1Pediatric Board Review Course Pediatric Hematology/Oncology Kusum Viswanathan, MDVice Chair, Dept of PediatricsBrookdale Univ Hospital and Medical Center
2Case 1 Most likely explanantion: Rh hemolytic disease 6 week old term infant refd for anemia. Hb 7.5, Retic 2 %. Mother O+, Baby A -, Direct Coombs +, Cord blood Hb 14.2 g/dL. Jaundice of 15mg/dL at 48 hours of life, recd photo Rx and discharged at 5 days. No complaints, pale, Bili 3.5, Direct 0.5.Blood smear shows spherocytesMost likely explanantion:Rh hemolytic diseaseG 6 PD deficiencyHereditary spherocytosisPhysiologic anemiaABO incompatibilty
3Newborn -anemia Hemoglobin at birth is 17 g/dl, MCV over 100. Falls to by 6 weeks of age- nadir.Erythropoietin production shifts from liver to kidneys and reduces because of increase in PaO2.Anemia at birth could be :May not have equilibrated- repeatHemorrhage, may not have had time to mount a retic responseAcute hemorrhage- pallor and tachypneaLook at MCV- low MCV-suggestive ofchronic feto-maternal hemorrhageAlpha Thalassemia trait.Kleihauer-Betke- Hb F resistance to acid elution
4Newborn-Thrombocytopenia A newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000.Differential diagnosis:Production defects:TAR, Magakaryocytic hypoplasia, Trisomy 13, 18.Wiskott-Aldrich(small plt, X-linked, Ezcema , SCT cure)Infections- viral, bacterial, Infiltration (Gauchers, Niemann Paick, Leukemia)Destruction:Allo-immune- Platelet group incompatibiltyAuto-immune: Mat ITP, Drugs (thiazide, tolbutamide), SLEInfections: CMV, Rubella, herpes, DICLoss: Kasabach- Merritt syndrome (hemangiomas, DIC- Rx DIC and hemangioma with Steroids, interferon, VCR)
5Immune thrombocytopenia Auto-immune: Pregnant women with ITP/Hx of ITPPassive transfer of antibodies (IgG) from mother.Even when mother has a normal platelet count (Splenectomy)Nadir-few days; Platelets < 50,00 have 1% risk of ICH.IVIG to mother, Fetal platelet counts, C sec, US, IVGG to babyIso-Immune: Normal platelet count in motherSimilar to Rh disease; PL A1 antigen/ Zw a negative mother.97% of population is PL A 1 positiveSensitization early in pregnancyPlt function defect because Anti-PL A1 interferes w/aggregation.Severe bleeding more likely; first born affected;Recovery in 2-3 weeksMother’s washed (PLA1 neg) platelets; IVIG; Ultrasound; Steroids
7Older child-Thrombocytopenia 10 year old male treated with Valproic acid for seizures presents with fever. He appears Ok with no skin lesions, lymphadenopathy or hepatosplenomegaly.CBC WBC 5, Hb 12, Platelet 65,000. BUN 12, Creatinine 0.6 md/dl.What is the Most likely cause:ITP (Immune thrombocytopenic purpura)HUS (Hemolytic Uremic Syndrome)HS Purpura (Henoch- Schonlein Purpura)ALL (Acute lymphoblastic leukemia)Drug induced purpura
8Other causes Hemolytic Uremic Syndrome Henoch-Schonlein Purpura ALL Hemolysis, sick patient, Uremia, microangiopathicHenoch-Schonlein PurpuraPurpuric lesions on lower extremities and buttocksAbd pain, arthritis. IgA depositionALLlymphadenopathy (LN), hepatosplenomegaly,other cell lines affectedDrug induced-LikelyBy reducing production or increasing destruction
10ITP Usually acute onset; immune mediated; post viral Peak 2-5 years of age, males=femalesSpontaneous bruises, petechiaePE –no lymphadenopathy (LN), hepatosplenomegaly.CBC- other cell lines normal, large plts on smearTreat if plt< 10,000 or wet ITP, avoid NSAIDS, AspirinTreat- IVIG best response, hours; Side effects.Anti-D (WInRho) Rh+ ,hemolysis, quick responseSteroids good response, SE, inexpensive, need BMBM- Increased megakaryocytes, otherwise normal
11Large platelets Normal platelet 7-10 days Large platelets: ITPMay Hegglin (Dohle bodies in neutrophils, Plt function normal).Bernard Soulier syndrome (AR, Plat function disorder).Small platelets: Wiskott Aldrich syndrome ( X-linked, recurrent infections,eczematoid rash, plt dysfunction)
