Leukemia

白禮源 Li-Yuan Bai, MD, PhD

Division of Hematology and Oncology
China Medical University Hospital

Dec 20, 2011

 Outlines
•血液細胞生成 Peripheral blood
•血液惡性疾病
•骨髓增生疾病
•骨髓化育不良
•急性骨髓性白血病
Bone marrow
•急性淋巴球性白血病
•慢性淋巴球性白血病
•結論
血液細胞生成
 WHO 2008
• Myeloproliferative neoplasms (MPD)
• Myeloid and lymphoid neoplasms with eosinophilia and
abnormalities of PDGFRA, PDGFRB or FGFR1
• Myelodysplastic/myeloproliferative neoplasms (MDS/MPD)
• Myelodysplastic syndromes (MDS)
• AML and related precursor neoplasms
• Acute leukemias of ambiguous lineage
• Precusor lymphoid neoplasms
• Mature B-cell neoplasms
• Mature T-cell and NK-cell neoplasms
• Hodgkin lymphoma (HL)
• Histiocytic and dendritic cell neoplasms
• Post-transplant lymphoproliferative disorders (PTLD)
 WHO2008
慢性骨髓性白血病

真性紅血球增多症
骨髓纖維化
原發性血小板增多症
 CML Polycythemia Vera

Essential Thrombocytosis Myelofibrosis

 Epidemiology of CML
• Median age range at presentation: 45 to 55
years
• Incidence increases with age
– Up to 30% of patients are >60 years old
• Slightly higher incidence in males
– Male-to-female ratio—1.3:1
• At presentation
– 50% diagnosed by routine laboratory tests
– 85% diagnosed during chronic phase
Sawyers CL. N Engl J Med. 1999;340:1330-1340.
Faderl S, et al. Ann Intern Med. 1999;131:207-219.
 The Ph Chromosome and the
bcr-abl Gene
Chromosome 22 Chromosome 9
9 q+
9 c-bcr 1 2-11 c-abl

Ph (or 22q-)
22
2-11 p210Bcr-Abl
bcr 2-11 p185Bcr-Abl
bcr-abl
Exons
abl
FUSION Introns
PROTEIN
WITH CML Breakpoints
TYROSINE
ALL Breakpoints
KINASE
ACTIVITY
t(9;22) translocation bcr-abl gene structure
Pasternak G, et al. J Cancer Res Clin Oncol. 1998;124:643-660.
Melo JV. Blood. 1996;88:2375-2384.
 Therapeutic Options for CML
• Leukapheresis and plateletpheresis
• Chemotherapy with hydroxyurea or busulfan
• IFN-α–based treatments
• Allogeneic stem cell transplantation (SCT)
• Tyrosine kinase inhibitor
Imatinib (Glivec)
Nilotinib, Dasatinib
骨髓化育不良 (Myelodysplastic Syndrome)
WHO2008
Normal PB / BM MDS
 Epidemiology
• Mean age at onset 68 years
• Slightly male preponderance
• 35-100/106 in general population, 120-
500/106 in aged (老人較多)
• Increased recognition by physicians
recently
 International Prognostic Scoring System
( 整合性 score )

Variable 0 0.5 1 1.5 2

BM blast % <5 5-10 11-20 20-30

Karyotype Good Intermediate - Poor -

Cytopenias 01 23 - - -

Good: normal, -Y, del(5q), del(20q)

Poor: complex (≥3 abnormalities), Ch 7 change
Intermediate: others
Geenberg P. Blood 1997;89:2079
 WHO2008
AML(1)
 WHO2008
AML(2)
 台灣 1994 每十萬
ALL 0.96
AML 2.25
CLL 0.41
CML 0.72

Wintrob’s Clin Hematol 11th e

Factors Contributing to AML
Hereditary
Solvents (benzene)
Smoking
Ionizing radiation
Atomic bomb exposure
Nuclear power exposure
Medical radiation
Nonionizing radiation (?)
Chemotherapy
Alkylating agents
Topoisomerase II inhibitors
Other drugs
Chloramphenicol
Phenylbutazone
Viruses: no direct evidence
Wintrob’s Clin Hematol 11th e
 AML: Clinical Presentations
• Weight loss over 50%
• Organomegaly 50%
• Hemorhagic signs/symptoms 50%
• Fever 20%
• Bone pain <20%
• CNS involvement 5-20% children, 16% adults
• Leukemia cutis 13%
• Granulocytic sarcoma 2-14%
• Testicular infiltration 1-8%

Wintrob’s Clin Hematol 11th e

 Diagnosis of AML
• Clinical
• Morphology
• Cytochemistry
• Flow cytometry
• Cytogenetic
• Molecular
Pathology & Genetics:
Tumours of Haematopoietic
and Lymphoid Tissues. IARC
Chromosomal and Genetic Classcification
Important pretreatment prognostic factors

• t(15;17)(q22q12): M3, DIC

• Inv(16)(p13q22): M4Eo
• T(8;21)(q22;q22): M2, granulocytic sarcoma
• 11q23: M5
• FLT3-Internal tandem duplication
• NPM1
• c-Kit
• … Wintrob’s Clin Hematol 11th e
 急性淋巴球性
白血病
(Acute Lymphoblastic
Leukemia)

WHO2008
 Epidemiology
• 1.4 in 100,000 in NCI report.
• The incidence in blacks less than in whites.
• Slight male predominance 1.3:1.
• A bimodal age-specific incidence.

