BLEEDING

Mildred Tactacan-Rondilla, MD
FPPS, FPSHBT, FPSPH
 HEMOSTASIS

CLOT FIBRINOLYSIS
FORMATION
COAGULATION CASCADE
 ASSESSMENT
BLEEDING PROBLEMS

• NORMAL COAGULATION FUNCTION

Vasculature
microcirculation
endothelium
Platelets
Quantity and Quality
Coagulation Factors
Extrinsic Factors
Intrinsic Factors
 ASSESSMENT
BLEEDING PROBLEMS
• BLEEDING HISTORY
Personal History
location of bleeding
surgical procedures
menstruation/childbirth
transfusion requirement
Family History
Medication History
PETECHIAE

• Typical of
platelet disorders
• Donot blanch
with pressure
• Not palpable
SKIN
MUCOSAL
ECCHYMOSES/PURPURA
• Typical of
coagulation
factor disorders
• Palpable
• Blanches with
pressure
ECCHYMOSES/PURPURA
HEMATOMA
HEMATOMA
 ASSESSMENT
BLEEDING PROBLEMS

• When to suspect clotting disorder

Too many bruises for the degree of
trauma
New bruises keep on appearing
Multiple bruises of different stages
 CLINICAL FEATURES
BLEEDING DISORDERS
PLATELET COAGULATION
DISORDER DISORDER
Site of Bleeding Skin, mucous Deep in soft tissues
membranes ( muscles, joints)
Petechiae Yes No
Ecchymoses Small, superficial Large, deep
Hemarthroses/muscle Rare Common
bleeding
Bleeding after Yes No
cuts/scratches
Bleeding after Immediate Delayed 1-2 days
trauma/surgery Usually mild Severe
 ASSESSMENT
BLEEDING PROBLEMS
LABORATORY DIAGNOSIS
Standard Coagulation Testing
Platelet Count
PT, APTT
Fibrinogen Levels
Additional Options
Platelet function testing-BT, CRT
Specific factor assay
Fibrin degradation products
 SCREENING TESTS
( APTT,PT, PLATELET CT)
APTT APTT,PT PT N PT,PTT,PC N PT, PTT
N PT, PC N PTT, PC PC

Platelet function
defect
VWD

Excessive
Severe liver coumadin Some large w/o large
dysfunction- Platelets Platelets
hepatitis,cirrhosis Peripheral Lack of
VWD Vit K deficiency consumption production

Acquired ab ITP Aplastic anemia

agst F8 HUS Acute Leukemia
ALLERGIC VASCULAR PURPURA

• Non thrombocytopenic
purpura
• Allergic symptoms
• Normal PT, PTT, BT,
CRT
ALLERGIC VASCULAR PURPURA

• Non thrombocytopenic
purpura
• Allergic symptoms
• Acute or chronic
inflammation of the
blood vessels of joints,
kidney, GIT

HENOCH SCHONLEIN
PURPURA
 IDIOPATHIC (AUTOIMMUNE)
THROMBOCYTOPENIC PURPURA
 ITP

Morbus Maculosus Hemorrhagicus

Werlhof in 1735
Autoimmune Thrombocytopenic Purpura ( ATP )
Immune Thrombocytopenic Purpura ( ITP)
Idiopathic Thrombocytopenic Purpura
ITP
• Most common cause of acute onset of
thrombocytopenic purpura in a well child
• 1-4 yo
• Occurs 1-4 week after exposure to a
common viral infection ( 50-65% )
• an autoantibody directed against the platelet
surface develops with resultant sudden onset
of thrombocytopenia
 PRECEEDING INFECTIONS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Rubeola and Rubella

• Viral Respiratory Disease

• Varicella Zoster Virus

• EBV
• Nonspecific Viral Infections
 PATHOGENESIS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• binding of the antibody to the platelet

surface
• circulating antibody-coated platelets
recognized by the Fc receptors on the
splenic macrophages
• ingested and destroyed
Triggers
•Infection
•Immunization
•Toxin

antibody

thrombocytopenia
CLASSIFICATION
Primary versus Secondary

Acute versus Chronic

* Chronic ITP defined as platelet count of

< 150 x 109/L for > 12 months

Childhood versus Adult

 CLINICAL MANIFESTATIONS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

1. Skin and Mucous Membranes

“Dry” purpura-ecchymoses and petechiae
“Wet” purpura - skin + mucous membrane
( epistaxis, gingival <30 % )

2. Hematuria and GI bleeding < 10 %

3. CNS
• usually subarachnoid hemorrhage
• often multiple
• retinal /subconjunctival hemorrhage

4. Bleeding after trauma/surgery

 CLINICAL MANIFESTATIONS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

Pallor 15 %

Palpable Spleen 12 %
 CLINICAL MANIFESTATIONS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

