2008 WHO Revision Classification of Tumours

8/3/2019 2008 WHO Revision Classification of Tumours

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WHO Classification of Tumours of

the Hematopoietic and Lymphoid

Tissues, 4th Ed.(with emphasis on the myeloid neoplasms)

J. Vardiman, University of Chicago, Chicago, IL


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The WHO Classification, 4th Edition


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Why classify?

Classification is the language of medicine: diseases

must be described, defined and named before they can

be diagnosed, treated and studied. Furthermore, aconsensus on definitions and terminology is essential

for both clinical practice and investigation.

N.L. Harris, et al. Introduction to the WHO classification of tumours of

haematopoietic and lymphoid tissues, in WHO Classification of Tumoursof Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris

NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, (Eds), IARC, Lyon


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Discussion Outline1.Background/Principles of the WHO Classification2.Unique features of the 4th edition:

- Acknowledges the need for better minimal diagnosticcriteria to distinguish reactive and/or pre-neoplastic lesionsfrom early or overt neoplasms

-Acknowledges some cases may have biologic features thatoverlap classification subgroups and thus will be difficult orimpossible to classify into existing nomenclature

3. Controversial / confusing issues in the myeloidneoplasms:

- MPN, prefibrotic PMF vs. ET

- Classification issues in MDS

- New categories in AML and old categoriesredefined


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The WHO Classification was ajoint effort of the EAHP and the

SH, sponsored by the WHO.

The WHO and the Societies

selected editors to propose alist of diseases; authors for the

individual chapters were

chosen for their expertise in

various areas.

All editors and authorsvolunteered their efforts.


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Two clinical advisory

committees one for lymphoid

and one for myeloid

neoplasms each comprised

of ~50 internationally

recognized clinicians/clinical

scientists, met with the

pathologists to discuss the

merits of the proposed

classification

More than 150 pathologists,clinicians and scientists

participated in the final writing

of the 4th edition

Clinical Advisory Committees

Lymphoid (top) and Myeloid (below)


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Principles of the WHO Classification:

1)Utilizes all available information clinical findings,morphology, immunophenotype, and genetic

features in an attempt to define disease entities

of clinical significance; the relative importance ofeach feature may vary among different diseases

2)It is a consensus classification in which amajority of experts have agreed, not necessarily

unanimously, to the criteria for the definition and

classification of specific disease entities


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CML a prototype for the integration of clinical,

morphologic, and genetic data:Disease -> chromosome-> genes-> pathways-> designed Rx

BCR-ABLfusion gene

tyrosine kinase

constitutive act.

imatinib

But, mysteries still remain ..


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Karyotype: 46 XX, t(9:22)(q34;q11.2), PCR: BCR-ABL1 fusion detected


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Karyotype: 46 XX; PCR: BCR-ABL1 NOT DETECTED


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Karyotype: 46 XX; PCR: BCR-ABL1 NOT DETECTED; JAK2V617F DETECTED


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Karyotype: 46 XX, t(9:22)(q34;q11.2), PCR: BCR-ABL1 fusion is present

JAK2V617F is present


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Discussion Outline

1.Background/Principles of the WHO Classification2.Unique features of the 4th edition:

- Acknowledges the need for better minimal diagnosticcriteria to distinguish reactive and/or pre-neoplastic lesionsfrom early or overt neoplasms; attempts to provide workablecriteria for diagnosis and further study

-Acknowledges some cases may have biologic features thatoverlap classification subgroups and thus will be difficult orimpossible to classify into existing nomenclature; attempts toidentify these gray zones such as B-cell lymphoma,unclassifiable with features intermediate between DLBCL andBurkitt or between DLBCL and classical HL

3. Controversial / confusing issues in the myeloidneoplasms:

- MPN, prefibrotic PMF vs. ET




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. the frequent application of immunophenotypic

and genetic studies to blood, bone marrow and

lymph node samples often lead to the discovery ofabnormalities where there is no clear cut evidence

of disease at least of a neoplastic disease and

the question arises whether these may be

predisposing, pre-neoplastic, or early

neoplastic lesions, or, be even inconsequential.


