Programme

1. Hematological malignancies: acute leukemias, lymphomas2. Solid tumors, part I: Brain tumors, neuroblastoma, Wilms tumor, hepatoblastoma, germ cell tumors3. Solid tumors, part II: soft tissue sarcomas, osteosarcoma, Ewing sarcoma, late effects after anticancer treatment4. Anaemias 5. Coagulation disorders

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)

Laboratory:Lk 3,91Er 2,91Hb 9,2Ht 25,1Blood smear: neutr-9% ly- 45% bl-46%LDH 976

Ear, nose, throat: -lymph nodes infiltration (isolated or multiple) -Mikulicz syndrome (infiltration of salivary glands and/or tear glands)

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: WBC <10x10 9/l Age 2-7 Female Response on steroid (+) Pre-B-ALL Hyperploid FAB L1 ↑LDH moderate

Unfavorable: WBC >50 x 10 9/L Age < 2 and >10 Male Response on treatment

(-) Hypoploid, t(9;22)/t(9;11) FAB L2/L3 ↑↑LDH high 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 abnormalities

Affected gene

Comments

M1/M2 t(8;21)

ETO-AML 1 Auer rods

M3 t(15;17)t(11;17)

PML-RARA Promyelocytic 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 Down syndrome

Prognostic factorsFavorable Unfavorable

WBC <100,000 >100,000

FAB class M1, M3, M4 with eosinophils

Infants with 11q23,Secondary AML, CNS involvement

Chromosomal abnormalities

t(8;21) and t(15;17),inv(16), t(9;11)Wild-type FLT3

Mutation of FLT3 receptor, t(9;22), del(7)and del(11)

Ethnicity White ethnicityMRD (-)Rapid response to therapy

Black ethnicityMRD(+)

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 - phenotype

Main occurence

Burkitt lymphomaBurkitt-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

Burkitt lymphomaBurkit-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 weeksNon-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%