1.No Symptoms

2. Mild Symptoms
• bruising and petechiae
• occasional minor epistaxis
• very little interference with daily living
 CLINICAL MANIFESTATIONS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

3. Moderate Symptoms
• more severe skin and mucosal lesions
• more troublesome epistaxis and menorrhagia

4. Severe Symptoms
• bleeding episodes-menorrhagia, epistaxis,
melena
• requiring transfusion or hospitalization
• symptoms interfering seriously with the
quality of life
 ACUTE VS CHRONIC ITP
IDIOPATHIC THROMBOCYTOPENIC PURPURA

Feature Acute Chronic

Peak age Children; 2-6 yo Adults; 20-40 yo
Sex predilection F:M None 3:1
Preceding infection Common 1-3 Unusual
weeks
Onset of bleeding Abrupt Insidious
Hemorrhagic bullae in (+) in severe Absent
the mouth cases
Platelet count < 20,000 30,000-80,000
Eosinophilia and Common Rare
lymphocytosis
Duration 2-6 weeks Months or years
Spontaneous remission 80 % of cases Uncommon
Source: Wintrobes Clinical Hematology 11th ed
 OUTCOME
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Severe bleeding is rare ( <3%);

<1% ICH
• 70-80% spontaneous resolution
within 6 months
• Objective of early therapy –
raise platelet count to
>20,000/mm3 and prevent ICH
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Severe thrombocytopenia
< 20,000/mm3 with normal or
increased platelet size
• Normal hemoglobin, WBC and
differential
• Bone marrow aspiration/biopsy- normal
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

Blood
• Megathrombocytes
• Small platelets and platelet fragments
• Anemia proportional to extent of blood
loss
• Normal WBC and differential count
• Atypical lymphocytes
• Prolonged Bleeding Time
• Absent or deficient CRT
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

BONE MARROW ASPIRATION

1. Unusual cases refractory to treatment
2. Abnormalities in the PE or in the
peripheral blood ( young lymphocytes)
3. The initial treatment will be
corticosteroids
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

BONE MARROW ASPIRATION

• Increase in number and size of
megakaryocytes
• Normoblastic hyperplasia
• Normal granulocytes
• Occasional eosinophilia
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

BONE MARROW ASPIRATION

• Increase in number and size of
megakaryocytes
• Normoblastic hyperplasia
• Normal granulocytes
• Occasional eosinophilia
 LABORATORY FINDINGS
IDIOPATHIC THROMBOCYTOPENIC PURPURA

1. PIFT – Direct Platelet

Immunofluorescence Test
• used to detect the presence of platelet-
associated immunoglobulin (PAIg)
2. Assays for antibodies for specific platelet
membrane glycoproteins IIb/IIa and Ib/IX
3. TPO assay
4. Reticulated platelets
• Thiazole orange staining to assess platelet
maturity
 TREATMENT
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Aim: Platelet count > 20,000/mm3

• No therapy for mild bleeding
symptoms, petechiae and bruising
(ASH)
• For children with mucocutaneous
bleeding (ASH):
• IVIG (0.8-1 g/kg/day for 1-2days; increase
in platelet count within 48hrs in 95% of
cases)
• Short course corticosteroids
• Prednisone 1-4 mg/kg/day
 TREATMENT
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Platelet transfusion contraindicated

unless life-threatening bleeding
• Splenectomy indications:
• older child ( ≥4yr) with severe ITP that
lasted > 1yr and whose symptoms are not
easily controlled with therapy
• life threatening hemorrhage (ICH)
 CHRONIC ITP
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• 20% patients with acute ITP have

persistent thrombocytopenia for > 12
months
• Careful reevaluation for associated
disorders: autoimmune disease (SLE),
chronic infectious disorders ( HIV)
and other non-immune causes
 TREATMENT
IDIOPATHIC THROMBOCYTOPENIC PURPURA

• Aimed to maintain platelet count

>50,000/mm3
• IVIg, corticosteroids, IV anti-D,
Rituximab
• Romiplostim and Eltrombopag
• stimulate thrombopoiesis
• Splenectomy: CR in 64-88%
HEMOPHILIA
 HEMOPHILIA
• Deficiency of factors VIII and IX are the
most common severe inherited bleeding
disorders
• Genes for factors VIII and IX are carried
near the terminus of the long arm of X
HEMOPHILIA

chromosome and are therefore X-linked

 INHERITANCE
• Sex linked
• Afflicts males

XY XXh XX XhY

XX XXh XY XhY XXh XY XXh XY

 HEMOPHILIA
1. Hemophilia A (85%) Factor VIII
deficiency
2. Hemophilia B (15%) factor IX
deficiency
3. Hemophilia C - factor XI deficiency;
autosomal deficiency with mild to
HEMOPHILIA

moderate bleeding symptoms, nor

correlated with the amount of factor XI
 PATHOPHYSIOLOGY
• Injury → platelet plug (initial hemostatic
event) + fibrin clot formation →
prevents further hemorrhage
• Factors VIII and IX participate in a
complex required for the activation of
Factor X, together with phospholipid
and calcium, they form the “tenase” or
HEMOPHILIA

factor X-activating complex

COAGULATION CASCADE
 CLINICAL MANIFESTATIONS
• 90% have evidence of increased bleeding
by 1 year of age in severe hemophilia
• Soft tissues
• ecchymoses and hematomas
• bleeding from minor traumatic lacerations
• Joints-hemarthroses- hallmark
HEMOPHILIA