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MGUS-Approx. 3% of pts. >50 yrs. of age, 9% >85 yrs.-M component less than myeloma (


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WBC=6.8K/uL

69% lymphs

4.69 K/uL abs lymphs

45% of lymphs: CD19+,CD5+,CD23+,Lambda

2100 clonal B-lymphocytes/uL

ficolled specimen


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Monoclonal B-cell lymphocytosis of

undetermined significance (MBCL)

-3-12% of the population >40 years of age (anincidence more than 100 times the incidence of CLLin the general population)

-Size of clone may range from


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Rossi D, et al. The

prognosis of clinicalmonoclonal B cell

lymphocytosis* differsfrom prognosis of Rai 0

chronic lymphocytic

leukemia and isrecapitulated by biological

risk factors. British Journalof Hematology

2009;146:64-75

* Clinical monoclonal B cell

lymphocytosis is diagnosed

during evaluation of

lymphocytosis, whereas low

count monoclonal Blymphocytosis is found in

patients with normal

lymphocyte counts


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WHO Definition of CLL/SLLIn the absence of extramedullary tissue involvement, there must be

> 5 x 109/L monoclonal B-lymphocytes* with a CLL

phenotypein the peripheral blood to make the diagnosis of

CLL. In such cases, the lymphocytosis should be present for atleast 3 months. The diagnosis of CLL may also be made with lower

lymphocyte counts if there is cytopenia or disease-relatedsymptoms.

SLL is used for non-leukemic cases with the tissue morphologyand immunophenotype of CLL; lymphadenopathy, no cytopenias

due to BM infiltration by CLL/SLL, and


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Genotypic and/or immunophenotypic findings of anentity but no clinical disease.

Precursor or predisposing factor?

Monoclonal gammopathy of undetermined significance

Monoclonal lymphocytosis of uncertain significance

Isolated in situ follicular lymphoma

Normal lymphoid tissue with isolated follicles showing BCL2expression, with or without evidence of lymphoma elsewhere. Significance asan isolated finding (no lymphoma elsewhere) remains uncertain.

BCL2 CD10

BCL2 CD10


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Minimal Diagnostic Criteria for MDS


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* Neutrophil granularity depends on optimal staining

*


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34 yr. old woman with refractory anemia

CDA Type II


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68 yr. old woman with refractory macrocytic anemia


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60 year old man with pancytopenia: MDS or Aplastic Anemia?


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Major questions at CAC meeting

regarding MDS

1.Can minimal diagnostic criteria for MDS be betterdefined?

2.Some patients dont fit into previous WHOcategories, e.g., patients with refractorythrombocytopenia. Can refinements be made toprovide better correlation with specific clinical

features?

3.Does there need to be a separate classification forchildhood MDS?


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MDS Minimal Diagnostic Criteria

WHO 2001, 2008

The diagnosis of MDS is made when 10% or more ofthe cells of at least one myeloid lineage shows

unequivocal morphologic dysplasia, and when allcauses of secondary or transient dysplasia

(nutritional deficiency, viral disorders, medication,

growth factor therapy, copper deficiency, heavy metalpoisoning, etc.) have been adequately excluded.


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MDS-minimal criteria, 2008

In the presence of a persistent, refractory cytopenia butinconclusive diagnostic morphologic findings, the following

cytogenetic abnormalities can be considered as presumptive

evidence of MDS:

Unbalanced:

-7 or del(7q)

-5 or del (5q)

i(17q) or t(17p)

-13 or del(13q)

del (11q)

del(12p) or t(12p)

del(9q)

idic (X)(q13)

Balanced:

t(11;16)(q23;p13.3)

t(3;21)(q26.2;q22.1)

t(1;3)(p36.3;q21.2)

t(1;22)(p21;q23)

inv(3)(q21q26.2)

t(6;9)(p23;q24)

Other:

Complex abn (3 or more)


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-Abnormal light scatter properties-Abnormal antigen density-Abnormal expression of non-myeloid antigens-Abnormal maturation pattern, withdyssynchronous/abnormal expression of antigensnormally expressed during maturation

Multiparameter flow

cytometry in MDS


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FCI Erythroid Abnormalities in MDS

Stetler-Stevenson, M. et al. Blood 2001;98:979

Normal

CD71

Gly A

CD45

SSC

Erythroid Gate

MDS

CD71

Gly A

CD71

Gly A

MDS


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MDS: Minimal Diagnostic

Criteria,WHO 2008

FC results are highly suggestive of MDS if thereare three or more aberrant features in erythroid,granulocytic or monocytic maturation. They are notsufficient, however, for the diagnosis of MDS.

