Pediatric oncology and hematology

Hematological malignancies:
 Acute lymphoblastic leukemia

 Acute non-lymphoblastic (myeloblastic)

leukemia
 Non-Hodgkin lymphoma

 Hodgkin lymphoma
Childhood leukemia
 Uncontrolled proliferation of immature blood cells
with a different immunological subtypes which is
lethal within 1 –6 months without treatment
 The disorder starts in the bone marrow, where
normal blood cells are replaced by leukemic cells
 Morphological (FAB), immunological, cytogenetic,
biochemical, and molecular genetic factors
characterize the subtypes with various response to
treatment
Incidence

 Most frequent neoplasm in children (28 – 33%)

 45/ 1million children under the age of 16 years
 Incidence peak at 2 – 5 years
 75-80%- acute lymphoblastic leukemia -ALL
15-20% - acute
myelogenous (non-lymphoblastic) leukemia
AML/ ANLL
<5% - undifferentiated acute
leukemia and chronic myelogenous leukemia -CML
Ethiology

 Unknown
 Higher risk in congenital disorders:
-trisomy 21 (14 times higher) and other trisomies
-Turner syndrome
-Klinefelter syndrome
-monosomy 7
-neurofibromatosis type 1
-Fanconi anemia (high
fragility of chromosomes)
-Bloom syndrome, Kostmann S., Shwachman-Diamond S.,
-ataxia- teleangiectasia
-congenital agammaglobulinemia
-Wiskott- Aldrich S.
 Ionizing radiation (atomic bomb developed high
incidence of leukemia)
 Chemical and drugs:
-benzene
-chloramphenicol
-
alkylating agents
 Infection (viral –HTLV, EBV, HIV)
 Immunodeficiency: agamma/hypogammaglobulinemia,
Wiskott-Aldrich S, HIV infection
Acute lymphoblastic
leukemia
 80% of leukemias
 Girl – to- boy ratio is 1: 1.2
 Peak incidence 2 – 5 years
 Incidence in white children is twice as high as in
nonwhite children
Clinical manifestation

 General aspects:
- history and symptoms reflect:
1. the degree of bone marrow infiltration by
leukemic cells
and
2. the extramedullary involvement of the disease

- the duration of symptoms is days to several weeks,

occasionally – several months
- often: low –grade fever, signs of
infection, fatigue, bleeding, pallor
 The symptoms depend on the degree of cytopenia:

- anemia: pallor, fatigue, tachycardia, dyspnea,

occasionally- cardiovascular decompensation
- leukopenia:infections, temperature elevation

- thrombocytopenia: petechiae, mucosal bleeding,

epistaxes, prolonged menstrual bleeding
Specific signs and symptoms

 Eye: bleeding, infiltration of local vessels,

CNS: at time of diagnosis less than 5%
have CNS leukemia with meningeal signs
(morning headache, vomiting, papilla
edema, focal neurological signs)
Ear, nose, throat:
-lymph nodes
infiltration (isolated or multiple)

-Mikulicz syndrome (infiltration of salivary

glands and/or tear glands)
Laboratory:
Lk 3,91
Er 2,91
Hb 9,2
Ht 25,1
Blood smear: neutr-9% ly- 45% bl-46%
LDH 976
Skin:
maculopapular skin infiltration,
often of deep red color (infants)
 Cardiac involvement:
-leukemic
infiltration or hemorrhage
-occasionally cardiac
tamponade due to pericardial infiltration
-tachycardia, low blood pressure or
other signs of cardiac insufficiency
 Mediastinum:
-enlargement
due to leukemic infiltration by lymph nodes
and /or thymus (observed in T-cell
leukemia)
 Pleura/and pericardium: effusion
 Kidney enlargement
 Lymphadenopathy

Gastrointestinal involvement:
-hepato- and/or splenomegaly
 Testicular involvement: enlargement of one
or both testes without pain , hard consistency
 Penis: priapism is occasionally associated with
elevated WBC
 Bone and joint involvement:
-bone pain
initially present in 25 % to 50% of
patients ! -bone or
joint pain, sometimes with swelling and
tenderness due to leukemic infiltration of the
periosteum.