• Urinary
• GIT
• Brain
 LABORATORY FINDINGS
• Factor Assay
• Low levels of Factors VIII and IX
• Hemostatic levels
• Factor VIII >30-40%
• Factor IX >25-30%
• Prolonged PTT
HEMOPHILIA
 CLINICAL SEVERITY
• Mild- >5 % FA
• bleeding after severe trauma or surgery
• Moderate- 1-5 % FA
• hemorrhage with mild trauma at intervals
ranging from weekly to monthly
• Severe- <1 % FA
HEMOPHILIA

• frequent episodes of bleeding into muscles,

joints, skin with minimal or no recognized
trauma
 TREATMENT
• Factor Concentrate:
• Mild to moderate bleeding- 35-50%
• Life threatening- 100%
• Desmopressin acetate (mild
Hemophilia A)
• Factor IX gene therapy
HEMOPHILIA

• Emicizumab – humanized monoclonal

antibody can bridge activated factor IX
&X
DISSEMINATED INTRAVASCULAR
COAGULOPATHY
 DIC
DISSEMINATED INTRAVASCULAR COAGULOPATHY

• Thrombotic microangiopathy
• Heterogenous group of conditions
• Results in consumption of clotting
factors, platelets and anticoagulant
proteins
 DIC
DISSEMINATED INTRAVASCULAR COAGULOPATHY

CONSEQUENCE:
widespread deposition of fibrin →
tissue ischemia
necrosis
generalized hemorrhagic state
microangiopathic hemolytic anemia
 DIC
DISSEMINATED INTRAVASCULAR COAGULOPATHY

TRIGGERS:
Hypoxia
Acidosis
Tissue necrosis
Shock
Endothelial damage
Accompanies severe systemic disease
usually with shock
 CLINICAL MANIFESTATIONS
DISSEMINATED INTRAVASCULAR COAGULOPATHY

• Bleeding
• Petechiae
• Ecchymoses
• Tissue necrosis
• Anemia (microangiopathic HA)
 LABORATORY FINDINGS
DISSEMINATED INTRAVASCULAR COAGULOPATHY

• Low Fibrinogen, prothrombin,

Factors V and VIII
• Prolonged PT, PTT, TT
• Low platelets
• Elevated FDP, D-dimer assay
 TREATMENT
DISSEMINATED INTRAVASCULAR COAGULOPATHY

• Treat the underlying trigger

• Restore normal homeostasis by
correcting the shock, acidosis and
hypoxia
• Blood Components for replacement
therapy in hemorrhage (platelets,
cryoprecipitate, FFP)
 APCD
• Postneonatal Vit K deficiency
• Breastfed
• lack of oral intake of Vit K, alterations in
the gut flora due to prolonged intake of
broadspectrum antibiotics, malabsorption of
Vit K
• Change in sensorium, seizures
• Prolonged PT, PTT
• Treatment: Vit K, FFP
HEMATOLOGIC CANCERS
Mildred Tactacan-Rondilla, MD
FPPS, FPSHBT, FPSPH
 THE LEUKEMIAS
Most common malignant neoplasms in
childhood ( 31%) younger than 15 yr
THE LEUKEMIAS
ALL:77%
AML:11%
CML:2-3%
JMML:1-2%
THE LEUKEMIAS
• Genetic abnormalities in a
hematopoietic cell gives rise to
unregulated clonal proliferation of
cells
ONCOGENESIS
ONCOGENE DYSFUNCTION
 CLASSIFICATION
ACUTE
Profusion of immature hematopoietic or
lymphoid precursors

CHRONIC
Expansion of mature marrow elements

CONGENITAL LEUKEMIA
Diagnosed during first month of life
 ACUTE LEUKEMIA

RESULTING IN:

1. Anemia pallor
2. Thrombocytopenia bleeding
3. Neutropenia infections
4. DEATH
 ACUTE LEUKEMIA
1. Bone Marrow
2. Lymphadenopathy
3. Hepatomegaly
4. Splenomegaly
5. RES including extramedullary tissues
example: skin, CNS, testicles, etc.
 CLINICAL MANIFESTATIONS
ACUTE LYMPHOBLASTIC LEUKEMIA