Cases with inconclusive morphologic andcytogenetic findings and three or more aberrantfeatures by flow cytometry should be re-evaluatedover several months for definitive morphologic orcytogenetic evidence of MDS.


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68 yr. old woman with refractory macrocytic anemia


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Idiopathic cytopenia of undeterminedsignificance (ICUS)

-Is not a myelodysplastic classification category-May be used to describe patients with arefractory cytopenia of undetermined cause;

follow-up in some cases may show sufficient

evidence to classify them as MDS


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Enumeration of Blasts in MDS

- Blast % should be determined from a visual 500 cell

differential performed on cellular aspirate smears

- CD34 by flow cytometry is not recommended as a

substitute for visual inspection; not all blasts are CD34+and the specimen for flow may be hemodilute

-CD34 by IHC on bone marrow biopsy may be helpfulwhen the aspirate is hemodilute or cannot be obtained

Pic of CD34biopsy here

CD34


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Discussion Outline1.Background/Principles of the WHO Classification2.Unique features of the 4th edition:

- Acknowledges difficulties in distinguishing somepredisposing or pre-neoplastic lesions from truly neoplasticdisorders; attempts to establish workable criteria forclassification and further evaluation of such lesions

- Acknowledges that in some cases there may bemorphologic and biologic overlap between subgroups, andattempts to identify these gray zones in classification, e.g.,Burkitt vs. DLBCL, Classical HL vs. DLBCL

3.Controversial / confusing issues in the myeloid

neoplasms:- MPN, prefibrotic PMF vs. ET




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WHO Classification of Myeloid

NeoplasmsI. Myeloproliferative Neoplasms*II. Myeloid/Lymphoid Neoplasms associated with

eosinophilia and abnormalities ofPDGFRA,PDGFRB orFGFR1**

III.Myelodysplastic / Myeloproliferative Neoplasms*IV.Myelodysplastic SyndromesV. Acute myeloid Leukemia* Name change

* * New category


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Myeloproliferative NeoplasmsChronic myelogenous leukemia, BCR-ABL1 positive

Chronic neutrophilic leukemia

Polycythemia vera*

Primary myelofibrosis*Essential thrombocythemia*

Chronic eosinophilic leukemia, not otherwise

specified*

Mastocytosis*

Myeloproliferative neoplasm, unclassifiable

* name change, new addition and/or change in diagnostic criteria


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Changes in the Criteria for Diagnosis and

Classification of the MPN influenced by:

1)Acquired somatic gene mutations andrearrangements that encode abnormal tyrosine

kinases involved in the pathogenesis of MPN can alsobe used as diagnostic markers

2) Relatively recent appreciation that histologic featuresin the bone marrow biopsy often correlate with

clinical features and outcome in MPN, particularly PV,

ET and PMF, and can be used as diagnostic criteria inconjunction with other clinical and laboratory

parameters


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Any of these abnormalities identifies the case as neoplastic


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JAK2 V617F1.How does one mutation lead to three different diseases?

A. Mutated JAK2is the sole event and the

phenotype depends on

Genetic background of the patient

Level ofJAK2V617F allele burden

B. Mutated JAK2is a secondary event to an earlier

genetic defect that predisposes to the mutation and

determines the phenotype

C. Any of, all of, or none of the above


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Genetic background of the patient determines the

phenotype

1. PV is more common in men, ET is more common in women2. Analysis of single nucleotide polymorphisms in JAK2, MPL,

EPORand G-CSFRshowed specific SNPS in germline JAK2

and EPOR that were associated with either PV or ET

3. Families with a predilection to develop MPN acquire theJAK2V617F as a somatic mutation, indicating an inherited

predilection for the disease; in some families only PV, ET or

PMF occurs, but in others all diseases are represented.