Wintrob’s Clin Hematol 11th e

Clinical Findings at Diagnosis in Adults ALL
Findings (%)
Male 59-63
Symptoms
Fever/infection 3-56
Bleeding 33
Lymphadenopathy 40-57
Hepatomegaly 24-47
Splenomegaly 31-56
Mediastinal mass 10-15
Central nervous system leukemia 1-7
Other organ involvement
Pleura 2.9
Pericardium 1.0
Retina 1.0
Skin 0.6
Tonsils 0.6
Testis 0.3
Wintrob’s Clin Hematol 11th e
Chromosomal Abnormalities at Diagnosis in ALL

Patients (%)
Chromosomal Abnormalities
Adults Children
Normal karyotype 16-34 9
Numerical abnormalities
Hypodiploid 4-9 1
Hyperdiploid (>50 chromosomes) 2-9 25
Structural abnormalities
t ( 9; 22 ) 11-30 4
t ( 4; 11 ) 3-7 6
t ( 10; 14 ) 4-6 4
t ( 8; 14 ) 4 2
t (1; 19 ) 3 5
9p abnormality 5-16 7-13
6q abnormality 2-6 4-6
12p abnormality, including t (12; 21) 4-5 22

Wintrob’s Clin Hematol 11th e

 慢性淋巴球性白血病
(Chronic Lymphocytic Leukemia)

• Most common leukemia of Western world.

• Less frequent in Asia and Latin America.
• Male to female ratio is 2:1.
• Median age at diagnosis is 65-70 years.
• Clonal B cell malignancy
• Nonproliferating mature but immunologically
dysfunctional lymphocytes in blood, marrow, lymph
nodes, and spleen
 CLL--Clinical findings
• 40% of CLL are
asymptomatic at diagnosis
• In symptomatic, most
common complaint is
fatigue
• Enlarged LN (cervical and
supraclavicular most) and
splenomegaly
• LN discrete, freely
movable, and nontender
CLL Classification

Gribben JG. Blood 2010:115:187

 CLL Staging System

Binet Rai
 CLL – treatment
• Watch and wait
• Monotherapy
– glucocorticoids
– alkylating agents (Chlorambucil, Cyclophosphamide)
– purine analogues (Fludarabine, Cladribine, Pentostatin)
• Combination chemotherapy
– Chlorambucil/ Cyclophosphamide + Prednisone
– Fludarabine + Cyclophosphamide +/- Mitoxantrone
– CVP, CHOP
• Monoclonal antibodies
– Alemtuzumab (anti-CD52)
– Rituximab (anti-CD20)
• Hematopoietic stem cell transplantation
– allogeneic with reduced intesity conditioning
– autologous
Lymphoproliferative
Disorder
中國醫藥學大學附設醫院
血液腫瘤科 葉士芃
 Lymphoproliferative
Disorder
Lymphoproliferative disorders are those in
which lymphocytes, white blood cells
produced in the lymphatic tissue (the
lymph nodes, spleen, thymus, for
example), are over-produced or act
abnormally.
A disease in which cells of the
lymphatic system grow excessively.
 Lymphoproliferative
Disorder
Neoplastic Non-neoplastic

proliferation proliferation

• Lymphoma • Infectious immune

reaction
• Leukemia (chronic
lymphocytic • Non-infectious immune

leukemia) reaction

• Plasma cell myeloma

 Normal Counterpart

• A cancer cell must has a normal cell

counterpart.
• The process by which a normal cell is
converted to a malignant cell is termed
malignant transformation
Viral
Infection
Toxin
Radiation
Senescence
 Patients at Increased Risk of
NHL
• Immunosuppression (transplant recipients;
AIDS)
• Autoimmune disease (SS, RA, Hashimoto
thyroiditis)
• Male gender
• Increasing age
• Family history of NHL
• Drug history (Phenytoin, MTX,
immunosuppressive)
• Occupational history (herbicides, wood
dust, solvent, painting, hair dye…)
 Lymphoma

Lymphoma
Non-Hodgkin’s lymphoma
(NHL)
B-cell  B-cell NHL
T-cell  T-cell NHL

Hodgkin’s disease (HD)

B-Lymphocyte Ontogeny
T Lymphocyte Ontogeny
Classification of Lymphoma
Different cell origin of lymphoma

Different morphology / pathology of

lymphoma
Different clinical presentation of
lymphoma
Different prognosis of lymphoma
Different treatment of lymphoma
 Concepts of Classification

• 1800-1900, leukemia Vs lymphoma

• 1910, Hodgkin’s Vs non-Hodgkin’s
lymphoma
• 1950s, Rapport classification
• 1970s, Kiel classification
• 1980s, Working formulation
• 1990s, REAL/WHO classification

Progress of Classification = Progress of

 (國考)

Seminars in Oncology, Vol 30, No 2, Suppl 4 (April), 2003: pp 3-9

 Non-Hodgkin’s
Lymphoma
• Distinct disease entity : Different morphology,
genetic abnormality, clinical presentation,
prognosis
• B-cell NHL Diffuse large B-cell lymphoma
Follicular lymphoma (Gr
1/2/3) Mantle cell
lymphoma
Marginal zone lymphoma (MALT lymphoma)
Burkitt lymphoma
• T-cell NHL Lymphoblastic lymphoma
Peripheral T cell
 Taiwan Vs Western