• Initial presentation: anorexia, fatigue,

malaise, irritability, intermittent low
grade fever, bone/joint pain/joint
swelling
• Bone marrow failure: pallor, fatigue,
exercise intolerance, bruising, oral
mucosal bleeding or epistaxis, fever
CLINICAL MANIFESTATION
1. Pancytopenia
Anemia- pallor
Thrombocytopenia- bleeding
Neutropenia- infections
2. Hepatosplenomegaly-30-40%
3. Lymphadenopathy- 30-50 %
4. Mediastinal mass- 71 % T cell ALL
5. CNS- 1-10 % ( T cell ALL)
 CLINICAL MANIFESTATIONS
ACUTE LYMPHOBLASTIC LEUKEMIA

• Organ infiltration: lymphadenopathy,

hepatosplenomegaly (30-40%),
testicular enlargement (25% occult),
CNS involvement (5% with cranial
neuropathies, headache, seizures; 10-
15% blasts in CSF), mediastinal
mass (T cell ALL)
EXTRAMEDULLARY LEUKEMIA

▪ CNS ▪ BONES AND JOINTS

▪ 5 % at dx ▪ GIT
▪ SPINAL CORD ▪ OCULAR
▪ THYMUS- 10 % ▪ CARDIAC
▪ TESTICULAR ▪ PULMONARY
▪ 1-6 % ▪ SKIN
▪ RENAL
▪ OVARIAN
▪
 ACUTE LYMPHOBLASTIC
LEUKEMIA
• First disseminated cancer shown to be
curable
• Peak incidence at 2-3 yr of age; more
in boys of all ages
ACUTE LYMPHOBLASTIC LEUKEMIA

• More common in children with

chromosomal abnormalities
• Environmental factors like radiation can
increase incidence as well as EBV
infections
• Among identical twins, if the first twin
develops leukemia a) during the first
year of life, second twin has >70% risk,
b) if at 5-7 y/o, risk is twice of the
general population
PREDISPOSING FACTORS Genetic Conditions Environmental Factors

Down syndrome Ionizing radiation

Fanconi anemia Drugs
Bloom syndrome Alkylating agents
Diamond Blackfan anemia Epipodophyllotoxin
Shwachman-Diamond Benzene exposure
Syndrome
Kostmann syndrome
Neurofibromatosis type 1
Ataxia-telangiectasia
SCID, PNH, Li-Fraumeni
syndrome
 DIAGNOSIS
ACUTE LYMPHOBLASTIC LEUKEMIA

• Anemia, thrombocytopenia,
neutropenia and blasts in the
peripheral blood, elevated LDH
• Bone marrow evaluation: > 25%
blasts; CSF analysis
CLASSIFICATION

MORPHOLOGY
IMMUNOPHENOTYPE
HISTOCHEMISTRY
BIOCHEMICAL
MOLECULAR
 MORPHOLOGY
LYMPHOBLAST MYELOBLAST
Higher N/C ratio Lower N/C ratio
Small rim of light blue Abundant dark blue staining
staining cytoplasm cytoplasm with granules
generally without Auer rods
granules
Smooth homogenous More firmly developed nuclear
nuclear chromatin chromatin
Indistinct nucleoli More distinct punched out
nucleoli
LYMPHOBLAST
( BMA )
MYELOBLAST
( BMA )
 CELLULAR CLASSIFICATION
ACUTE LYMPHOBLASTIC LEUKEMIA

• Based on morphology, phenotype

(membrane markers), cytogenetic and
molecular genetic features
• Morphology – adequate for diagnosis; FAB
classification based on morphology to
define specific immunophenotypes; WHO
classification reviews chromosome
translocations and evidence of dysplasia
 CELLULAR CLASSIFICATION
ACUTE LYMPHOBLASTIC LEUKEMIA

• Other parameters – for classification,

prognosis and choice of treatment
• B cell: 85%, T cell: 15%, mature B
cell: 1%
• Chromosomal abnormalities are used
to sub-classify ALL into prognostic
groups
 FAB CLASSIFICATION
ACUTE LYMPHOBLASTIC LEUKEMIA

FAB Morphology
ALL, Small cells with high N/C ratio
FAB L1 Scanty, pale blue cytoplasm
Indistinct nucleoli and nuclear membranes round or
clefted
ALL, Larger, more heterogenous, lower N/C ratio
FAB L2 Prominent nucleoli with perinuclear chromatin
condensation
Irregular nuclear membranes-renifrom or irregular
ALL, Mature B cells immunophenotypically
FAB L3 Homogenous groups of cells with deeply
basophilic cytoplasm with cytoplasmic vacuolation
 WHO CLASSIFICATION
ACUTE LYMPHOBLASTIC LEUKEMIA

