolated erythrocytosis

The textbook characterizes marrow production as panmyelosis.

Red-cell mass is the chief determinant of hyperviscosity symptoms.

JAK2 activation reduces dependence on erythropoietin signaling.

Thrombotic and bleeding events are important complications.

PV phenotype

JAK2 pathway

Red-cell expansion

Viscosity / thrombosis

Slide 53 · In polycythemia vera, viscosity drives injury

Increased red-cell mass

Altered circulation and blood flow

Thrombosis risk / tissue symptoms

Possible organ damage

A normal-looking hematocrit does not exclude PV when iron deficiency modifies erythrocyte production.

Slide 54 · Essential thrombocythemia is clonal thrombopoiesis

Platelet production is increased despite normal growth controls.

JAK2, CALR, and MPL mutations converge on thrombopoietin-related signaling.

Marrow shows increased megakaryocytes, often unusually large.

Relative absence of overt fibrosis separates ET from fibrotic myelofibrosis.

ET phenotype

JAK2 / CALR / MPL

Megakaryocyte expansion

Platelet excess

Slide 55 · Excess platelets can coexist with bleeding

The platelets may be both numerous and functionally abnormal.

ET produces thromboses as well as spontaneous bleeding.

Acquired von Willebrand disease can contribute to bleeding in some patients.

Reactive thrombocytosis must be excluded when appropriate.

Quantity ≠ function

Excess count

Poor function

Clot OR bleed

Slide 56 · Primary myelofibrosis begins with a neoplastic clone

Mutated hematopoietic clone

Abnormal megakaryocyte signaling

Nonneoplastic fibroblast activation

Marrow collagen deposition

Fibroblasts depositing collagen are reactive rather than the primary neoplastic population.

Slide 57 · Myelofibrosis distorts marrow architecture

Megakaryocytes can be clustered with atypical bulbous or cloud-like nuclei.

Increasing fibrous tissue displaces functional hematopoietic spaces.

Advanced cases may have marked cytopenias and even osteosclerosis.

Bone marrow biopsy is essential to define the process.

Fibrogenic milieu

Atypical megakaryocytes

Reactive fibroblasts

Collagen fibrosis

Slide 58 · Extramedullary hematopoiesis changes the blood picture

Marrow fibrosis / displacement

HSC trafficking to spleen or liver

Extramedullary blood formation

Splenomegaly + immature circulating cells

The source associates fibrosed marrow with leukoerythroblastosis and dacryocytes.

Slide 59 · Teardrop cells are not specific for myelofibrosis

Dacryocytes may arise during abnormal red-cell transit through distorted marrow.

Nucleated red cells and early granulocytes can enter the blood.

Together these features create a leukoerythroblastic picture.

Other marrow infiltrative diseases can produce the same findings.

Suggestive, not unique

Distorted marrow

Cell deformation

Dacryocytes

Slide 60 · MPNs share complications but not identical mechanisms

Phenotype

Dominant mechanism

Representative concern

CML

BCR-ABL kinase / granulocytic output

Progression to blast crisis

PV

JAK2-associated erythroid excess

Thrombosis / hyperviscosity

ET

Megakaryocytic output + platelet dysfunction

Thrombosis or hemorrhage

PMF

Megakaryocyte-driven stromal fibrosis

Marrow failure / splenomegaly

Slide 61 · Start diagnosis with the dominant blood phenotype

CBC and differential

Peripheral smear morphology

Marrow aspirate / core biopsy

Cytogenetic + molecular integration

The order is a diagnostic framework, not a replacement for entity-specific criteria.

Slide 62 · Marrow morphology resolves apparently contradictory counts

Identify blasts, differentiated precursors, dysplasia, and megakaryocytic pattern.

Assess marrow cellularity and architecture rather than counts alone.

Evaluate stromal fibrosis when clinically indicated.

Interpret the marrow in the setting of circulating counts and symptoms.

Biopsy + aspirate

Cellularity

Maturation / blasts

Fibrosis

Slide 63 · Molecular testing establishes identity and mechanism

Clinical suspicion

Key molecular context

Diagnostic value

CML

BCR::ABL1

Defines the disease

Classic Ph-negative MPN

JAK2 / CALR / MPL

Supports clonal kinase signaling

AML

Recurrent fusions / mutated genes

Subtype and risk information

MDS

Mutation profile + cytogenetics

Supports integrated classification

Slide 64 · Important interpretation traps

A normal leukocyte count does not exclude AML when blasts remain in marrow.

A hypercellular marrow does not guarantee effective peripheral production.

Reactive thrombocytosis can resemble ET.

Iron deficiency may mask erythrocytosis; Dacryocytes are not unique to PMF.

Integrate evidence

Single test

Context missing

Wrong category

Slide 65 · Case: Cytopenias with circulating blasts

Clinical pattern

New fatigue, mucosal bleeding, low platelets; Marrow contains many immature cells.

Reasoning

AML is favored: An immature myeloid clone suppresses normal hematopoiesis. Confirm lineage and genetics.

The source does not support diagnosis from symptoms alone.

Slide 66 · Case: Hypercellular marrow with peripheral anemia

Clinical pattern

Persistent cytopenia; Marrow contains numerous precursors with dysplastic nuclei.

Reasoning

Consider MDS: Precursor expansion coexists with ineffective output. Exclude mimics and integrate genetics.

Hypocellularity is not a prerequisite for MDS.

Slide 67 · Case: Leukocytosis with left-shifted granulocytes

Clinical pattern

Marked granulocytic proliferation, basophilia, splenic enlargement.

Reasoning

CML enters the differential. BCR::ABL1 detection establishes the defining molecular lesion.

Mature granulocytic expansion differs from an undifferentiated blast population.

Slide 68 · Case: Splenomegaly, anemia, dacryocytes

Clinical pattern

Leukoerythroblastosis, teardrop erythrocytes, and a large spleen.

Reasoning

Marrow fibrosis / displacement is likely. Assess megakaryocytes, reticulin, and alternative infiltrative causes.

The smear suggests a mechanism; It does not independently prove primary myelofibrosis.

Slide 69 · A single explanatory model organizes the family

Proliferation

How strongly does the clone expand?

Differentiation

Are mature cells produced normally, poorly, or not at all?

Evolution

Has the clone acquired fibrosing or blast-transforming behavior?

These three questions organize phenotype without replacing disease-specific diagnostic criteria.

Slide 70 · The major patterns in one view

Family

Dominant problem

Typical clue

Potential course

AML

Blast arrest

Marrow failure

Rapid clinical deterioration

MDS

Ineffective maturation

Dysplasia + cytopenias

AML progression

MPN

Excess mature-cell output

Cytoses / extramedullary sites

Spent fibrosis or leukemia

Slide 71 · Final synthesis: Diagnose the mechanism and its stage

Establish whether the dominant process is blastic, dysplastic, or proliferative.

Relate the phenotype to its progenitor compartment and mutated cellular program.

Read the smear, marrow, and molecular findings together.

Account for overlap and clonal evolution rather than assuming static boundaries.

Slide 72 · Principal reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 13: Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus.

Myeloid Neoplasms, pp. 560–561; contextual disease sections, pp. 561–571.

Text and concepts are paraphrased; diagrams are original editable teaching schematics.