50

40

30
Taiwan
20 Western

10

0
High Grade Intermediate Low Grade
Grade

Chen AL. JFMA 1989

 Taiwan Vs Western

90
80
70
60
50
HD NHL
40
30
20
10
0
Taiwan Western

Chen AL. JFMA 1989

 Clinical Presentation of
Lymphoma
• Lymphadenopathy (** chest /
abdomen)
• Extranodal tumor (BM; GI; CNS;
others…)
• Hepatosplenomegaly
• B symptoms
Unexplained fever
Drenching night sweating
Unintended loss of BW (10% within
6Mo)
 Diagnostic Approach

• Morphology
• Immunohistochemistr
y Pathology
• Cytogenetics (O)
• Molecular genetics Fine needle
aspiration
• In situ hybridization cytology (X)
 Staging Evaluation
• Physical examination (node, liver, spleen,
skin, CNS)
• Performance status (ECOG)
• B symptoms
• Whole body CT scan
• Gallium-67 / Positron emission tomography
(PET)
• Bone marrow aspiration and biopsy
• Blood test (CBC/DC, LDH, HIV, HBV, HCV,
biochemistry)
 Ann Arbor Staging System
Stage Anatomic description
A single lymph node region or a single extra-lymphatic
I
organ or site (IE)
Two or more lymph node regions on the same side of the
II diaphragm (II) or localized involvement of an extra-
lymphatic organ or site (IIE)
Lymph node regions on both sides of the diaphragm
III without (III) or with (IIIE) localized involvement of an extra-
lymphatic organ or site
Diffuse involvement of one or more extra-lymphatic organs
IV
or sites
 Prognostic Factors – IPI Score

Age
LDH *
PS *
Stage *
Extranodal
disease
Survival Curves According to
IPI
 Therapy Principles
• Based on pathology and stage of disease
• Estimate “risk” of the patient (Basing on IPI
score?? or other prognostic index)
殺雞用雞刀 殺牛用牛刀
• Treatment modality
– Chemotherapy with or without radiotherapy
– High dose chemotherapy with stem cell support
– Immunotherapy (Monoclonal antibody = MoAb)
– Target therapy
 Follicular B-cell
Lymphoma
• Old age; Long median survival
• Slow and continuous decline in survival
• Usually advanced stage at diagnosis of
disease
• Responded to therapy, but relapse is the
rule
• Transform over time to more a aggressive
course
• Allogeneic transplant  the only chance
Treatment of Follicular
Lymphoma
• Watchful waiting
• Local radiation
• Chemotherapy
• Immunotherapy
(MoAb)
• MoAb-
Chemotherapy
• Transplantation
 Diffuse Large B Cell
Lymphoma
• 35 to 40% of all NHL
• 40 to 50% of case are curable in adult
• Expression of CD19, CD20, CD22,
CD79a
• Rapidly enlarging symptomatic mass
• One-third patients with B symptoms
• 30% localized disease (stage I & II)
• Heterogenous group of disease
 Treatment of Diffuse Large B-
Cell Lymphoma

MoAb-Chemotherapy (1st line)

Transplantation (for relapse)
Local radiotherapy (for stage I/II,
extranodal site; bulky disease)
 Relapsed
Aggressive
Lymphoma

APBSCT
vs
Chemo

Figure 60. Survival in patients randomized to

DHAP chemotherapy v.s intensification with
BEAC and autograft (PARMA study)
Hodgkin’s
Disease
 Hodgkin’s Disease
• Characteristics of Reed-Sternberg cells
• Peak at the age of 30 and 50 years
• Etiology : HIV and EBV
• WHO classification
– Lymphocyte predominant (B-cell origin)
– Lymphocyte-rich
– Nodular sclerosis
– Mixed cellularity Origin unknown
– Lymphocyte-depleted
 Hodgkin’s Disease

• 80 % of the patient: Ann Arbor stage I or

II (neck, mediastinum, axilla, spleen,
para-aortic)
• 90% of the patient has complete
response
• 90% are alive at 10 years
• Continuous spreading / bulky disease
(>10cm)
• B symptoms: fever (Pel-Ebstein fever),
night sweats
 Treatment of Hodgkin’s
Disease
Classic HD: (NS, MC, LD, LR)
• Radiotherapy
• Chemotherapy +/- stem cell transplantation
• Stage I/II non-bulky: C/T (ABVD) x 4 + R/T
or ABVD x 6
• Stage I/II bulky: C/T (ABVD) x 4-6 + R/T
• Stage III/IV non-bulky: C/T (ABVD) x 6-8
• Stage III/IV bulky: C/T (ABVD) x 6-8 +/- R/T
• Relapse: C/T followed by stem cell
 Chronic Lymphocytic
Leukemia
• Accumulation of non-
proliferating mature-
appearing lymphocyte in
blood, lymph node and
spleen
• Derived from mature B-
cell
• Most common leukemia
in Western countries
• Predominance in male
• Unknown etiology
 CLL: Clinical Presentation
• A disease of elderly, usually > 60Y/O
• Often asymptomatic, with PB lymphocyte >
5000 (>4wk)
• Weight loss, malaise, night sweating,
frequent infection if disease progressed.
• Generalized lymphadenopathy,
hepatosplenomegaly, anemia, and bone
marrow failure in advanced disease.
• May have autoimmune phenomenon (ITP,
AIHA)
 Transformation of CLL