Precursor B lymphoblastic leukemia/lymphoblastic

lymphoma
ALL with t(9:22)(q34;q11.2);BCR-ABL(Philadelphia
chromosome
ALL with t(v;11q23)(MLL rearranged)
ALL with t(1;19)(q23;p13.3);TCF3-PBX1 (E2A-PBX1)
ALL with t(12;21)(p13;q22);ETV6-RUNX1 (TEL-
AML1)
Hyperdiploid >50
T(5;14)(q31;32);IL3-IGH
Precursor T lymphoblastic leukemia/lymphoma
 IMMUNOPHENOTYPING
ACUTE LYMPHOBLASTIC LEUKEMIA

Cell Line Cluster of Designation ( CD)/

Antigens
B Cell CD 19, CD 22, HLA-DR
Early Pre-B CD 19, CD 20, CD 10, HLA-DR
Pre-B CD 19, CD 22, CD 10, HLA-DR
Mature B Cell CD 19, CD 22, HLA-DR, KAPPA,
LAMBDA
T Cell CD 3, CD 5, CD 7, HLA-DR
Myeloid CD 13, CD 33, HLA-DR
Mixed Lineage Lymphoid and myeloid markers
AUL CD 34, CD 38, CD 7, HLA-DR
 CYTOCHEMICAL STAINING
ACUTE LYMPHOBLASTIC LEUKEMIA

Periodic Acid Schiff Cytoplasmic glycogen; red

(PAS) 80 % lymphoblasts; fine
staining in myeloid
Myeloperoxidase Cytoplasmic granular
enzymes; brown –black
75 % myeloblasts
Sudan Black Cytoplasmic lipids; black
Myeloblasts

Non- Specific Esterase Stains granules and Auer

(NSE) rods; monocytes and
monoblast
PERIODIC ACID SCHIFF ( PAS)
 MOLECULAR STUDIES
ACUTE LYMPHOBLASTIC LEUKEMIA

Hyperdiploid t (1:19) t (9:22)

Pseudodiploid t ( 4:11 )( q21:q23)
Hypodiploid t ( 8:14), t ( 2:8 ), t ( 8:22)
BIOCHEMICAL MARKERS

TdT
HEXOSAMINIDASE
PURINE NUCLEOSIDE
PHOSPHORYLASE
5’ NUCLEOTIDASE
ADENOSINE DEAMINASE
 DIFFERENTIAL DIAGNOSIS
ACUTE LYMPHOBLASTIC LEUKEMIA

• Pancytopenia: aplastic anemia,

myelofibrosis, familial hemophagocytic
lymphohistiocytosis
• Single cell line cytopenia: TEC, ITP,
congenital or acquired neutropenia
• Infectious mononucleosis (fever,
lymphadenopathies)
• JIA (fever, bone pain)
• AML, small round blue cell tumors
• neuroblastoma, rhabdomyosarcoma,
Ewing sarcoma, retinoblastoma
 TREATMENT
ACUTE LYMPHOBLASTIC LEUKEMIA

• Effective therapy is the single most

important prognostic factor in ALL
• Survival is related to age and subtype
 RISK-DIRECTED THERAPY
ACUTE LYMPHOBLASTIC LEUKEMIA

•Standard of current ALL

treatment and accounts for age at
diagnosis, initial WBC count,
immunophenotype, cytogenetic
characteristics, early treatment
response
GOOD RISK PROGNOSTIC FACTORS

Age 1-10 y/o

Initial WBC < 50,000/mm3
National Cancer Institute: Standard Risk
Female
Absent lymphomatous disease
Platelet count ≥100
Morphology FAB L1
Immunophenotype CD 10, CD 20
Cytogenetics- hyperdiploid
DNA Index ≥ 1.16
Ig at Diagnosis Normal IgM, IgA, IgG
Response to Induction D14 BMA< 5 % blasts
POOR RISK PROGNOSTIC FACTORS

Age < 1 or ≥ 10 years

Initial WBC ≥ 50,000/mm3
National Cancer Institute: High Risk
Male
Lymphomatous or Bulky disease
Platelet count < 100
Morphology FAB L2 or L3
Immunophenotype SIg +, CD10-,CD20-
Cytogenetics- Pseudodiploid
DNA Index < 1.16
Response to Induction D14 > 25 % blasts
 PHASES OF TREATMENT
ACUTE LYMPHOBLASTIC LEUKEMIA

1. Remission Induction: 4-wk multiagent

therapy; eradicate leukemic cells from
bone marrow; CR of 98% ; <5% blasts
2. Consolidation: intensive CNS therapy
and intensive systemic therapy ; <5%
CNS relapse rate ( from 60%)
3. Intensification: eradicate residual
disease
4. Maintenance: 2-3 years
 SUPPORTIVE CARE
ACUTE LYMPHOBLASTIC LEUKEMIA

