WHO and Beyond: Practical Strategies for Myeloid

Neoplasms

Kathryn Foucar, M.D.kfoucar@salud.unm.edu

2019 Hawaii HemepathConference

Objectives:• Define the Pathologists’ expanding

role in disease classification• Discuss blood and bone marrow

features that are clues to subtypes of myeloid neoplasms

• Discuss new WHO 2016 classification criteria

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Myeloid Neoplasms- WHO 2016

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AML: 25 subtypes; 3 new genetic entities(numerous prognostic “types”)(new criteria for blast enumeration)(new familial/germline predisposition category)

MDS: 7 subtypes(all new names; some integration of molecular)

MDS/MPN: 5 subtypes; 1 new entity(new molecular genetic criteria)

MPN: 8 subtypes(new molecular genetic criteria)

Complexity of Classification• WHO 2016: Many exclusionary criteria within

some entities • Elaborate morphologic criteria for MDS despite

evidence of limited reproducibility (Major issue when genetic studies normal)

• 25 subtypes of AML with many additionalgenetic features contributing prognostic information

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Diagnostic Approach • Morphology and clinicopathologic

correlation are still step 1• CBC and blood smear review • Count blasts, assess dysplasia • Determine lineage of blasts by flow

cytometry, especially when increased• Integrate unique morphologic features

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Blast Enumeration • Morphology is gold standard for

blast enumeration • Cytochemical stains uniquely

helpful in some circumstances• Flow blast percent does not replace

morphologic blast present 6

Blast Lineage Determination • Flow cytometry required for all

acute leukemias to confirm lineage

• IHC can be used for blast lineage determination in selected circumstances

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Systematic Approach• Recognize blasts and blast equivalents • Promonocytes always included in blast percentage• Promyelocytes only included in blast percentage in

APL• Blast percentage based on total BM cells for all

AML subtypes (revised erythroleukemia criteria)• Blast enumeration based on morphologic

differential cell count (not flow cytometry percents)8

Myeloid Blasts

9Morphologic Assessment/Enumeration

Blast Lineage?

10Acute megakaryoblastic leukemia

Clumps of Abnormal Cells

11Acute megakaryoblastic leukemia

Systematic Approach: Dysplasia• What morphologic features constitute dysplasia?• Dysplastic cells must exceed 10% in a lineage in MDS;

≥50% in AML-MRC• Dysplasia assessment very challenging

– lack of consensus at 10% threshold– better consensus at 40% threshold, especially for

megakaryocytes • Dysplasia assessment based on blood and BM aspirate

smears for erythroid and granulocytic lineages• Megakaryocyte dysplasia based on evaluation of at

least 30 megakaryocytes on core biopsy sections 12

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Dysplasia in Each Lineage

Percent Dysplastic cells critical

Megakaryocyte Assessment for Dysplasia

14Increased, hypolobated megakaryocytes

Dysplasia Caveats• Many benign causes of RBC

pathology in blood and bone marrow

• Excellent stain quality essential to assess neutrophils, identify blasts

• Adequacy of BMA and Bx key• Know key MDS mimics 15

Routine Assessment for Myeloid Neoplasms Blood: CBC

Morphology (dysplasia assessment)Blast percent

BMA: Morphology (dysplasia assessment)Blast percentPossible MPO, NSEIron stain essential

BM bx, clot section:

CellularityBone Confirm BMA findingsAssess megakaryocytes morphology and distribution

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CBC findings at presentationAML Hematopoietic failure (markedly reduced RBC,

absolute neutrophil and platelet counts);usually no maturation

Variable % blasts; highly variable WBC

MDS Cytopenia(s) requiredDysplasia (≥ 10% required)Virtually never have leukocytosis at presentation Variable blast % (<20%)

MDS/MPN Hybrid blood pictureAt least one elevated and one reduced HP lineage Variable blast % (<20%)

MPN At least one elevated lineage (cytosis) No cytopenias in stable phaseLow blast % in stable phase

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MDS MPN AML

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Comparison of Blood Features

MDS CML AML

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Comparison of Bone Marrow Features

Atypical CML

2073y/o F: WBC 160, Hgb 8, PLT 112

Integration of CBC, Blast %, and Dysplasia Assessment

• Reasonable prediction of correct WHO category (exceptions)

• Allows for upfront determination of appropriate specialized testing

• Allows pathologist to alert clinician regarding potential medical emergencies (e.g. APL)

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Reporting Requirements • WHO Subtype of Myeloid Neoplasm• All standard items (Bld, CBC,

morphology, special stains, IP and cytochemical stains)