• Diffuse large-cell lymphoma (Richter

syndrome)
• Hodgkin disease
• Prolymphocytic leukemia
• Multiple myeloma
• Acute leukemia (myeloid, lymphoid,
 CLL: Staging

Binet staging
MS (Y)
A lymphocytosis, < 3 areas of LN 14

B lymphocytosis, >= 3 areas of LN

5

C BM compromised with A/B 2.5

(Hb < 10g/dl; PLT < 100,000/µl)
 CLL: Treatment

Treatment of CLL
• Observation for asymptomatic patients
• Chemotherapy (oral chlorambucil) for
patient with symptoms, bulky LN,
progressive disease…
• Radiotherapy: for bulky LN or
hepatosplenomegaly
• Fludarabine, 2-CDA
• Monoclonal antibody (Rituximab, Zevalin)
Clinical Approach to
Lymphadenopathy
 Causes of
Lymphadenopathy
• Infection
• Autoimmune
• Iatrogenic
• Potential
malignancy
• Malignancy
• Others VGHKS
 Medical History

• Duration: Recent onset (<15 D) suggest an

infectious etiology.
• LN enlargement gradually over period of
weeks to months favor malignancy.
• Localized symptoms
• Systemic (B) symptoms
• Medication Hx – iatrogenic (Dilantin,
carbamazepine, primidone, gold, allopurinal,
hydralazine …)
 PE: Extension of LNs

• Localized (single anatomic area): TB,

pyogenic infection, metastatic tumors.
• Localized to Limited (2-3 anatomic
areas): HD, Kikuchi's disease,
toxoplasmosis, nonspecific.
• Generalized (4 or more anatmoic
areas): AIDS, infectious mononucleosis,
viral infection, low-grade NHL, CLL
 PE: LN Size

• LN < 1cm2 : nonspecific etiology (90%),

few infectious mononucleosis or
toxoplasmosis.

• LN 1~2.25cm2 (1.5x1.5cm): malignancy

(9%), nonspecific etiology (50%).

• LN > 2.25cm2 : malignancy (40%),

nonspecific etiology (20%).
 PE: LN Texture
• Rock-like hard nodes are typical of
metastasis.
• Hard nodes also observed in nodular
sclerosis of HD and TB adenitis.
• Rubbery texture is consistent with NHL.
• Soft texture: dose not allow a definite
diagnosis.
• Tenderness/pain 
inflammation/infection
 Conclusion
Important Factors in Assessing
Lymphadenopathy

Patient's age.
Physical characteristics of the LNs.
Node locations.
Clinical symptoms associated with
LAPs.
Lymphoproliferative
Disorder
中國醫藥學大學附設醫院
血液腫瘤科 葉士芃

CMUH
 Lymphoproliferative Disorder

Lymphoproliferative disorders are those in which

lymphocytes, white blood cells produced in the
lymphatic tissue (the lymph nodes, spleen,
thymus, for example), are over-produced or act
abnormally.
A disease in which cells of the lymphatic
system grow excessively.

CMUH
 Lymphoproliferative Disorder

Neoplastic proliferation Non-neoplastic proliferation

 Lymphoma  Infectious immune reaction

 Leukemia (chronic  Non-infectious immune

lymphocytic leukemia) reaction

 Plasma cell myeloma

CMUH
 Normal Counterpart

 A cancer cell must has a normal cell counterpart.

 The process by which a normal cell is converted
to a malignant cell is termed malignant
transformation

CMUH
Viral
Infection
Toxin
Radiation
Senescence

CMUH
 Patients at Increased Risk of NHL
 Immunosuppression (transplant recipients; AIDS)
 Autoimmune disease (SS, RA, Hashimoto thyroiditis)
 Male gender
 Increasing age
 Family history of NHL
 Drug history (Phenytoin, MTX, immunosuppressive)
 Occupational history (herbicides, wood dust, solvent,
painting, hair dye…)
 Congenital disorder (Ataxia telangiectasia, SCID…)

CMUH
 Lymphoma
Lymphoma
Non-Hodgkin’s lymphoma (NHL)

B-cell  B-cell NHL

T-cell  T-cell NHL

Hodgkin’s disease (HD)

CMUH
B-Lymphocyte Ontogeny

CMUH
T Lymphocyte Ontogeny

CMUH
 Classification of Lymphoma

Different cell origin of lymphoma

Different morphology / pathology of lymphoma

Different clinical presentation of lymphoma
Different prognosis of lymphoma
Different treatment of lymphoma

Classification
CMUH
 Concepts of Classification

 1800-1900, leukemia Vs lymphoma

 1910, Hodgkin’s Vs non-Hodgkin’s lymphoma
 1950s, Rapport classification
 1970s, Kiel classification
 1980s, Working formulation
 1990s, REAL/WHO classification

Progress of Classification = Progress of Science

CMUH
 (國考)