• Prevent tumor lysis syndrome

treatment in high WBC count leukemia
• Empiric antimicrobial therapy and
transfusion in severe myelosuppression
• Prophylaxis for Pneumocystis jiroveci
 PROGNOSIS
ACUTE LYMPHOBLASTIC LEUKEMIA

• Overall 5-yr survival: 90%

 ACUTE MYELOGENOUS
LEUKEMIA
• Accounts for 11% of all cases of childhood
leukemia; relative increase in frequency to
36% in adolescence ( 15-19 yr)
• Associated with chromosomal abnormalities
• Other risk factors: ionizing radiation,
chemotherapeutic agents, organic solvents,
PNH
 CELLULAR CLASSIFICATION
ACUTE MYELOGENOUS LEUKEMIA

• Based on Bone marrow aspiration > 20%

blasts, flow cytometry, chromosomal and
molecular genetic techniques
• WHO Classification incorporates
morphology, chromosomal abnormalities
and specific gene mutations
 FAB CLASSIFICATION
ACUTE MYELOGENOUS LEUKEMIA

FAB Morphology FAB Morphology

AML, Undifferentiated AML, Monocytic
FAB M0 FAB M5 leukemia
AML, Myeloblastic AML, Erythroleukemia
FAB M1 without maturation FAB M6
AML, Myeloblastic with AML, Megakaryocytic
FAB M2 maturation FAB M7 leukemia
AML, Hypergranular
FAB M3 promyelocytic
AML, Myelomonocytic
FAB M4 leukemia
 WHO CLASSIFICATION
ACUTE MYELOGENOUS LEUKEMIA

Acute myeloid leukemia with recurrent genetic

abnormalities
AML with Provisional entity
t(8;21)(q22;q22.2) AML AML:AML with BCR-
with inv (16) ABL1
APL with PML-RARA AML with mutated NPM1
AML with t(9;11) AML with biallelic
AML with t(6;9) mutaions of CEBPA
AML with inv(3) Provisional entity: AML
AML megakaryoblastic with mutated RUNX1
with t(1;22)
AML with myelodysplasia related changes
 WHO CLASSIFICATION
ACUTE MYELOGENOUS LEUKEMIA

Therapy related myeloid neoplasms

Acute myeloid leukemia not otherwise specified
AML with minimal Pure erythroid leukemia
differentiation Acute megakaryoblastic
AML without maturation leukemia
AML with maturation Acute basophilic leukemia
Acute myelomonocytic Acute panmyelosis with
leukemia myelofibrosis
Acute monoblastic/
monocytic leukemia
 WHO CLASSIFICATION
ACUTE MYELOGENOUS LEUKEMIA

Myeloid sarcoma
Myeloid proliferation related to Down syndrome
Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
 CLINICAL MANIFESTATIONS
ACUTE MYELOGENOUS LEUKEMIA

• Symptoms secondary to bone marrow

failure
• Subcutaneous nodules or blueberry muffin
lesions in infants, infiltration of the gingiva
in monocytic subtypes, signs of DIC in
APL, chloromas or granulocytic sarcomas
 DIAGNOSIS
ACUTE MYELOGENOUS LEUKEMIA

• Bone marrow aspiration and biopsy, flow

cytometry, special stains, molecular and
chromosomal studies
 PROGNOSIS & TREATMENT
ACUTE MYELOGENOUS LEUKEMIA

• Aggressive multiagent chemotherapy induces

remission in 85-90%
• Survival rate is 60-70% ( 15% in 1970’s )
• Anthracycline with high dose cytarabine
• Favorable prognostic features- improved
outcome with chemotherapy alone and HSCT is
used for relapse
• Unfavorable prognostic features- HSCT
• ATRA, tretinoin combined with anthracycline
and cytrabine for APL
 PROGNOSIS & TREATMENT
ACUTE MYELOGENOUS LEUKEMIA

Chromosomal Genetic Morphology Prognosis

Abnormality Alteration
t(8;21) RUNX1- Myeloblasts with Favorable
RUNX1T1 differentiation
Inv (16) CBF-B-MYHII Myeloblasts plus Favorable
abnormal eosinophils
t(15;17) PML-RARA Promyelocytic Favorable
11q23 KMT2A(MLL) Monocytic Unfavorable
abnormalities
FLT3 mutation FLT3-ITD Any Unfavorable
del(7q), -7 Unknown Myeloblasts without Unfavorable
differentiation
Source: Natahn DG et al: Natahan and Oski’s hematology of
infancy and childhood, Philadelphia , 2003
CHRONIC MYELOGENOUS
LEUKEMIA
•
 CML
CHRONIC MYELOGENOUS LEUKEMIA