Differential diagnosis:
rheumatic fever,
rheumatoid arthritis -
radiological changes: diffuse demineralization,
osteolysis,
Laboratory findings

 Red cells:
-hemoglobin – normal/
moderate /markedly low -low
number of reticulocytes
 White blood cell :
- normal/ low/ high
-in
children with high WBC- leukemic blast cells present
 Platelets:
-usually low
 Coagulopathy:
-in children with hyperleukocytosis
-more common in AML
-low levels of prothrombin,
fibrinogen, factors V, IX, and X may be present
 Chemistry:
-the serum uric acid is often high
initially - the serum
potassium level may be high (cell lysis) -
serum hypocalcemia or hypercalcemia (in marked
leukemic bone infiltration)
abnormal liver function > increased level of
transaminases
 Bone marrow analysis: >25% blasts
-characterize the blast
cells -
determine the degree of reduction of normal
hematopoiesis
-morphological,
immunological, biochemical, and cytogenetic
analyses
Differential diagnosis: aplastic anemia,
myelodysplastic syndrome, neoplastic infiltrations
(neuroblastoma, NHL)
Leukemic cell characterization and
classification:

 Morphology: FAB classification:

ALL - L1,

ALL-L2,

ALL-L3

AML M0 – M7
 chemistry:

ALL: + periodic acid

Schiff(PAS) AML: + Sudan black,
+ peroxidase
Immunological characterization:
-monoclonal antibodies to
leukemia-associated antigens differentiate between
types of leukemic cells:
* lympoid stem cells:
CD19, HLA-DR, CD 24 (+/-)
* early pre-B cells: CD19, HLA-
DR, CD24
* pre-B cells: CD19, HLA-DR, CD24, CD10,
CD20(+/-)
* B-precursors cell: CD19, HLA-DR, CD24, CD10,
CD20
* T-cell lineage: CD7, CD2, CD1, CD4, CD8,CD3
 Cytogenetic characterization:
- in 85% of children abnormal
karyotype in the malignant clone
*t(9;22)
(BCR-ABL) –unfavorable prognosis
*t (4;11) in infants , poor prognosis
-ploidy and structure of chromosomes
(rearrangements) -hypoploidy- poor prognosis
-DNA
index (DI)
Prognostic factors

Favorable: Unfavorable:
 WBC <10x10 9/l  WBC >50 x 10 9/L
 Age 2-7  Age < 2 and >10
 Female  Male
 Response on steroid (+)  Response on treatment (-)
 Pre-B-ALL  Hypoploid, t(9;22)/t(9;11)
 Hyperploid  FAB L2/L3
 FAB L1  ↑↑LDH high
 ↑LDH moderate  visceromegaly
Differential diagnosis

 Leukemic reaction in bacterial infection, acute

hemolysis,tuberculosis, sarcoidosis, histoplasmosis
 Lymphocytosis: pertussis
 Infectious mononucleosis
 Aplastic anemia
 Idiopathic thrombocytopenia
 Bone marrow infiltration by a solid tumor (NBL,NHL,
RMS)
 Rheumatoid arthritis, rheumatoid fever
 Therapy
 In experienced center
 Subdivided into:
-remission induction
-consolidation with CNS
prophylaxis -
maintenance phase

Prognosis
 Rate of first remission in ALL: more than 90%
 80% of children survive without relapse
Response on treatment

 Reaction on steroids (7.day)

 Reaction on chemotherapy (15. and 33. day)
 Minimal residual disease - MRD (-)
Acute myelogenous
leukemia
 Heterogeneous group of malignant hematological
precursor cells of the myeloid, monocytic, erythroid
or megakaryocytic cell lineage
 Epidemiology: 15-20% of all leukemias in children
 Frequency remains stable throughout childhood
with slight increase during adolescence
 No difference in incidence between boys and girls
FAB classification

 M0: immature myeloblastic leukemia

 M1: myeloblastic leukemia
 M2: myeloblastic leukemia with signs of maturation
 M3: promyelocytic leukemia
 M4: myelomonocytic leukemia
 M5: monocytic leukemia
 M6: erythroleukemia
 M7: megakaryocytic leukemia
Cytogenetics
FAB Chromosomal Affected Comments
abnormalities gene
M1/M2 t(8;21) ETO-AML 1 Auer rods

M3 t(15;17) PML-RARA Promyelocytic

t(11;17) leukemia
M4or M5 t(9;11) AF9-MLL Infants, high
initial WBC
M5 t(11q23) MLL Infants, high
initial WBC
M5 t(1b;11) AF10-MLL Infants, high
initial WBC
M5 t(11;17) AF17-MLL Infants, high
initial WBC
M7 t(1;22) Infants with
 Prognostic factors
Favorable Unfavorable