Seminars in Oncology, Vol 30, No 2, Suppl 4 (April), 2003: pp 3-9

CMUH
 Non-Hodgkin’s Lymphoma
 Distinct disease entity : Different morphology, genetic
abnormality, clinical presentation, prognosis
 B-cell NHL Diffuse large B-cell lymphoma
Follicular lymphoma (Gr 1/2/3)
Mantle cell lymphoma
Marginal zone lymphoma (MALT lymphoma)
Burkitt lymphoma
 T-cell NHL Lymphoblastic lymphoma
Peripheral T cell lymphoma, unspecified
Extranodal NK/T cell lymphoma, nasal type
CMUH
 Taiwan Vs Western

50

40

30
Taiwan
20 Western

10

0
High Grade Intermediate Low Grade
Grade

Chen AL. JFMA 1989

CMUH
 Taiwan Vs Western

90
80
70
60
50
HD NHL
40
30
20
10
0
Taiwan Western

Chen AL. JFMA 1989

CMUH
 Clinical Presentation of Lymphoma

 Lymphadenopathy (** chest / abdomen)

 Extranodal tumor (BM; GI; CNS; others…)
 Hepatosplenomegaly
 B symptoms
Unexplained fever
Drenching night sweating
Unintended loss of BW (10% within 6Mo)
 Unusual presentation of auto-antibody
 Abnormal blood cell count
CMUH
 Diagnostic Approach

 Morphology
 Immunohistochemistry
 Cytogenetics Pathology (O)
 Molecular genetics Fine needle aspiration
 In situ hybridization cytology (X)

CMUH
 Staging Evaluation
 Physical examination (node, liver, spleen, skin, CNS)
 Performance status (ECOG)
 B symptoms
 Whole body CT scan
 Gallium-67 / Positron emission tomography (PET)
 Bone marrow aspiration and biopsy
 Blood test (CBC/DC, LDH, HIV, HBV, HCV, biochemistry)
 Lumbar puncture, endoscopy (selective)

CMUH
 Ann Arbor Staging System
Stage Anatomic description
A single lymph node region or a single extra-lymphatic
I
organ or site (IE)
Two or more lymph node regions on the same side of the
II diaphragm (II) or localized involvement of an extra-
lymphatic organ or site (IIE)
Lymph node regions on both sides of the diaphragm
III without (III) or with (IIIE) localized involvement of an extra-
lymphatic organ or site
Diffuse involvement of one or more extra-lymphatic organs
IV
or sites CMUH
 Prognostic Factors – IPI Score

Age

LDH *
PS *
Stage *

Extranodal
disease

CMUH
Survival Curves According to IPI

CMUH
 Therapy Principles
 Based on pathology and stage of disease
 Estimate “risk” of the patient (Basing on IPI score??
or other prognostic index)
殺雞用雞刀 殺牛用牛刀
 Treatment modality
 Chemotherapy with or without radiotherapy

 High dose chemotherapy with stem cell support

 Immunotherapy (Monoclonal antibody = MoAb)

 Target therapy
CMUH
 Follicular B-cell Lymphoma

 Old age; Long median survival

 Slow and continuous decline in survival
 Usually advanced stage at diagnosis of disease
 Responded to therapy, but relapse is the rule
 Transform over time to more a aggressive course
 Allogeneic transplant  the only chance of cure
 The type of therapy remained controversy

CMUH
Treatment of Follicular Lymphoma

 Watchful waiting
 Local radiation
 Chemotherapy
 Immunotherapy (MoAb)
 MoAb-Chemotherapy
 Transplantation
 Selected therapy
CMUH
 Diffuse Large B Cell Lymphoma

 35 to 40% of all NHL

 40 to 50% of case are curable in adult
 Expression of CD19, CD20, CD22, CD79a
 Rapidly enlarging symptomatic mass
 One-third patients with B symptoms
 30% localized disease (stage I & II)
 Heterogenous group of disease

CMUH
 Treatment of Diffuse Large B-Cell
Lymphoma

 MoAb-Chemotherapy (1st line)

 Transplantation (for relapse)
 Local radiotherapy (for stage I/II, extranodal
site; bulky disease)

CMUH
 Relapsed
Aggressive
Lymphoma

APBSCT
vs
Chemo
Figure 60. Survival in patients randomized to
DHAP chemotherapy v.s intensification with
BEAC and autograft (PARMA study)
CMUH
Hodgkin’s Disease

CMUH
 Hodgkin’s Disease
 Characteristics of Reed-Sternberg cells
 Peak at the age of 30 and 50 years
 Etiology : HIV and EBV
 WHO classification
 Lymphocyte predominant (B-cell origin)
 Lymphocyte-rich
 Nodular sclerosis
 Mixed cellularity
Origin unknown
 Lymphocyte-depleted
CMUH
 Hodgkin’s Disease

 80 % of the patient: Ann Arbor stage I or II (neck,

mediastinum, axilla, spleen, para-aortic)
 90% of the patient has complete response
 90% are alive at 10 years
 Continuous spreading / bulky disease (>10cm)
 B symptoms: fever (Pel-Ebstein fever), night
sweats
 Cause of death is often NHL, leukemia, other
cancers or complication of treatment
CMUH
 Treatment of Hodgkin’s Disease
Classic HD: (NS, MC, LD, LR)
 Radiotherapy
 Chemotherapy +/- stem cell transplantation
 Stage I/II non-bulky: C/T (ABVD) x 4 + R/T or ABVD x
6
 Stage I/II bulky: C/T (ABVD) x 4-6 + R/T
 Stage III/IV non-bulky: C/T (ABVD) x 6-8
 Stage III/IV bulky: C/T (ABVD) x 6-8 +/- R/T
 Relapse: C/T followed by stem cell transplantation CMUH
 Chronic Lymphocytic Leukemia