• Clonal disorder of the hematopoietic

tissue
• 2-3% of childhood leukemia
• 99% of cases have specific translocation
• t(9;22)(q34;q11)
• Philadelphia chromosome
• BCR-ABL fusion protein
 CLINICAL MANIFESTATIONS
CHRONIC MYELOGENOUS LEUKEMIA

• Fever
• Fatigue
• Weight loss
• Anorexia
• Splenomegaly
 DIAGNOSIS
CHRONIC MYELOGENOUS LEUKEMIA

• High WBC count with myeloid cells

in all stages of differentiation in the
peripheral blood and bone marrow
• Cytogenetic and molecular studies
 PHASES
CHRONIC MYELOGENOUS LEUKEMIA

• Chronic phase
• elevated WBC with predominance of
mature forms
• Accelerated phase
• occurs 3-4 years from chronic phase
• increasing blasts
• Blasts Crisis phase
• acute leukemia
 TREATMENT
CHRONIC MYELOGENOUS LEUKEMIA

Imatinib
• inhibits BCR-ABL tyrosine kinase
• cytogenetic response in >70% of
patients
• current standard treatment
JUVENILE MYELOMONOCYTIC
LEUKEMIA
 JMML
JUVENILE MYELOMONOCYTIC LEUKEMIA

• Previously known as Juvenile chronic

myelogenous leukemia (JCML)
• Clonal proliferation of hematopoietic
stem cells
• Affecting children < 2yr
• <1 % of childhood leukemia
• No Philadelphia chromosome
 CLINICAL MANIFESTATIONS
JUVENILE MYELOMONOCYTIC LEUKEMIA

• Rashes
• Lymphadenopathy
• Splenomegaly
• Hemorrhagic manifestations
 DIAGNOSIS
JUVENILE MYELOMONOCYTIC LEUKEMIA

• Elevated WBC count with increased

monocytes, thrombocytopenia, anemia
and normoblasts
• BMA with myelodysplastic changes and
blasts <20%
• Mutation in the RAS oncogene pathway
JUVENILE MYELOMONOCYTIC LEUKEMIA

• HSCT
TREATMENT
 THE LYMPHOMAS
Most common cancer in adolescents; >25%
of newly diagnosed in 15-19 yr
Malignant process involving the
lymphoreticular system
HODGKIN LYMPHOMA
 HL/HD
• 6% of childhood cancers
• 5% ≤14 yr old ( 3rd most common)
HODGKIN LYMPHOMA

• 15% 15-19 yr old ( peak)

• Rare before 5 y/o
• Peaks at 15-34 and after 55 y/o
• male > female
• Associated with EBV
 PATHOGENESIS
• Reed-Sterberg (RS) cell
• pathognomic feature
• hallmark of HL
HODGKIN LYMPHOMA

• Clonal in origin, arises from the

germinal center B cells but has lost B
cell gene expression and function
• Combination of somatic mutations,
chromosomal instability, and complex
chromosomal rearrangements
 CLINICAL MANIFESTATIONS
• Enlarged nodes-firm, rubbery, non-tender
• Chronic cough- mediastinal
• Night sweats
HODGKIN LYMPHOMA

• Fever
• Weight loss
• Lethargy
• Fatigability
• Anorexia
• Pruritus
• Immune disorders
 DIAGNOSIS
• Lymph node biopsy
• light microscopy
• immunohistochemical
HODGKIN LYMPHOMA

• molecular studies
• CXR,
• CT scan
• Bone marrow biopsy
• Laparotomy
 RYE CLASSIFICATION OF HL
Lymphocyte Predominance 10-20%
Occassional RS cells, mostly mature lymphocytes; Best
prognosis
HODGKIN LYMPHOMA

Nodular Sclerosis 50-70%

Collagen bands in lymph nodes; RS cells appear as
lacunar cells
Mixed Cellularity 40-50 %
Mixture of lymphocytes, plasma cells, eosinophils,
histiocytes, reticular cells, RS cells
Lymphocyte Depletion <10%
Bizarre malignant reticular cells, RS cells and few
lymphocytes; Poorest prognosis
 NEW WHO/REAL CLASSIFICATION
Nodular Lymphocyte Predominance
Classical Hodgkin lymphoma
• Lymphocyte rich
HODGKIN LYMPHOMA

• Mixed Cellularity
• Nodular Sclerosis
• Lymphocyte Depletion

Source: Harris NL et al, Clinical Advisory Committee Meeting, 1997

 LUGANO CLASSIFICATION
Stage Involvement Extranodal Status
I One node or group of adjacent Single extranodal lesions
nodes without nodal involvement
HODGKIN LYMPHOMA