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Dosage of JAK2 V617F determines the

phenotype

1. Homozygosity ofJAK2V617F is found in ~30% of PV, ~5%of ET, and ~15% of PMF patients

2. Transgenic models with low JAK2V617F expression leadsto thrombocytosis, and ET-like phenotype; not PV

3. Analysis of erythroid colonies from patients with PValways shows homozygous cells regardless of allele

burden of patient; analysis of ET patients almost never

shows homozygous cells

Sooooo maybe PV, ET and PMF are a single disease

process, and the phenotype just depends on the genedosage?


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The JAK 2mutation is a secondary event, and an

unknown pre-JAK2lesion determines the phenotype

1. Discrepancy between clonal vs. JAK2mutated cells; by X-inactivation studies a number of women have been shown to

have 100% clonal granulopoiesis, but to have a JAK2 V617F /

JAK2 less than 25% in the granulocytes

2.Commonly, in patients with mutated JAK2 who develop blasttransformation, the acute phase blasts lack the mutation

TET2

mutations?


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JAK2 V617F1.How does one mutation lead to three different diseases?

A. Mutated JAK2is the sole event and the

phenotype depends on

Genetic background of the patient

Level ofJAK2V617F allele burden

B. Mutated JAK2is a secondary event to an earlier

genetic defect that predisposes to the mutation and

determines the phenotype

C. Any of, all of, or none of the above


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Any of these abnormalities identifies the case as neoplastic


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Pertinent Histopathologic

Findings in MPN

Lineages involved in the proliferation

Maturation pattern within the lineagesMegakaryocyte topography

Megakaryocyte cytology

Reticulin/Collagen Fibrosis

correlate with other clinical and laboratory

findings and with disease progression


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Polycythemia vera,(polycythemic stage)

-Panmyelosis

-Megakaryocytes ofvariable sizes, lackingsignificant cytologicdysplasia, often loosely

clustered

PV


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Panmyelosis in a patient with polycythemia vera


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Fibrotic phase, PMF


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Primary myelofibrosis, Prefibrotic phase


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Essential

thrombocythemia

- Variably cellular bone

marrow, often normally

cellular

-Increased numbers of

large megakaryocytes with

hyperlobulated nuclei,

minimal granulocytic or

erythroid proliferation


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Revised WHO criteria for PV

MAJOR CRITERIA:1. Hemoglobin > 18.5 g/dL in men, >16.5 g/dL in women orother evidence of increased red cell volume/mass*

2.JAK2 V617F or other functionally similarJAK2 mutation

MINOR CRITERIA:1. Bone marrow biopsy hypercellular for age with panmyelosis

2. Low serum EPO

3. Endogenous erythroid colony formation in vitro

*Hb or Hct >99th percentile of method specific reference range for age, sex,

altitude of residence, red cell mass >25% above normal predicted mean value,

Diagnosis requires: Major criteria 1 & 2 plus one minor criterion,

or Major criterion 1 plus two minor criteria


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Peripheral Blood Mutation screening for JAK2 V617F

&

Serum EPO measurement

V617F (+)

EPO Decr

V617F (+)

EPO Nl or Inc

V617F (-)

EPO Decr

V617F (-)

EPO Nl or Inc

PV highly

likelyPV likely PV possible PV unlikely

Bm Bx

encouraged,not essential

Bm Bx

recommendedto confirm

JAK2 exon 12

screen, Bm Bx

If not c/w PV, ?

congenital PVEpoR mutation

Consider

secondaryPV

If you suspect PV: Hb >18.5 g/dL (M), >16.5g/dL (F)


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Revised WHO criteria for ET

1. Sustained platelet count 450 x 109/L

2. Bone marrow biopsy showing proliferation of enlarged,

mature megakaryocytes; no significant granulocytic or

erythroid proliferation

3. Not meeting WHO criteria for PV, PMF, CML,BCR-ABL1+,

or MDS

4. Demonstration ofJAK2 V617F or similar activating

mutation, or demonstration that the thrombocytosis is not

reactive

All 4 criteria must be met


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Revised WHO criteria for PMF

Major criteria:

1. Not meeting WHO criteria for PV, CML, MDS, or other MPN2. Megakaryocyte proliferation/ atypia accompanied by reticulin and/or

collagen fibrosis, or in absence of fibrosis, atypical megakaryocyte

proliferation and marrow hypercellularity with granulocytic proliferation

3.