 Accumulation of non-
proliferating mature-
appearing lymphocyte in
blood, lymph node and spleen
 Derived from mature B-cell
 Most common leukemia in
Western countries
 Predominance in male
 Unknown etiology

CMUH
 CLL: Clinical Presentation
 A disease of elderly, usually > 60Y/O
 Often asymptomatic, with PB lymphocyte > 5000
(>4wk)
 Weight loss, malaise, night sweating, frequent
infection if disease progressed.
 Generalized lymphadenopathy, hepatosplenomegaly,
anemia, and bone marrow failure in advanced
disease.
 May have autoimmune phenomenon (ITP, AIHA)
CMUH
 Transformation of CLL

 Diffuse large-cell lymphoma (Richter syndrome)

 Hodgkin disease
 Prolymphocytic leukemia
 Multiple myeloma
 Acute leukemia (myeloid, lymphoid, undifferentiated)

CMUH
 CLL: Staging

Binet staging
MS (Y)
A lymphocytosis, < 3 areas of LN 14

B lymphocytosis, >= 3 areas of LN 5

C BM compromised with A/B 2.5

(Hb < 10g/dl; PLT < 100,000/µl)

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 CLL: Treatment

Treatment of CLL
 Observation for asymptomatic patients
 Chemotherapy (oral chlorambucil) for patient with
symptoms, bulky LN, progressive disease…
 Radiotherapy: for bulky LN or hepatosplenomegaly
 Fludarabine, 2-CDA
 Monoclonal antibody (Rituximab, Zevalin)
 Allogeneic HSCT for patient age < 55 with MSD

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Clinical Approach to
Lymphadenopathy

CMUH
Causes of Lymphadenopathy

 Infection
 Autoimmune

 Iatrogenic

 Potential malignancy

 Malignancy

 Others

VGHKS
CMUH
 Medical History

 Duration: Recent onset (<15 D) suggest an infectious

etiology.
 LN enlargement gradually over period of weeks to
months favor malignancy.
 Localized symptoms
 Systemic (B) symptoms
 Medication Hx – iatrogenic (Dilantin, carbamazepine,
primidone, gold, allopurinal, hydralazine …)

CMUH
 PE: Extension of LNs

 Localized (single anatomic area): TB, pyogenic

infection, metastatic tumors.
 Localized to Limited (2-3 anatomic areas): HD,
Kikuchi's disease, toxoplasmosis, nonspecific.
 Generalized (4 or more anatmoic areas): AIDS,
infectious mononucleosis, viral infection, low-
grade NHL, CLL
CMUH
 PE: LN Size

 LN < 1cm2 : nonspecific etiology (90%), few

infectious mononucleosis or toxoplasmosis.

 LN 1~2.25cm2 (1.5x1.5cm): malignancy (9%),

nonspecific etiology (50%).

 LN > 2.25cm2 : malignancy (40%), nonspecific

etiology (20%).

CMUH
 PE: LN Texture

 Rock-like hard nodes are typical of metastasis.

 Hard nodes also observed in nodular sclerosis of
HD and TB adenitis.
 Rubbery texture is consistent with NHL.
 Soft texture: dose not allow a definite diagnosis.
 Tenderness/pain  inflammation/infection
 Painless  TB, malignancy

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 Conclusion

Important Factors in Assessing

Lymphadenopathy

Patient's age.
Physical characteristics of the LNs.
Node locations.
Clinical symptoms associated with LAPs.

CMUH
 Anemia

林振源
中國醫藥大學附設醫院血液腫瘤科
101年1月

CMUH
 Erythropoiesis

Pluripotent
Stem Cell + Growth factors
CMUH
http://www.graphicpulse.com/medill/bloodweb.jpg 2
 Erythroid Maturation
Early Intermediate Late

Proerythroblast Polychromatophilic Reticulocyte

(Pronormoblast) Normoblast
Basophilic Orthochromatophilic Erythrocyte
Normoblast Normoblast

CMUH
Modified from http://t2.gstatic.com/images?q=tbn:ANd9GcTZqr9M178-q5fsV8hO4MkTMy-KHHFwqGs584Plok4fgHTjJlZ1sw 3
 RBC in PB

http://accessmedicine.com/loadBinary.aspx?name=harr&filename=harr_c057f003.jpg
CMUH
http://homebirthchoices.com/wp-content/uploads/2010/01/CBC-1.jpg 4
 RBC volume & RDW

http://www.ispub.com/journal/the-internet-journal-of-hematology/volume-7-number-2/
discriminant-functions-in-distinguishing-beta-thalassemia-trait-and-iron-deficiency-
anemia-the-value-of-the-rdw-sd.article-g01.fs.jpg CMUH
http://library.med.utah.edu/WebPath/jpeg5/HEME023.gif 5
 Question
CBC 的數據中足以顯示 RBC 大小是否正常的數據為：

Hct, MCV

MCV, MCHC

MCV, MCH

MCV, RDW

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6
 What’s
the
FUNCTION
of
RBC???
CMUH
7
 Hb and Oxygen