• Percent blasts in blood and BM for all myeloid neoplasms

• Dysplasia percent (each lineage): MDS, MDS/MPN, AML

• Flow cytometry findings 22

Specialized Testing Goals• Lineage of blasts and potential MRD

monitoring by FCI• Confirmation of specific myeloid

neoplasm subtypes by genetic testing, also used in MRD monitoring

• Prognosis assessment by genetic testing; clonal evolution assessment

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Final Integrated Report• Once all specialized (often referral) testing completed

• ASH-CAP CPG requirement for all acute leukemias

• Most feasible at referral centers24

In the world of Myeloid Neoplasms, CML has always led

the way25

Battle between Bennett

and Virchow

Leukemia First Described in 1845

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Clinico-Pathologic Correlation

Blood:Buffy Coat CML:WBC > 900,000WBC’s

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Unstained

130 years ago150 years ago 28

1960Nowell and Hungerford

291st Neoplasm linked to cytogenetic abnormality

Philadelphia Chromosome

Courtesy J. Anastasi

1973

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t(9;22) (q34.1;q11.2)

31Courtesy J. AnastasiDavid Baltimore, 1980’s

1980’s; different groups

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t(9;22) (q34.1;q11.2)

Ph1: reciprocal translocationBCR-ABL1 fusion gene

1982-1985

Translocation results in constitutive tyrosine kinase activity CML 32

CML

•1st genetically defined leukemia

•Must document BCR-ABL1fusion gene for diagnosis

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Source: Kalidas, et al. NEJM 2001; 286:895-898

Leukemogenic Effects

of Constitutive

Non-Receptor Tyrosine

Kinase Activation

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Source: Kalidas, et al. NEJM 2001;286:895-898

Therapy to Block Tyrosine Kinase Activity (1987-1998 )

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Blast-Phase in CML: 1983-present

Source: Hehlmann, R. How I treat CML blast crisis. Blood 2012;120:737.

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CML•First genetically defined

distinct clinicopathologicentity

•Diagnosis cannot be made without genetic confirmation of BCR-ABL1.

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Clincopathology Entity Model Applied to all WHO Neoplasms

• Entities based on clinical features, morphology, IP, cytogenetics or molecular (2001-Present)

• Entire new group of germline predisposition neoplasms added (family history and molecular genetic confirmation)

• Entitles based on Clinical Advisory Committee discussions

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Acute Myeloid Leukemia• Blast enumeration, dysplasia assessment and

lineage confirmation by flow cytometry still essential

• Progressively greater role of molecular genetic testing in defining entities, refining prognosis assessment, minimal residual disease monitoring, and identifying patients for possible targeted therapies.

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AML: Many Diseases• 198 recurrent mutations (molecular)• 819 recurrent structural chromosomal

abnormalities (CC)• Ongoing recognition of additional

mutations or relevant combinations of mutations

40Watt, Knowles Neoplastic Hematopathology, 3rd edition, 2014

AML – Types of Mutations

41Source: CDWatt,et al. Knowles Neoplastic Hematopathology. 2014.

Class I: Non-specificClass II: AML-definingClass III: Epigenetic

Source: NEJM 366(12):1079-89, 2012

Molecular Fine Tuning of Prognostic Group

42Integration of molecular with karyotype

Additional Reporting Requirements

•Integrate cytogenetics, FISH and molecular results in terms of diagnosis, prognosis and targeted therapy

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Myelodysplasia and MDS/MPN

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• Key CBC parameters, morphologic features and blast percentage

• Lesser role of genetics in defining entitles (some exceptions)

• Major role of genetics in risk stratification, possible targeted therapy

CMML

45WBC 24.3, Hgb 8.1, PLT 349

CMML-BX

46Hypercellular; Gran.pred, abnormal megas

Other Myeloid Neoplasms

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• Similar clinicopathologic approach to define specific entities in neoplasms with <20% blasts

• MPN: Key CBC parameters, BM morphology, evidence of splenomegaly and additional genetic testing beyond BCR-ABL1 are key (e.g. JAK2, CALR, MPL, and CSF3R)

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•59a36

BM: hyperlobulated megas; Bld: ↑ ↑ plts

Essential Thrombocythemia1.7 million plts

Role of the Pathologist

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Primary care setting1. Recognition of myeloid neoplasm and general

neoplasm category2. Exclusion of myeloid neoplasm lookalikes3. Rapid diagnosis or recognition of possible

APL4. Oversee acquisition of specimens for all

necessary specialized testing (unless patient transferred)

Role of the Pathologist

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Tertiary care setting

1. Integrate routine and esoteric testing

2. Provide comprehensive risk stratification information

3. Monitor treatment response and minimal residual disease testing