Hematological Malignancy

Disease presentations and diagnostic process

2013/3/161

Myelopoiesis

G, D, E
A
M

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)

Updated entities of common

hematological malignancy
Myeloid
Acute myeloid leukemia (AML)
Myeloproliferative neoplasms (MPN)
(including CML)
Myelodysplastic syndromes (MDS)

Lymphoid
Hodgkins lymphoma (HD)
Non-Hodgkins lymphoma (NHL)
Myeloma (MM)

2008 WHO classification of

hematological malignancy
Myeloid
Acute myeloid leukemia (AML)
Acute leukemia of ambiguous
lineage
Myeloproliferative neoplasms
(MPN)
(including CML)
Myeloid and lymphoid
neoplasms with eosinophilia
and 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-cell
neoplasms
Immunodeficiency-associated
lymphoproliferative disorders
Histiocytic and dendritic cell
neoplasms

Classifications of lymphoid neoplasms

1966 Rappaport (modified in 1974)

1974 Kiel classification (updated in 1992)
1982 NCI Working Formulation
1994 Revised European-American Classification of
Lymphoid neoplasms (REAL)
2001 WHO classification
2008 WHO classification

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15

ICD-O-3WHO 2008obsolete items

Leukemia vs. Lymphoma

B (T)lymphoblastic
leukemia (ALL)

B (T)lymphoblastic
lymphoma (LL)

Chronic
lymphocytic
leukemia (CLL)

Small
lymphocytic
lymphoma (SLL)

16

Leukemia vs. Lymphoma

T-ALL

ATLL

T-lymphoblastic
leukemia/lymphoma

Adult T-cell
leukemia/lymphoma

17

Clinical Groupings of Currently Recognized NHL

B 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

Extranodal

Extranodal marginal zone/MALT lymphoma

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 lymphoma

Highly aggressive

T cells

T cell CLL/PLL
Large granular lymphocyte leukemia

Mycosis fungoides

Anaplastic large cell lymphoma

Peripheral T cell lymphoma

(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

21

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)

22

Genetic Testing/Cytogenetics

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

23

Genetic Abnormalities
1.
2.
3.
4.

Translocation: t(1;2)
Inversion: inv16
Deletion: -7 or 7Addition: +8 or 8+

24

Gene Translocation

Courtesy: National Human Genome

Research Institute

25

Gene Inversion

Diego Diez, Ph, Bioinformatics Center, Institute for Chemical Research, Kyoto University.
26
Gokasho, Uji, Kyoto 611-0011 JAPAN diez@kuicr.kyoto-u.ac.jp

Gene Deletion

Courtesy: National Human

Genome Research Institute

27

Gene Addition

Walters L, Palmer JG. The Ethics of Human Gene

Therapy. Oxford University Press. 1997.
28

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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

http://www.pathologyoutlines.com

31

Cytogenetics vs. Molecular

markers
Bcr-abl = t(9;22) ?
Specific loci
Sensitivity of test
Micro-translocation

RUNX1-RUNXT1 = ETO-AML1

32

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 .

33

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

Cytochemistry

Myeloid: MPO
Monocyte: NSE
Lymphoid: PAS

Immunophenotype

Myeloid: CD13,33
B-lympho: CD10,19,20
T-lympho: CD3,4,7
Stem cell: CD34,117
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Da Vinci Code in Leukemia

Morphology

Minimal differentiation, M0
Without maturation, M1
Maturation, M2
M3M7

Cytogenetics

t(8;21) in M2
t(15;17) = M3
Inv(16) in M4

Molecular
markers

RUNX1-RUNX1T1 = t(8;21)
PML-RARa = t(15;17)
CBFb-MYH11 = inv(16)
FLT3,NPM1

Chemotherapy
(remission) Induction
Re-induction: relapse vs. repeat

Consolidation
Maintenance

37

Hematopoietic stem cell transplantation

Normal hematopoiesis and immunity

High dose chemotherapy
Graft versus tumor
(leukemia,lymphoma,myeloma) effect

38

Hematopoietic stem cell transplantation

Relationship
Autologous
Syngeneic
Allogeneic
- Sibling
- Unrelated

Stem cell
source

Match

Conditioning
intensity

Bone marrow
Peripheral blood
Cord blood

Matched
Mismatched
Haplo-identical

Myeloablative
Non-myeloablative
(reduced intensity)

