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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
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
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
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)
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.
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:
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
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
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
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
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