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Hematological MalignancyDisease presentations and diagnostic process

12013/3/16


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Myelopoiesis


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G, D, E

A

M


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AG: antigen

GC: geminal center

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Traditional concepts of common

hematological malignancy Leukemia

Acute myeloid leukemia (AML)

Acute lymphoid leukemia (ALL)

Chronic myeloid leukemia (CML)

Chronic lymphoid leukemia (CLL)

Lymphoma Hodgkins lymphoma (HD)

Non-Hodgkins lymphoma (NHL)

Myeloma(MM)

Others Myeloproliferative disorders (MPD) Myelodysplastic syndromes (MDS)


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Updatedentities of common

hematological malignancy Myeloid


Myeloproliferative neoplasms (MPN)

(including CML) Myelodysplastic syndromes (MDS)

Lymphoid

Hodgkins lymphoma (HD)

Non-Hodgkins lymphoma (NHL)

Myeloma (MM)


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2008 WHO classification of

hematological malignancy

Myeloid


Acute leukemia of ambiguouslineage

Myeloproliferative neoplasms(MPN)(including CML)

Myeloid and lymphoidneoplasms with eosinophiliaand abnormalities of PDGFRA,

PDGFRB or FGFR1

Myelodysplastic syndromes(MDS)

MDS/MPN

Lymphoid

Hodgkin lymphoma (HD)

Precursor lymphoid neoplasms

Mature B cell neoplasms(including MM)

Mature T- and NK-cellneoplasms

Immunodeficiency-associatedlymphoproliferative disorders

Histiocytic and dendritic cellneoplasms


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Classifications of lymphoid neoplasms

1966Rappaport (modified in 1974)

1974Kiel classification (updated in 1992)

1982NCI Working Formulation 1994Revised European-American Classification of

Lymphoid neoplasms (REAL)

2001WHO classification

2008WHO classification

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ICD-O-3WHO 2008obsolete items


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Leukemia vs. Lymphoma

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B (T)-

lymphoblasticleukemia (ALL)

B (T)-

lymphoblasticlymphoma (LL)

Chroniclymphocytic

leukemia (CLL)

Smalllymphocytic

lymphoma (SLL)


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Leukemia vs. Lymphoma

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T-ALL

T-lymphoblasticleukemia/lymphoma

ATLL

Adult T-cellleukemia/lymphoma


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Clinical Groupings of Currently Recognized NHL

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B cells T cells

Indolent (untreated survival measured in years)

Disseminated

B cell CLL/SLL/PLL

Lymphoplasmacytic lymphoma

Splenic marginal zone lymphoma/SLVL

Hairy cell leukemia

Plasmacytoma/myeloma

T cell CLL/PLL

Large granular lymphocyte leukemia

Extranodal Extranodal marginal zone/MALT lymphoma Mycosis fungoides

Nodal

Nodal marginal zone B cell lymphoma

Follicular lymphoma, follicle center lymphoma

Mantle cell lymphoma

Aggressive (untreated survival measured in months)

Diffuse large B cell lymphomaAnaplastic large cell lymphoma

Peripheral T cell lymphoma

Highly aggressive (untreated survival measured in weeks)

Precursor B lymphoblastic lymphoma/leukemia

Burkitts lymphoma

Precursor T lymphoblastic lymphoma

Adult T cell lymphoma/leukemia


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Morphology Descriptions

Complete remission

Normal CBC, normal BM

No excess of blasts

Blasts < 5%

Dysplasia

Dyserythroid, dysmega, megaloblastoid change,

pseudo-maturation arrest, pseudo-Pelger-Huet

anomaly

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Genetic Testing

Laboratory studies of blood, bone marrow, or

tissue to analyze DNA to identify

chromosome abnormalities which diagnose

specific neoplasms

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Normal Chromosomes

46 in each cell

Each chromosome has a specific number

Example: (1;2)Short arm p and a long arm q

Example: (p13;q22)

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Genetic Testing/Cytogenetics

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Appelbaum, MD, Frederick R. Leukemia [Internet]. Version 5. Knol. 2008 Jul 28. Available

from: http://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJw
http://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJwhttp://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJw


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Genetic Abnormalities

1. Translocation: t(1;2)

2. Inversion: inv16

3. Deletion: -7 or 7-4. Addition: +8 or 8+

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Gene Translocation

25Courtesy: National Human GenomeResearch Institute


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Gene Inversion

26

Diego Diez, Ph, Bioinformatics Center, Institute for Chemical Research, Kyoto University.

Gokasho, Uji, Kyoto 611-0011 JAPAN [email protected]
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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Gene Deletion

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Courtesy: National Human

Genome Research Institute


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Genetic Testing

FISH: Identifies genetic changes and

translocations.

Polymerase chain reaction (PCR): Measures

cancer cells that cannot be detected by

FISH.

Karyotyping: To arrange and classify

chromosomes based on number, size,

shape, and other characteristics.

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FISH to Identify NPM/ALK Fusion

Gene

31http://www.pathologyoutlines.com


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Cytogenetics vs. Molecular

markers

Bcr-abl = t(9;22) ?

Specific loci

Sensitivity of test

Micro-translocation

RUNX1-RUNXT1 = ETO-AML1

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Immunophenotyping

Cells from blood, BM, tissue used to

determine types of antigens or markers on

surface of cell. Referred to as CD

CD; cluster of differentiation: Used to

define the findings in immunophenotyping .