12A 2 year old boy presents for evaluation of a chronic pruritic eruption. His medical history is remarkable for recurrent epistaxis, otitis media, and pneumonia. Physical examination reveals erythematous, slightly scaling patches on the trunk and in the antecubital and popliteal fossae. Petechiae are present profusely. Of the following, these findings are MOST suggestive ofAcrodermatitis enteropathicaAtaxia telangiectasiaAtopic dermatitisLangerhans cell histiocytosisWiskott-Aldrich syndrome
13Platelet function defects Normal platelet numberGlanzmann thrombastheniaAR, Abnormal aggregationBleeding disorder, check h/o consanguinityHermansky Pudlak Syndrome:AR, Decreased dense granules, In Puerto Ricans, Oculocutaneous albinism
15AnemiaAn 18 month old girl brought in for pallor. Normal diet and PMH. She is alert, interactive, only pallor, normal vital signs, No hepatosplenomegaly, lymph nodes or bruises.CBC- Normal WBC, Plt, Hb 4.5g/dl, MCV 74,AnemiaReduced productionIncreased destructionLossWhat else do you want??
16Reticulocyte count Normal/Low- reduced production Iron deficiency anemia- MCV will be lowALL (leukemia)- other findings, LN, HSMDiamond Blackfan anemia- Us < 1 year of age; facial/thumb abn, Cong heart dis, MCV Incr, rbc ADA increased, responds to steroids, BMT curative.TEC: Over 1 year of age, Pallor, transient rbc production failure, improves, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .
18Microcytic AnemiaThe diet of an 18-month-old child consists only of milk. She consumes 60 oz/day. Findings include: Comfortable, pallor, resting heart rate 85 beats/min, hemoglobin concentration 6.5 g/dL; mean corpuscular volume 57 fL; reticulocyte count 1.2%; and guaiac-negative stool. Peripheral smear reveals marked hypochromia and microcytosis.Of the following, the most appropriate INITIAL step in the management of this patient is toA. administer intramuscular ironB. begin oral ferrous sulfateC. obtain serum iron levelsD. refer for bone marrow evaluationE. transfuse with packed red blood cells
20Iron deficiencyLow MCV, low MCHC, low retic, RDW will be normal initially, will increase after treatment, Low Iron, Incr TIBC, Transferrin low, Ferritin lowCauses: Inadequate dietary intakeToddlers, too much milk, less solids, Breast fed need iron supplementspoor absorptionBlood loss: Menstrual, GI tract, Meckels, EpistaxisD/D:Thalassemia trait- MCV much lower in prop to anemia,Anemia of chronic disease- low Fe, low TIBC, normal/high Ferritin.
21Thalassemia Minor Quantitative defect in globin chains Reduced production of Beta chainsHb electrophoresisHb A- 2 Alpha, 2 BetaHb F- 2 Alpha, 2 GammaHb A2- 2 Alpha, 2 DeltaExcess Alpha combines with Gamma, Delta- Increased Hb F and A 2.Smear abnormalities significant even with MILD anemia.AnemiaLow MCV, normal RDW, normal reticSmear shows anisopoikulocytosis, target cells, microcytes, misshapen cells, basophilic stipplingHb Electrophoresis: Increased Hb A2 and/or F.Normal iron studies, no response to iron
22Thalassemia Major No production of Beta chains Autosomal recessive 25 % chance with each pregnancyPre natal testing for carriersChorionic villous sampling for diagnosisTransfusion dependent-allows for normal developmentPen Prophylaxis, Anti oxidantsSplenectomy after age 5Iron overload- inherent and transfusionNeed chelators
23Thalassemia- Alpha Reduced Alpha chains 4 types- carried on 4 allelles. (x x/x x)One absent- Silent carrier (x-/x x)2 absent- Alpha Thal trait (xx/- - or x -/x -)3 absent- Hb H disease (x -/- - ) Has 4 excess Beta chains)4 absent- Hydrops fetalis (- -/- -)NB period: Excess Gamma forms Hb Barts- FAST moving Hb on Newborn screening
24Case3 year old patient is brought to the ER with complaints of feeling very tired over the past 3 days.Patient is pale, jaundiced with the spleen tip palpable.CBC Hb 5, Retic 5 %, LDH Increased,What does this sound like??