Demonstration of JAK2 V617F, or that bone marrow fibrosis is notsecondary to infection, autoimmune disorder or other chronic

inflammatory condition, lymphoproliferative disorder, metastatic cancer,

or toxic myelopathy

Minor criteria

1. Leukoerythroblastosis 3. Increase in LDH

2. Anemia 4. Palpable splenomegaly

Diagnosis requires meeting all 3 major and 2 minor criteria


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Primary myelofibrosis, Prefibrotic phase


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Comparison of classification of cases of ETaccording to PVSG vs WHO Criteria for MPDs

Theile J, Kvasnicka HM Ann Hematol 2003;82:148

PVSG Criteria

WHO Criteria

ET=162 (33.55)

PMF, Prefibrotic* = 321 (66.5)

*grade 0 or 1 reticulin fibrosis

483 pts


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PMF-0

PMF-1

ET

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Relative survival according to WHO (%)

5 yrs. 10 yrs. 15 yrs.

ET 100.0 4.4 99.1 7.8 83.9 17.6PMF-0 92.1 7.1 80.8 11.7 67.9 23.7

PMF-1 83.0 9.5 67.3 17.8 55.4 29.8

Years after diagnosis

%S

urvival

n=476

Survival in early MPNs with thrombocythemia


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- Evaluated 370 patients with ET diagnosed according to PVSG criteria

-Three experienced observers used the WHO criteria for diagnosis ofET and pre-fibrotic PMF

-The diagnoses were not reproducible among the three observers-Concluded that WHO histologic criteria are difficult to apply, and theyfound no survival differences between ET and PMF, indicating there is

no validity to the distinction of ET from pre-fibrotic PMF with

thrombocythemia the WHO criteria are not reproducible

-Of note is that nearly 25% of the patients in the study diagnosed as ETby PVSG guidelines had 3+ to 4+ fibrosis (scale 1-4); some hadosteosclerosis*

Blood 2008;111:60-70

*Campbell P, et al. J Clin Oncol 2009;27:2991-2119


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A B C D E

F

ET:

PMF:

Representative fields from 10 of 145 cases of MPN evaluated independently by

four observers (JT, AO, CH, JV) and classified at ET or pre-fibrotic PMF

Observer reproducibility on these 10 cases was 100%, with observer

reproducibility of about 80-85% of all cases


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Myeloid/lymphoid

neoplasms with

eosinophilia

Abnormalities of:

PDGFRA, PDGFRB,

orFGFR1

1. All result from formation of a fusion gene encoding an abnormal tyrosinekinase, usually but not invariably with > 1500 eos/uL.

2. Cases with rearranged PDGFRA usually present as CEL, often with mastcell proliferation as well; rare cases present as T-LBL with eosinophilia

3. Cases with rearranged PDGFRB have features of CMML with eosinophiliaor CEL

4. Patients with rearranged PDGFRA orPDGFRB respond to imatinib5.

Cases with FGFR1 rearrangements may present as CEL (8p11myeloproliferative syndrome) but presentation as T- or B-lymphoblastic

leukemia/lymphoma with eosinophilia is also common

6. Their similarities yet variable clinical and morphologic presentationsargued for their placement in a separate and unique subgroup


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Summary of changes in MPN

1. Name change from MPD to MPN2. Mastocytosis included in the MPN category3. Cases previously diagnosed as CEL may be diagnosed in the

category Myeloid/Lymphoid Neoplasm with eosinophilia andabnormalities of PDGFRA, PDGFRB or FGFR1when these

specific abnormalities are present and when not present, in the

MPN category CEL, NOS

4. Diagnostic algorithms of PV, ET and PMF now incorporateinformation about mutated JAK2and similar activatingmutations as well as pertinent histologic features

5. The threshold for platelet count for ET has been lowered to 450x 109/L


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Major questions at CAC meeting

regarding MDS

1.Can minimal diagnostic criteria for MDS be betterdefined?