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Additional Immunophenotyping

Flow cytometry: Cells from blood, BM, tissue

are treated with antibodies and passed in

front of a laser beam.

Immunocytochemistry (IHC): Shows specific

antigens in cells from blood, BM, by using

either fluorescent dyes or enzymes as

markers

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Common IHC/Cytochemistry

Markers

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Myeloid: MPO

Monocyte: NSE Lymphoid: PAS

Cytochemistry

Myeloid: CD13,33 B-lympho: CD10,19,20

T-lympho: CD3,4,7

Stem cell: CD34,117

Immunophenotype


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Chemotherapy

(remission) Induction

Re-induction: relapse vs. repeat

Consolidation

Maintenance

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Normal hematopoiesis and immunity

High dose chemotherapy

Graft versus tumor

(leukemia,lymphoma,myeloma) effect

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Hematopoietic stem cell transplantation


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Autologous

SyngeneicAllogeneic

- Sibling

- Unrelated

Bone marrowPeripheral blood

Cord blood

MatchedMismatched

Haplo-identical

Hematopoietic stem cell transplantation

RelationshipStem cell

source

MyeloablativeNon-myeloablative

(reduced intensity)

Match

Conditioning

intensity

Matched-sibling allogeneic PBSCT with BuCy2


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Other Therapies

Steroid

Target therapy

Others

Thalidomide

Anagrelide

Aspirin

Phlebotomy

Bisphosphonate

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Leukemia ()

(blasts)

20%

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Acute

leukemia

Chronicleukemia

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AML

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Acute Leukemia

Diagnosis

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Diagnosis

Blasts >= 20%in PB orBM

CBC

Variable WBC

Often anemiaand thrombo-cytopenia

Cytogenetics

As listed inSSF1

Molecularmarkers

As listed inSSF2

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SSF1/SSF2

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Acute Leukemia

Treatment

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Treatment

Induction

AML:A7D3

ALL:protocol

Consolidation

AML:HD Ara-C

ALL:protocol

BMT

Poor risk

Often alloSCT

Follow-up

CBC

BM

STR if alloSCT

STR: short tandem repeat

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CML

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Chronic Myeloid Leukemia (CML)

Diagnosis

Diagnosis

t(9;22) orBcr-Abl+

Morphology ?

CBC

Leukocytosis

Thrombocytosisif CP

Often anemia

Cytogenetics

Ph t(9;22)

Molecularmarkers

Bcr-Abl

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Chronic Myeloid Leukemia (CML)

Treatment

Treatment

TKIs Imatinib

Dasatinib

Nilotinib

BMT

Seldom

Mini-alloSCT ifnecessary

Follow-up

CBC Ph chromosome

Bcr-Abl

TKIs: tyrosine kinase inhibitors

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Myeloproliferative Neoplasm (MPN)

Diagnosis

Diagnosis

(CBC or BM)+/- JAK2

CBC

Cytosis

Cytogenetics

Usuallynormal

Molecularmarkers

JAK2

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Myeloproliferative Neoplasm (MPN)

Treatment

Treatment

Phlebotomy Hydroxyurea

Anagrelide

Aspirin

BMT

Myelofibrosis

Follow-up

CBC

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MDS

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Myelodysplastic syndrome (MDS)

Diagnosis

Diagnosis

BM cyto/path+/-chromosome

CBC

Anemia orbicytopeniaorpancytopenia

Cytogenetics

Variable

Molecularmarkers

NA

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Myelodysplastic syndrome (MDS)

Treatment

Treatment

Supportive care Azacitidine

Lenalidomide

C/T

BMT

Sometimes foryoung if highrisk

Follow-up

CBC BM for blasts

h h k ( )56


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Chronic Lymphocytic Leukemia (CLL)

Diagnosis

Diagnosis

CBC +(FC orpathology)

CBC

Leukocytosiswithlymphocytosis

Cytogenetics

Variable

Molecularmarkers

NA

FC: flow

cytometry

h i h i k i ( )57


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Chronic Lymphocytic Leukemia (CLL)

Treatment

Treatment

Obs

C/T

Rituximab

BMT

Seldom

Follow-up

CBC

CT

C/T: chemotherapy

CT: computed tomography

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Lymphoma

NHL vs. HD

L h (NHL & HD)59


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Lymphoma (NHL & HD)

Diagnosis

Diagnosis

Pathology

Cytology ?

CBC

Usually normal

Variable if BMinvolvment

Cytogenetics

Variable

Usually normal

Molecularmarkers

NA

L h (NHL & HD)60


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Lymphoma (NHL & HD)

Treatment

Treatment

C/T +/-rituximab

RT

BMT

Often autoSCT

AlloSCT forrepetitiverelapse

Follow-up

CT

C/T: chemotherapyRT: radiotherapy

CT: computed tomography

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MM

M lti l M l (MM)62


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Multiple Myeloma (MM)

Diagnosis

Diagnosis

BM +/- IEP +CRAB

CBC

Variable

Usuallycytopenia

Cytogenetics

Variable

Usuallynormal

Molecularmarkers

NA

IEP: immunoelectrophoresis

CRAB: hypercalcemia, renal

failure, anemia, bone lesions


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Brief Summary of Common Hematological Malignancy

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