25Reticulocyte count- Increased HemolysisIntrinsic-Membrane defects-Hereditary spherocytosis (HS)Enzyme-G 6 PD deficiencyHemoglobinopathiesExtrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysisLossBlood loss
27G-6PD deficiencyA previously normal African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. The most likely diagnosis isHereditary spherocytosisSickle cell diseaseHepatitisG6PD deficiencyAvoid certain medications (Sulfas), Fava beans in Mediterranean.Seen in African American- avoid moth balls.Blister cellsBite cellsBlister cellsBite cells
29HS- with severe anemia All patients with hemolytic anemia are susceptible A 6 year old girl who has hereditary spherocytosis presents with a 1 week history of fever. Physical examination and history reveal abdominal pain, vomiting, fatigue and pallor. Her hemoglobin is typically about 10 g/dL with a reticulocyte count of 9%, but now, her hemoglobin is 4 g/dL and the reticulocyte count is 1%. Her bilirubin is 1 mg/dL. Of the following, the MOST likely cause for this girl’s present illness is infection withCoxsackie virusEpstein-Barr virusHepatitis A virusInfluenza A virusParvovirus B19
30Newborn ScreeningYou get a call from a frantic parent because she received a letter from the State regarding her baby’s test results on NBS.FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH.FSA- Sickle B+ thal, Sickle cell traitFSC- SC diseaseFAS- Sickle cell traitFAC- Hb C traitFAE- Hb E traitFE - Hb EE disease, E-Thal
31Sickle cellHemolysis- life span days. Abnormal cell shape, abnormal adherence to endothelium, decreased oxygenation, Increased polymerization.Symptoms start by 2-4 months of age.Hb electrophoresis, S >75 %.Start Penicillin daily and give until age 5. Prevention of pneumococcal infections.PPV (Pnu-23) age 2, 5Folic acid daily
32Sickle cell- Higher risk High WBCLow HemoglobinMultiple episodes of dactylitisLow Hb FAssociated Alpha thal trait- better clinical course
34Case12 year old female with SS disease complains of right sided chest pain and upper back pain for one day.P/E reveals slightly reduced breath sounds and a Pulse OX of 86 %. CXR shows an infiltrate on the right lower lobe.What is your diagnosis?What will you do next?
35Sickle cell Acute Chest Syndrome New infiltrate on X-ray, fever, chest pain, back pain, hypoxia.Due to infarction, infection, BM fat embolismTreat: Antibiotics to cover pneumococcus, Mycoplasma, Chlamydia, Bronchodilator, Oxygen, Incentive spirometry, transfusion, Steroids (controversial).Avoid overhydration
36Pulmonary Hypertension Prevalence of pulmonary HT in SCD from %.The presence of hemolysis, chronic anemia, and the need for frequent transfusions were directly associated with development of PHT.On follow-up, PHT was significantly associated with an increased risk of death Am J Hematol July N Engl J Med Feb 2004.
37TCD- Transcranial Doppler A routine TCD on a 4 year old patient with SS disease shows a Cerebral blood flow (CBF) of 210 cm/second.What is the next step?STOP studies- STOP I and II
38Sickle cell and Stroke Affects 10 % of patients Infarctive stroke (younger patients) and Hemorrhagic stroke (older)STOP I study established the role of yearly TCD (transcranial doppler) to measure cerebral blood flow velocity as a tool for determining stroke risk.Transfusion therapy as current therapy for high risk patients (CBF> 200cm/sec)Reversal of CBF velocity is not sufficient to stop transfusion therapy. (STOP II)
39Sickle cell and Transfusions Transfusion indications:Acute anemia (Aplastic, Hyperhemolytic, Sequestration)Hypoxia (ACS, chronic lung disease, Pulmonary hypertension)Stroke and stroke preventionIntractable pain, pre-operativeTypes of transfusionsIntermittentChronic simpleExchange (Partial, Total, Erythrocytapheresis)Hypertransfusion (transfusions in an effort to prevent patient from producing their own red cells)
40Iron overload One unit -200mg Iron No physiologic way of removal 10-20 transfusionsDesferioxamine available. Can be given IV or subq infusion or subq shots.Compliance an issue.December Oral chelator available (Deferasirox)- FDA approved.