DO2=(1.34×Hb×SaO2 ＋PaO2×0.003)× SV× HR

CMUH
http://1minutecure.com/DissociationHemoglobinOxygen.jpg 8
 How
RBCs
loss?
http://webs.ashlandctc.org/mflath/KEY%20SKELETAL%20I%20OBJECTIVES_files/image006.jpg
http://www.campcursos.com.br/vas2.jpg CMUH
http://images.medicinenet.com/images/illustrations/blood_cells.jpg 9
 Mechanisms of Anemia

Production Disorders:
• Hematopoietic Cell Damage
- Drugs, Radiation, Infections,
Toxins
• Factor Deficiency
-Iron (Heme Synthesis)
-Vitamin B12 (DNA Synthesis)
-Folate (DNA Synthesis)

CMUH
10
 CMUH
Nature Reviews Molecular Cell Biology 9, 72-81 (January 2008) 11
 Mechanisms of Anemia

Survival Disorders:
• Blood Loss
- External
- Internal
• Red blood Cell Destruction
- Hemolytic Anemias

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12
 Case #1
• 81-year-old male
• Hypertension
• Anemia noticed in health
examination (5.3 gm/dl)
• More frequent dizziness for two
months, and became dyspnea
What else should we ask more…

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13
 Case #1

• Associated Symptoms
– GI easy fullness since last year,
constipation and fecal caliber change
– No tarry stool
– No color change of urine
– PHx: no OP history

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14
 Case #1

• Preliminary study
– Complete Blood Count
– Reticulocytes count

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15
 Case #1
• Complete blood count
– WBC 5970/ul
– N/L/M/B/E 66.7/18.9/5.9/0.5/8.0 (%)
– RBC 3.29x106/ul, Hb 5.3 gm/dl
– MCV 60.5 fl
– Red cell distribution width (RDW) 20.5
– Reticulocytes count 0.90%

What else???
CMUH
16
 Case #1
• Ferritin 3.34 ng/ml ↓
• Fe/TIBC 4/429 (ug/dl) (↓ /↑)
• RBC  Low
• RDW  Increase
• Hb electrophoresis?

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17
Iron Deficiency Anemia

Case #1

Any thing else?

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 Case #1

• Fecal Occult Blood Test

– GI symptom
– Especially bowel habit change
– Result OB positive

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19
Case #1

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20
Case #1

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21
Colon cancer, with IDA

Case #1

CMUH
 Case #2
CBC I
WBC : 5.42 ×103 /ul (3.99-10.39)
RBC : 5.05 * x106/ul (男:4.5-5.5 女:4.0-4.5)
Hb : 10.0 * gm/dl (男:14.0-18.0 女:12.0-16.0)
Hct : 31.7 * % (男:39-52 女:35-48)
RDW : 15.2 * (11.5-14.5)
Platelet : 280 x103/ul (130-400)
MCV : 62.8 * fl (80-99)
MCH : 19.8 * pg (27-31)
MCHC : 31.5 * g/dl (33-37)

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23
 Case #2

• Ferritin 112 ng/ml

• Hb electrophoresis
– HbA 92.7 * % (96.5-98.5)
– HbA2 7.3 * % (1.5-3.5)

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24
 β-Thalassemia

Case #2
(not acquired, but we should know)

CMUH
 Case #3
• 25-year-old female
• Pregnancy 30 wks, first child
• Anemia 8+ gm/dl since 2 months ago,
dizziness in the past one week
• Hb around 10+ gm/dl without symptoms
before
• Post iron supplement for one month 
Hb 7.7 gm/dl, MCV 70.8 fl
• Diet/MC not marked
• Denied other systemic disease
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26
 Case #3
• Fe 188 μg/dl, TIBC 252 μg/dl
• Ferritin 77 ng/ml
• Visiting day (940622)
– WBC 10060/μl, D/C nonremarkable
– RBC 3.43x106/μl, Hb 8.0 gm/dl, MCV
75.5 fl,
RDW 21.3
– Plt 214 k/μl
– Reticulocytes 5.49%
– N-RBC(+)
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27
What’s The Next?

CMUH
 Case #3
• Red blood cell indices : MCV
– Microcytic
– Normocytic
– Macrocytic

• Reticulocyte Production Index

– [reticulocyte × (Hct / 45) × (1/shift
correction factor )]

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29
 Case #3
• Microcytic anemia?
Possible
– Thalassemia?
– Iron deficiency anemia? Possible

– Sideroblastic anemia?
– Anemia of chronic Less likely
disease?
• Production disorder?
– Hematopoietic Cell Less likely
Damage?
– Factor Deficiency? Possible

• Survival disorder? Possible

– Increased reticulocytes,
why?
– N-RBC, why?
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30
 Case #3
• Hb electrophoresis
– HbA 94.5%, HbA2 5.5%
 Further check cytogenetic study
• Ferritin 115 ng/ml
• Susp. hemolysis proscess
 LDH 300 IU/L
Bil-T 1.0 mg/dl
Haptoglobin <0.243 g/dl (0.45-2.0)
Direct Coombs’ test negative
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31
 β-Thalassemia
and
increased hemolysis

Case #3

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 Case #4

• 52-year-old female
• Anemia
– RBC 1.05x106/ul
– Hb 4.0 gm/dl
– Hct 12.8%
– MCV 121.9 fl
– RDW 17.3
– Reticulocyte 4.3%