II Two or more nodal groups on the Stage I or II by nodal extent

same side of the diaphragm with limited contiguous
extranodal involvement
II II As above with bulky disease Not applicable
bulky
III Nodes on both sides of the Not applicable
diaphragm; nodes above the
diaphragm with spleen involvement
IV Additional non-contiguous Not applicable
extralymphatic involvement
For all patients: A: absence; B: with B symptoms: , fever >380C for 3
days , 10 % weight loss over 6 months, night sweats
Source: Cheson BD et al: the Lugano classification, J Clin Oncol, 2014
 TREATMENT
• Surgery- staging
• Risk Adapted combined chemotherapy
HODGKIN LYMPHOMA

Hybrid Protocols
• COPP, ABVD, ABVE-PC, BEACOPP
• With or without low dose involved field
irradiation
 PROGNOSIS
• EFS:
• Early stage- 85-90%
HODGKIN LYMPHOMA

• Advanced stage- 80-85%

• 5yr OSR
• Early stage- >95%
• Advanced stage- 90%
NON-HODGKIN
LYMPHOMA
 NHL
• More common than HD in younger
NON-HODGKIN LYMPHOMA

children
• 2nd most common malignancy in 15-35 yr
• 60% of all lymphomas in children
• M:F is 3:1
• >70% advanced disease
• Immunodeficiencies
 CLINICAL MANIFESTATIONS
NON-HODGKIN LYMPHOMA

• Painless, unexplained lymph node

swelling, non-tender, firm
• Anterior mediastinal mass- cough,
dyspnea, pleural effusion, SVC syndrome
• Abdominal- mass, obstruction,
intussusception
• Bone Marrow- bone pains; >25% blasts;
• Meningeal- increase ICP
• Fever, weight loss
 DIAGNOSIS
• Lymph node biopsy
NON-HODGKIN LYMPHOMA

• flow cytometry for immunophenotypic origin

• cytogenetics
• FISH,
• RT-PCR
• CXR
• CT scan
• Bone marrow biopsy
 HISTOLOGY OF NHL
Low Grade Small Lymphocytic
NON-HODGKIN LYMPHOMA

Follicular, Small cleaved cell

Mixed small cleaved cell and large
cell
Intermediate Follicular predominantly large cell
Grade Diffuse small cleaved cell
Diffuse small cleaved and large cell
Diffuse large cell
High Grade Large cell immunoblastic
Lymphoblastic
Small non-cleaved cell- burkitts,
follicular ( non-burkitts)
 MAJOR PATHOLOGIC SUBTYPES
Burkitt Sporadic type- Abdominal
NON-HODGKIN LYMPHOMA

Lymphoma (BL) Endemic Type- head, neck,

BM,CNS
Lymphoblastic Intrathoracic, mediastinal
Lymphoma (LL) supradiaphragmatic mass, BM, CNS

Diffuse Large B Abdominal, mediastinal

Cell Lymphoma
(DLBCL)
Anaplastic Large Primary cutaneous 10% or systemic
Cell Lymphoma disease ( fever, weight loss)
(ALCL) Spread :liver, spleen, lung,
mediastinum or skin, BM, CNS
 INTERNATIONAL PEDIATRIC NHL
STAGING SYSTEM (IPNHLSS)
NON-HODGKIN LYMPHOMA

Staging Extent
I Asingle tumor with the exclusion of the
mediastinum or abdomen (N:nodal; EN:extranodal;
B:bone; S:skin )
II A single extranodal tumor with regional lymph node
involvement
Two nodes/sites on same side of the diaphragm
Primary GIT tumor with or without involvement of
the mesenteric nodes that is completely resectable

Source: Murphy SB: Classification, staging and results of treatment of childhood non-
Hodgkin’s lymphomas: Semin Oncol 1980
 INTERNATIONAL PEDIATRIC NHL
STAGING SYSTEM (IPNHLSS)
NON-HODGKIN LYMPHOMA

Staging Extent
III Two or more extranodal tumors ( including bone or
skin) above and/or below the diaphragm
Two or more nodal areas above and below the
diaphragm
Any intrathoracic tumor
Intraabdominal and retroperitoneal disease including
liver, spleen, kidneys, ovaries
Paraspinal or epidural tumor
Single bone lesion
IV Any of the above plus bone marrow ( stage IV BM) ,
CNS (stage IV CNS)
Source: Murphy SB: Classification, staging and results of treatment of childhood non-
Hodgkin’s lymphomas: Semin Oncol 1980
 TREATMENT
• Surgery- diagnostic
NON-HODGKIN LYMPHOMA

• Multiagent chemotherapy
• COPAD, BFM 95, FAB/LMB 96
• and/or Immunotherapy
• imatinib, brentuximab, crizotinib
• with intrathecal chemotherapy
• Radiation
• CNS involvement and SVC syndrome
 PROGNOSIS
• Localized disease ( Stage I and II ) : 90-
NON-HODGKIN LYMPHOMA

100 % SR
• Advanced disease (Stage III, IV ): 80-95
% SR