41Sickle cell and Hydoxyurea FDA approved for adultsStudies in children demonstrated efficacy and safety.Increases hemoglobin F levelIncreases hemoglobinDecreases WBC – ancillary effectHydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, Acute chest syndrome.
42Other important points Median life expectancy:Males 42 years, females 48 yearsImprovement related to Penicillin, immunizations, education.Bone marrow transplant (BMT) is a cureCord blood storage
43CaseA healthy 5 year old boy has a 2 day hx of fever, P/E normal, No hepatosplenomegaly, LN, no focus of infection. CBC WBC 3, Neutrophils 25 %, Hb 12, Platelet 200X109/L, ANC 750.The most appropriate management would be:Amoxicillin for 10 daysG- CSF for 10 days.BM aspirateRefer to a hematologistRepeat CBC in 1-2 weeks
44Neutropenia Severe neutropenia ANC < 500/mm3 Viral infection(hepatitis, Influenza, Measles, Rubella, RSV, EBV)- No Rx.Cyclic neutropeniaSporadic Autosomal dominant disorder21 day intervals, nadir < 200/uLG CSF treatmentSevere Congenital Neutropenia (Kostmann)AR, ANC< 200, BM arrest, high dose G CSF, risk of malignancy (MDS/AML) and sepsis. BMT cure.
45Neutropenia AutoImmune neutropenia Schwachman-Diamond Syndrome Self limited, G CSF only if necessaryMild infectionsSchwachman-Diamond SyndromeAR, Exocrine pancreatic failure, short stature, recurrent infections, mataphyseal dysostoses.G-CSF, Risk of myelodysplasia and AML, BMT curativeChronic benign Neutropenia??AI, < 3 years of age, skin and mucous membrane infections, Antibodies
46CaseA 2-year-old boy has had several 10-day-long episodes of fever, mouth ulcerations, stomatitis, and pharyngitis. These episodes have occurred at about monthly intervals. Absolute neutrophil counts have been 50/mm³on day 1 of each illness, 500/mm³ on day 10, and 1,500/mm³ on day 14.Among the following, the MOST likely cause for the findings in this patient isA. chronic benign neutropeniaB. cyclic neutropeniaC. Schwachman-Diamond syndromeD. severe congenital neutropeniaE.. transient viral bone marrow suppression
47Approach to a bleeding patient History:h/o trauma, H/o similar episodesh/o bruising, h/o surgery in the pasth/o circumcision, bleeding from the umbilical stump ,delayed wound healingTime of onset (Acute/chronic), any challenges eg. trauma, surgery or menstruationOverall health ( well/sick); Evidence of shock.bleeding disorders in the family (maternal uncles and aunts, grandparents)
48Abnormal BleedingEpistaxis unrelieved by 15 minutes of pressure, both nostrils, requiring an ER visit, documented drop of Hb.Menstrual periods( amount, pads, duration)Bleeding after procedures (circumcision, dental extractions, T and A-delayed bleed)Ecchymoses/bruising inconsistent with the degree of trauma
49Case13 year old girl just started her periods and has been bleeding for the past 16 days. She has used 14 pads a day and is tired. Her vital signs were stable, Hb was 9.5, PT, PTT were normal. The mother had heavy periods and her 6 year old brother has nose bleeds for the past 2 years.
50Bleeding patient Physical Examination: Type of bleeding: Superficial or deepBruises, PetechiaeEpistaxis, Gum bleeding, Excessive menstrual bleedingSite of bleedingBleeding into the joints and soft tissuesLook for evidence of shockMedication history (Aspirin, NSAIDS)
52Lab studies (What do they measure?) CBC and Peripheral smearPT, INR and PTTPT - Factor VII, common pathwayPTT- Factor VIII, IX, XI, common pathwayMixing studies (Inhibitors and deficiency)Specific coagulation factor assaysFibrinogen
53Circulating anticoagulant Mixing studyIf PT or PTT is prolonged, ask for a mixing study.Mix patient plasma with equal amount of normal plasma, the test will normalize if the abnormal result is because of a deficiency in factor.If there is an anticoagulant, it will not normalize or even if it does, it will become abnormal again after incubation.