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33
 Case #4
• Macrocytic anemia
– Vit. B12 deficiency
– Folic acid deficiency

• Reticulocytosis
– Increased bleeding
– Hemolysis

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34
 Case #4

• Vitamin B12 >1200 pg/ml (200-950)

• Folic acid >24.0 ng/dl (3.0-17.0)
• Direct Coombs’ test positive
• LDH 330 IU/L
• Haptoglobin < normal value

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35
Auto-
Immune
Hemolytic
Anemia

Case #4

CMUH
 Summary
of
Anemia approach

CMUH
 Evaluation of Anemia
• History
– Symptoms in “Main systems”
– Any change in image
– Nutrition
– Menses
– Personal history, OP, occupation
etc..
– Family history
• PE
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38
 心悸
Weakness
Pale skin
A fast heartbeat
Shortness of breath
Chest pain
Dizziness
Cognitive problems
Numbness or coldness in your extremities
Headache

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39
 Lab Evaluation
• Hemogram (“Complete”)
– Especially indices (MCV, MCHC), Ret., RDW
• Nutrition factor
– Serum iron/TIBC, ferritin
– Vit. B12, folic acid
• Morphology
– Smear of PB and BM (optional by indication)

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40
 Approach flowchart

3 important elements:
1. RBC/Hb

2. MCV/RDW

3. Reticulocyte count

From Harrison’s Harrison's Principles of

Internal Medicine, 18e CMUH
http://accessmedicine.com/loadBinary.aspx?name=harr&filename=harr_c057f017.gif 41
 Question
低色素小球性貧血與下列何種因素無關？

鉛中毒

食物中 Vit. B12 不足

食物中鐵不足

慢性發炎吞噬細胞釋放鐵有障礙

CMUH
42
Bleeding Tendency
Yu-Min Liao
Hematology-Oncology Section
China Medical University Hospital
Bleeding or Hemorrhage

Blood

Circulator system
 Blood Component

Flow Vascular
Reaction to damage wall of blood vessel

Vasoconstriction Tissue factor

Collagen exposed
 Reaction to collagen exposed

Anti-thrombogenic

Pro-thrombogenic
 Platelet
• Essential role in hemostasis, thrombosis and
coagulation of blood
• Fragmentation from megakaryocyte
• Regulated by thrombopoiectin (TPO)
• Circulates in the blood for 7 to 10 days
• Acute phase reactants
• Normal range between 150000 and
450000/µL
Reaction To tissue factor exposed
Vitamin K-dependent
• Prothrombin
• factor IX
• factor X
• factor VII
• protein C
• protein S
Anti-coagulant System

Blood Principles and Practices of Hematology 2nd Ed. Fig. 31-7

 Clinical Evaluation
• History
– Age of bleeding onset
– History of bleeding following dental extraction,
childbirth, minor surgery
– Transfusion history
– Family history
• physical examination
– Skin and mucous membrane
Purpura
 Clinical Manifestation
Plasma protein
Platelet defect
defect
Onset of bleeding
Immediate Delayed
after trauma
Site of bleeding Superficial Deep
Petechiae or
Physical finding Hematoma
ecchymosis
Response to Required sustained
Immediate
therapy systemic therapy
 Laboratory Tests
• Platelet counts determination

• Plasma coagulation function

– Prothrombing time
– Activated partial thromboplastin time

• Bleeding time
 International normalization
Add tissue factor,
Ratio (INR) =
Exogenous phospholipid
And Calcium (PT patient / PT normal ) ISI

ISI = international sensitivity index

Add surface activator Exogenous phospholipid And Calcium
 Classification of Thrombocytopenia
Increased destruction
• Immunologic process • Non-immunologic process
– Autoimmune – Thrombotic
• Idiopathic microangiopathic
• Secondary: infections, • DIC
pregnancy, collagen
vascular disease • TTP
– Alloimmune • HUS
• Neonantal – Damage by vascular surface
thrombocytopenia – Miscellaneous
• Post-transfusion • Infections
purpura • Massive blood
transfusion
 Initial Evaluation of Bleeding Patients

nl PT ↑APTT ↑ PT nl APTT ↑ PT ↑APTT nl PT nl APTT

Mixing Test
Prolonged test Normal test

Factor Inhibitor Factor Deficiency

 Acquired Defective Coagulation
• Anticoagulant drugs
• Disseminated intravacular coagulopathy
• Liver disease
• Vitamin K deficiency
• Coagulation factor inhibitor
• Paraproteinemia
• Amyloidosis
• Hypothyroidism
• Massive transfusion
 Bleeding Time
• Test of platelet-vessel interaction
• Capillary pressure of 40mmHg.
• Incision wound with reproducible length,
depth and indirection on forearm
• Influenced by platelet function / number,
hematocrit, skin quality and technique
• Not effective screening test
Management of Acute Hemorrhage
• Patient review
• Laboratories
– Basic evaluation
• Platelet counts
• PT/APTT
• Fibrinogen
– Blood smear examination for thrombocytopenia
Non-Transfusion Therapies for Acute Bleeding
• Desmopression (DDAVP)
– Raising the level of factor VIII and von
Willerbrand factor
• Antifibrinolytics
– Block binding of plasmin to fibrin
– For hemophilia and severe thrombocytopenia
• Conjugated estrogens
– Uremic patient with bleeding
• Recombinant factor VIIa