WBC <100,000 >100,000

FAB class M1, M3, M4 with Infants with 11q23,
eosinophils Secondary AML, CNS
involvement
Chromosomal t(8;21) and Mutation of FLT3
abnormalities t(15;17),inv(16), receptor,
t(9;11) t(9;22),
Wild-type FLT3 del(7)and
del(11)
Ethnicity White ethnicity Black ethnicity
MRD (-) MRD(+)
Rapid response to
therapy
Clinical presentation

 Bleeding: thrombocytopenia + coagulopathy (DIC)

 Leukostasis in the lungs or CNS
 Tumor lysis syndrome
 Granulocytic sarcoma (chloroma)
 Infection (fungal, opportunistic)
Therapy

 Induction/ consolidation/ intensification/ maintenance

- in AML3 + ATRA
 Allogeneic/ autologous stem cell transplantation

Prognosis
 5+year survival rate 50-60 %
Non-Hodgkin lymphoma
(NHL)
 Neoplasia of the lymphatic system and its
precursor cells with genetically disturbed regulation,
differentiation and apoptosis
 If marked bone marrow involvement is present the
clinical condition is equal of leukemia
 Incidence 5 –7 % of all neoplasias in childhood
 Peak incidence between 5 and 15 years
 Ratio of boys to girls 2:1
 Burkitt lymphoma (BL): endemic form in Africa
10:100,000 children and sporadic form in Europe
and USA
Etiology, pathogenesis and
molecular genetics

Often chromosomal alterations are detecable: in B-cell NHL

translocation of chromosome 14 - t(18;14)
Predisposing factors for NHL:
 Acquired immunodeficiency: autoimmune disorders, HIV
infection
 EBV infection
 Congenital B-cell defect, congenital T-cell defect with thymus
hyperplasia
 Bloom syndrome, Chedak-Higashi syndrome, SCID, ataxia
teleangiectasia, Wiskott-Aldrich syndrome
 Exposure to irradiation
 Drug induced, after immunosuppressive treatment
WHO classification

Histology Rate Immuno - Main occurence

phenotype
Burkitt lymphoma 50% B-cell Abdomen
Burkitt-like
lymphoma
Large B-cell 7-8% B-cell
lymphoma

Lymphoblastic 30% Pre-T-cell or Thorax, lymph

lymphoma pre-B-cell nodes, bone

Anaplastic, large cell 7-8% T-cell Lymph nodes, skin,

lymphoma soft tissue, bone
Burkitt lymphoma
Burkit-like lymphoma

 About 50% of NHL

 Localization: abdomen, lymphatic tissue of adenoids and tonsils
 80% with translocation t(8;14) or t(8;2) and t(22;8) with c-MYC
on chromosome 8q24 which stimulates proliferation
 40% with a p53 mutation
 Large B-cell lymphoma
 7-8% of NHL
 Localization: abdomen, peripheral lymph nodes, skin, bone

Lymphoblastic lymphoma
 30% of NHL
 Usually mediastinal localization

Anaplastic Large Cell Lymphoma

 7-8% of NHL
Clinical manifestations

Duration of symptoms: usually a few days to weeks

Non-specific symptoms: fatigue, nausea, anorexia, loss of weigth
and/or fever

In relation to localisation of NHL:

 Abdomen:
 especially the ileocecal region, mesentery, retroperitoneum,
ovaries > painfull, spasms, vomiting
 Obstipation, intussusception
 Apendicitis-like
 Ileus, ascites
Mediastinum:
 Mostly anterior or middle part of mediastinum > cough, stridor,
dyspnea, wheezing
 Edema of the neck and face with marked dyspnea may indicate
SVCS
 Pain of the back or abdomen
 Pleural effusion
Involvement of adenoid and tonsils, nasopharyngeal
lymph nodes, parotid gland swelling
Peripheral lymph nodes:
 Mostly cervical, supraclavicular and inguinal
 Lymph nodes are firm, not usually tender, but involving
multiple lymph nodes that usually occur unilaterally

Other locations:
CNS, cranial and peripheral nerves, skin, muscles,
bone, thorax, gonads, parotid gland, epidural region→
spinal cord compression
Differential diagnosis

 Lymph node enlargement in infectious diseases

 Autoimmune lymphoproliferative syndrome
 Hodgkin Lymphoma
 metastatic disease of sarcomas or neuroblastomas
 ALL: if more than 25% blasts = ALL, if less= NHL IV stage
Diagnosis:
-histology
-stage