2.Some patients dont fit into previous WHOcategories, e.g., patients with refractory

thrombocytopenia. Can refinements be made toprovide better correlation with specific clinical

features?

3.Does there need to be a separate classification forchildhood MDS?


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Myelodysplastic SyndromesRefractory cytopenia with unilineage dysplasia (RCUD)

Refractory anemia

Refractory neutropenia

Refractory thrombocytopenia

Refractory anemia with ring sideroblasts

Refractory cytopenia with multilineage dysplasia

Refractory anemia with excess blasts

Refractory anemia with excess blasts-1*

Refractory anemia with excess blasts-2

Myelodysplastic syndrome with isolated del (5q)Childhood myelodysplastic syndrome

Provisional entity: Refractory cytopenia of childhood

* Change in criteria


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Provisional entity: Refractory cytopenia of childhood (RCC)

Rationale:

Isolated refractory anemia is very uncommon in children, most kidswill present with neutropenia and/or thrombocytopenia, with/withoutanemia.

RARS is virtually never seen in children

In contrast to adult MDS, most children with RCC usually have

hypocellular bone marrow

RCC:

Evidence of multilineagedysplasia required

Blasts


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Read the classification guidelines

for MDS carefully !! A case of RCUD may have bicytopenia despite

unilineage dysplasia, but if there is pancytopenia,the dx is MDS, U

Cases of RCUD and RCMD have


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Summary of major changes in

MDS1. Patients who lack convincing morphologic evidence of

dysplasia but who have specific MDS-related cytogenetic

abnormalities should be considered as having presumptive

evidence of MDS

2. Refractory neutropenia and refractory thrombocytopenia areadded, along with refractory anemia, to the group of

Refractory cytopenia with unilineage dysplasia category

3. Patients with


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Acute Myeloid Leukemia and Related

Precursor Neoplasms,

WHO 2008

Acute myeloid leukemia with recurrent genetic abnormalities

Acute myeloid leukemia with myelodysplasia-related changes

Therapy-related myeloid neoplasms

Acute myeloid leukemia, not otherwise specified

Myeloid sarcoma

Myeloid proliferations related to Down Syndrome

Blastic plasmacytoid dendritic cell neoplasm


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WHO, 2001

AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

AML with inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11

APL with t(15;17)(q22;q12); PML-RARA

AML with 11q23 abnormalities; MLL


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AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1**

AML with inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11**

APL with t(15;17)(q22;q12); PML-RARA**

AML with t(9;11)((p22q23); MLLT3-MLL

AML (megakaryoblastic) with t(1;22)(p13;q13); RBV15-MKL1

AML with t(6;9)(p23;q34); DEK-NUP214

AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN-EVI1

Provisional entities:

AML with mutated NPM1

AML with mutated CEBPA

** Diagnosed as AML, regardless of blast count; others require >20% blasts


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Class I Mutations Class II Mutations

AMLproliferation and/orsurvival advantage; not

affecting differentiation

impaired hematopoietic

differentiation and

subsequent apoptosis

Gilliland and Griffin, Blood 100:1532, 2002 (modified by H. Dohner)


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Prognostic significance of mutations in

cytogenetically normal AML

Genetic alteration

Favorable:

NPM1 mutation

CEBPA mutationUnfavorable:

FLT3-ITD mutation

MLL-PTD mutation

WT1 mutation

*NPM1+FLT3 ITD

Incidence

~50%

~15%

~32%

~7%

~10%

~40% ofmutated NPM1

4-yr survival

~60%*

~62%

~24%

~25%

~10-25%

25%


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Schlenk, et al. New Engl J Med 2008:358:1909


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AML with myelodysplasia-related

features

-Diagnose when >20% blasts and myelodysplasia-relatedcytogenetic abnormalities are present

-Diagnose when >20% blasts are present and there is a historyof a preceding myelodysplastic syndrome

-Diagnose when >20% blasts are present and >50% of two ormore myeloid lineages are dysplastic

Ref

Figure: Wandt H, et al. Blood 2008;111:1855


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Documents

2008 WHO Revision Classification of Tumours