Programme

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Programme

• 1. Hematological malignancies acute leukemias,
  lymphomas
• 2. Solid tumors, part I Brain tumors,
  neuroblastoma,
• Wilms tumor, hepatoblastoma, germ cell tumors
• 3. Solid tumors, part II soft tissue sarcomas,
  osteosarcoma, Ewing sarcoma, late effects after
  anticancer treatment
• 4. Anaemias
• 5. Coagulation disorders
  

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Pediatric oncology and hematology

• Hematological malignancies
• Acute lymphoblastic leukemia
• Acute non-lymphoblastic (myeloblastic) leukemia
• Non-Hodgkin lymphoma
• Hodgkin lymphoma

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Childhood leukemia
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• 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

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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
  
  lt5 - undifferentiated acute leukemia
  and chronic myelogenous leukemia -CML

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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.
  

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• 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

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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

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Clinical manifestation

• General aspects
  -
  history and symptoms reflect
• the degree of bone marrow infiltration by
  leukemic cells
  and
• 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

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• The symptoms depend on the degree of cytopenia
  
• - anemia pallor, fatigue, tachycardia,
  dyspnea, occasionally- cardiovascular
  decompensation
• - leukopeniainfections, temperature elevation
  
• - thrombocytopenia petechiae, mucosal
  bleeding, epistaxes, prolonged menstrual bleeding

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Specific signs and symptoms

• Eye bleeding, infiltration of local vessels,

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CNS at time of diagnosis less than 5 have CNS
leukemia with meningeal signs (morning headache,
vomiting, papilla edema, focal neurological signs)
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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
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Skin maculopapular skin infiltration, often of
deep red color (infants)
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• 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

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Lymphadenopathy
Gastrointestinal involvement

-hepato- and/or splenomegaly
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• 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,

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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

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• 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
  gt increased level of transaminases

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• Bone marrow analysis gt25 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)

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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

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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
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• Cytogenetic characterization
  - in 85 of
  children abnormal karyotype in the malignant
  clone
  
  t(922) (BCR-ABL) unfavorable prognosis
  t
  (411) in infants , poor prognosis
• -ploidy and structure of chromosomes
  (rearrangements) -hypoploidy- poor prognosis
  
  -DNA index (DI)
  

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Prognostic factors

• Favorable
• WBC lt10x10 9/l
• Age 2-7
• Female
• Response on steroid ()
• Pre-B-ALL
• Hyperploid
• FAB L1
• ?LDH moderate

• Unfavorable
• WBC gt50 x 10 9/L
• Age lt 2 and gt10
• Male
• Response on treatment (-)
• Hypoploid, t(922)/t(911)
• FAB L2/L3
• ??LDH high
• visceromegaly

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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

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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

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Response on treatment

• Reaction on steroids (7.day)
• Reaction on chemotherapy (15. and 33. day)
• Minimal residual disease - MRD (-)

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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

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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

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Cytogenetics
FAB Chromosomal abnormalities Affected gene Comments
M1/M2 t(821) ETO-AML 1 Auer rods
M3 t(1517) t(1117) PML-RARA Promyelocytic leukemia
M4or M5 t(911) AF9-MLL Infants, high initial WBC
M5 t(11q23) MLL Infants, high initial WBC
M5 t(1b11) AF10-MLL Infants, high initial WBC
M5 t(1117) AF17-MLL Infants, high initial WBC
M7 t(122) Infants with Down syndrome
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Prognostic factors
Favorable Unfavorable
WBC lt100,000 gt100,000
FAB class M1, M3, M4 with eosinophils Infants with 11q23, Secondary AML, CNS involvement
Chromosomal abnormalities t(821) and t(1517),inv(16), t(911) Wild-type FLT3 Mutation of FLT3 receptor, t(922), del(7)and del(11)
Ethnicity White ethnicity MRD (-) Rapid response to therapy Black ethnicity MRD()
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Clinical presentation

• Bleeding thrombocytopenia coagulopathy (DIC)
• Leukostasis in the lungs or CNS
• Tumor lysis syndrome
• Granulocytic sarcoma (chloroma)
• Infection (fungal, opportunistic)

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Therapy

• Induction/ consolidation/ intensification/
  maintenance - in AML3 ATRA
• Allogeneic/ autologous stem cell transplantation
• Prognosis
• 5year survival rate 50-60

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Non-Hodgkin lymphoma (NHL)
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• 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 21
• Burkitt lymphoma (BL) endemic form in Africa
  10100,000 children and sporadic form in Europe
  and USA

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Etiology, pathogenesis and molecular genetics

• Often chromosomal alterations are detecable in
  B-cell NHL translocation of chromosome 14 -
  t(1814)
• 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

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WHO classification
Histology Rate Immuno - phenotype Main occurence
Burkitt lymphoma Burkitt-like lymphoma 50 B-cell Abdomen
Large B-cell lymphoma 7-8 B-cell
Lymphoblastic lymphoma 30 Pre-T-cell or pre-B-cell Thorax, lymph nodes, bone
Anaplastic, large cell lymphoma 7-8 T-cell Lymph nodes, skin, soft tissue, bone
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Burkitt lymphomaBurkit-like lymphoma

• About 50 of NHL
• Localization abdomen, lymphatic tissue of
  adenoids and tonsils
• 80 with translocation t(814) or t(82) and
  t(228) with c-MYC on chromosome 8q24 which
  stimulates proliferation
• 40 with a p53 mutation

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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

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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 gt painfull, spasms,
  vomiting
• Obstipation, intussusception
• Apendicitis-like
• Ileus, ascites

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• Mediastinum
• Mostly anterior or middle part of mediastinum gt
  cough, stridor, dyspnea, wheezing
• Edema of the neck and face with marked dyspnea
  may indicate SVCS
• Pain of the back or abdomen
• Pleural effusion

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Involvement of adenoid and tonsils,
nasopharyngeal lymph nodes, parotid gland swelling
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• 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

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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

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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

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• Radiological diagnosis
• Ultrasound
• Conventional X-ray
• CT of the thoracic, abdomen and skeletal disease
• MRI for CNS
• PET (positron emmision tomography)
• Bone scan

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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

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• 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)

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• Stages I II 10 20 of all NHL
• Stages III IV 80 90 of all NHL

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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 gt80

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Hodgkin Disease
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• 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

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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

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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)

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• B symptoms (in 20 -30)
• Fever higher than 38 C
• Night sweats
• Loss of more than 10 body weight
• Sometimes pruritus and/or nausea

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Open biopsy Not fine-nedle biopsy!!!

• Histological classification
• Lymphocyte predominance
• Nodular sclerosing
• Lymphocyte-depleted
• Mixed cellular

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Laboratory analyses

• Blood
• Bone marrow
• Ferritin, LDH
• Immunological analyses
• Stage- Radiological evaluation
• Chest (x-ray, CT)
• Abdomen (usg, CT)
• Bone scintigraphy
• PET-CT

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HL
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Staging classification

• I involvement of a single lymph node region(I)
  or a single extralymphatic organ (IE)
• IItwo 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 ofloss of 10 or more body weight in
  6 months preceding diagnosis, unexplained fever,
  drenching night-sweat, pruritus

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Differential diagnosis

• Toxoplasmosis, tuberculosis, atypical infections
• NHL
• Mononucleosis
• Metastatic disease
• Thymus hyperplasia
• Rheumatoid arthritis, LE
• Sarcoidosis

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Treatment

• Procedure depends on stage and histopathology
• Chemo- and radiotherapy (EuroNet protocol)
• 
  
• Prognosis
• Stage I/II EFS gt90
• Stage III/IV EFS 70-80