Matched-sibling allogeneic PBSCT with BuCy2

Other Therapies
Steroid
Target therapy
Others

Thalidomide
Anagrelide
Aspirin
Phlebotomy
Bisphosphonate
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Leukemia ()

Acute
leukemia

Chronic
leukemia

(blasts)
20%

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AML

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Acute Leukemia
Diagnosis

Diagnosis
Blasts >= 20%
in PB or BM

CBC
Variable WBC
Often anemia
and thrombocytopenia

Cytogenetics
As listed in
SSF1

Molecular
markers
As listed in
SSF2

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45

46

SSF1/SSF2

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Acute Leukemia
Treatment

Treatment
Induction
AML:A7D3
ALL:protocol
Consolidation
AML:HD Ara-C
ALL:protocol

STR: short tandem repeat

BMT
Poor risk
Often alloSCT

Follow-up
CBC
BM
STR if alloSCT

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CML

Chronic Myeloid Leukemia (CML)

Diagnosis

Diagnosis
t(9;22) or
Bcr-Abl+
Morphology ?

CBC
Leukocytosis
Thrombocytosis
if CP
Often anemia

Cytogenetics
Ph t(9;22)

Molecular
markers
Bcr-Abl

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Chronic Myeloid Leukemia (CML)

Treatment

Treatment
TKIs
Imatinib
Dasatinib
Nilotinib

BMT
Seldom
Mini-alloSCT if
necessary

TKIs: tyrosine kinase inhibitors

Follow-up
CBC
Ph chromosome
Bcr-Abl

50

Myeloproliferative Neoplasm (MPN)

Diagnosis

Diagnosis
(CBC or BM)
+/- JAK2

CBC
Cytosis

Cytogenetics
Usually
normal

Molecular
markers
JAK2

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Myeloproliferative Neoplasm (MPN)

Treatment

Treatment

Phlebotomy
Hydroxyurea
Anagrelide
Aspirin

BMT
Myelofibrosis

Follow-up
CBC

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MDS

Myelodysplastic syndrome (MDS)

Diagnosis

Diagnosis

CBC

BM cyto/path
+/chromosome

Anemia or
bicytopenia
or
pancytopenia

Cytogenetics
Variable

Molecular
markers
NA

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Myelodysplastic syndrome (MDS)

Treatment

Treatment

Supportive care
Azacitidine
Lenalidomide
C/T

BMT
Sometimes for
young if high
risk

Follow-up
CBC
BM for blasts

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Chronic Lymphocytic Leukemia (CLL)

Diagnosis

Diagnosis
CBC + (FC or
pathology)

FC: flow
cytometry

CBC
Leukocytosis
with
lymphocytosis

Cytogenetics
Variable

Molecular
markers
NA

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Chronic Lymphocytic Leukemia (CLL)

Treatment

Treatment
Obs
C/T
Rituximab
C/T: chemotherapy
CT: computed tomography

BMT
Seldom

Follow-up
CBC
CT

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Lymphoma
NHL vs. HD

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Lymphoma (NHL & HD)

Diagnosis

Diagnosis
Pathology
Cytology ?

CBC

Cytogenetics

Usually normal
Variable if BM
involvment

Variable
Usually normal

Molecular
markers
NA

Lymphoma (NHL & HD)

Treatment

Treatment
C/T +/rituximab
RT
C/T: chemotherapy
RT: radiotherapy
CT: computed tomography

BMT
Often autoSCT
AlloSCT for
repetitive
relapse

Follow-up
CT

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MM

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Multiple Myeloma (MM)

Diagnosis

Diagnosis
BM +/- IEP +
CRAB

CBC
Variable
Usually
cytopenia

IEP: immunoelectrophoresis
CRAB: hypercalcemia, renal
failure, anemia, bone lesions

Cytogenetics
Variable
Usually
normal

Molecular
markers
NA

Multiple Myeloma (MM)

Treatment

Treatment
C/T + novel agents
Thalidomide
Bortezomib
Lenalidomide

BMT
Often autoSCT for
young
AlloSCT for
repetitive relapse

sFLC: serum free light chain

Follow-up
M-protein
sFLC
BM

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Brief Summary of Common Hematological Malignancy

?

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