 Histological (lymph nodes, peripheral blood, bone marrow or

fluid resulting from pleural effusion or ascites)
 In abdominal stage: laparotomy
 In SVCS- emergency situation, noninvasive biopsy or
pretreatment with chemotherapy or/and radiotherapy
 Morphological, immunophenotypical and molecular /cytogenetic
analyses
 Serum lactate dehydrogenase (LDH)
 Serum uric acid
 Bone marrow aspiration
 CSF analysis
 Radiological diagnosis
 Ultrasound
 Conventional X-ray
 CT of the thoracic, abdomen and skeletal disease
 MRI for CNS
 PET (positron –emmision tomography)
 Bone scan
Staging ( Murphy/St.Jude)
 I- a single tumor (extranodal) or single anatomical area (nodal),
excluding mediastinum or abdomen
 II- a single tumor (extranodal) with regional involvement
On same side of diaphragm
a/ two or more nodal areas
b/ two single (extranodal) tumors with or
without regional node involvement
A primary gastrointestinal tract
tumor (usually ileocecal) with or without associated mesenteric
node involvement; gross complete resection
 III- On both sides of the diaphragm:
a/two single tumors (extranodal)
b/two or more nodal areas
ALL primary intrathoracic tumors (mediastinal,
pleural, thymic) All extensive primary intra-
abdominal disease, unresectable All primary
paraspinal or epidural tumors regardless of other sites

 IV- Any of the above with initial CNS or bone marrow

involvement (less than 25%)
 Stages I + II: 10 – 20% of all NHL
 Stages III+ IV: 80 – 90% of all NHL
Treatment

 Induction therapy should be begun as soon as possible!

 Tumor lysis syndrome prophylaxis or treatment
 Chemotherapy (in Poland -according to BFM protocols)
 Surgical procedure: total resection in I or II stage with localized
masses only
 BMT ( auto)
 Overall long-term survival >80%
Hodgkin Disease
 Progressive, painless enlargement of lymph nodes
with continuous extension between lymph node
region
 Pathogmonic histologically :Reed-Sternberg cells
 Incidence: 5-7% of all neoplasia in childhood
 Boys more than girls
 Rare before 5 years; increasing until the age of 11
years
 Peak incidence between 15 and 35 years of age
Etiology and pathogenesis

 Correlation with EBV infection, genetic predisposition, disturbed

humoral and cellular immune response
 High incidence in patients with LE, rheumatoid disorders,
ataxia teleangiectasia, agammaglobulinemia
Clinical presentation

 Painless enlargement of lymph nodes, mostly in the cervical and

supraclavicular regions
 Swollen lymph nodes are firm, not inflammatory and painfull to
palpation
 Most common involved lymph nodes: cervical (75%),
supraclavicular(25%), axillary, infradiaphragmatic
 Extranodal involvement: lung, bone, liver
 In mediastinal involvement: a cough, sometimes with dyspnea,
dysphagia and enlargement of the vessels of the neck (SVCS)
B symptoms (in 20 -30%)
 Fever higher than 38° C
 Night sweats
 Loss of more than 10% body weight
 Sometimes: pruritus and/or nausea
Open biopsy Not fine-nedle biopsy!!!

Histological classification:
 Lymphocyte predominance

 Nodular sclerosing

 Lymphocyte-depleted

 Mixed cellular
Laboratory analyses

 Blood
 Bone marrow
 Ferritin, LDH
 Immunological analyses

Stage- Radiological evaluation

 Chest (x-ray, CT)
 Abdomen (usg, CT)
 Bone scintigraphy
 PET-CT
HL
Staging classification

 I: involvement of a single lymph node region(I) or a single

extralymphatic organ (IE)
 II:two or more lymph node regions on the same side of the diaphragm
(II) or localized involvement of an extralymphatic organ or site one or
more lymph node regions on the same side of the diaphragm
 III: involvement of lymph node regions on both sides of the diaphragm
(III) which may be accompanied by involvement of an extralymphatic
organ (IIIe) or site, or both (IIIES)
 IV: diffuse or disseminated process
 A: absence of B symptoms
 B: presence of:loss of 10% or more body weight in 6 months preceding
diagnosis, unexplained fever, drenching night-sweat, pruritus
Differential diagnosis

 Toxoplasmosis, tuberculosis, atypical infections

 NHL
 Mononucleosis
 Metastatic disease
 Thymus hyperplasia
 Rheumatoid arthritis, LE
 Sarcoidosis
Treatment

 Procedure depends on stage and histopathology

 Chemo- and radiotherapy (EuroNet protocol)

Prognosis
 Stage I/II EFS >90%
 Stage III/IV EFS 70-80%