programme 1. hematological malignancies: acute leukemias, lymphomas 2. solid tumors, part i: brain...
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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
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%