54Factor XIII and VII deficiency Rare Autosomal RecessiveIf all tests are normal:PT, PTT, Platelet count and function, VW tests all normal.Think of doing Factor XIII assay for deficiencyBleeding after umbilical stump separationAbnormal clot solubility in 5M UreaFactor VIIIntracranial hemorrhageRare, homozygous stateProlonged PT, n PTTTreatment with Recombinant F VII
55CaseA healthy 2-day-old boy born at term undergoes circumcision prior to discharge from the hospital. Bleeding was noted at the site of circumcision 10 hours after the procedure and has increased steadily over the past 4 hours. Findings on physical examination are unremarkable except for bleeding along 2 to 3 mm of the surgical site; there are no petechiae or purpura.Of the following, the MOST likely cause of the bleeding isA. disseminated intravascular coagulationB. factor VIII deficiency hemophiliaC. immune thrombocytopenic purpuraD. neonatal alloimmune thrombocytopeniaE. von Willebrand disease
56Bleeding disorders Tests for bleeding Hemophilia A Hemophilia B Hemophilia CVW Disease
57Hemophilia Factor VIII deficiency (Hemophilia A)-85% X-linked recessive, Carriers asymptomaticSevere<1%, Moderate 1-5, Mild 6-30 %Treat Recombinant Factor VIII1 unit/kg raises factor level by 2 %. Half life 12 hrs. DDAVP for mild cases.Joint bleeds need100%, muscle bleeds 50 %.30 % develop inhibitors after infusions with concentrate (Approx 50 infusions)Factor IX deficiency (Hemophilia B)X-linked recessive, less common
58HemophiliaA patient with Hemophilia A has asked you about the possibility of his children being affected by the disease. The partner is normal.a. There is a 50 % chance that his sons will have the disease.b. There is a 50 % chance that his daughters will be carriersc. There is a 100 % chance that his sons will have the diseased. There is a 100 % chance that his daughters will be carriers
59Answer was d Case13 year old girl just started her periods and has been bleeding for the past 16 days. She has used 14 pads a day and is tired. Her vital signs are stable,Hb 9.5, PT, PTT normal.The mother had heavy periods and her 6 year old brother has nose bleeds for the past 2 years.Likely to have:
60Von Willebrand’s Disease 1-2 % of population Type I - 80 % of cases; Quantitative defect, Autosomal dominant (AD)Type %, Qualitative defect2A, 2b (thrombocytopenia), 2M,2N (AR)Type 3 - Severe (similar to hemophilia A)Autosomal recessive (AR)DDAVP- Releases VWF from endothelial cells and stabilizes Factor VIIISE: Water retention, Tachyphylaxis, hyponatremia.For mild Hemophilia, Type I VWD, 2Contra-indicated in Type 2BPlasma derived VWF containing concentrates
61Thrombophilia- CaseA 14 year old male presents with chest pain and difficulty breathing. He notes that his right calf has been swollen for the last 3 days and he has difficulty placing his foot on the ground. P/E Pain on dorsiflexion, Air entry reduced. CXR and EKG are normal. VQ scan shows a filling defect and a diagnosis of DVT and pulmonary embolism is made.What are the important questions on history?History of DVT in family membersH/o recurrent late miscarriages in mother and her sisters.H/o trauma and precipitating factors
62Causes Factor V Leiden (Activated Protein C resistance) Prothrombin G 20210A gene mutationProtein C deficiency and activityProtein S deficiency and activity.Anti thrombin III deficiency and activity.HyperhomocystenemiaAntiphospholipid syndromeRare disorders-Dysfibrinogenemia
63Hypercoagulable states Factor V Leiden % casesAbnormal factor V cannot be cleaved and inactivated by Protein C & there is thrombosis.Common in Caucasians (5.3 %)Non-O blood group more prone to thrombosisHomozygotes 1%Protein C- Vit K dependent, produced in liverActivated PC inactivates coagulation factors Va and VIIIa, The inhibitory effect is enhanced by Protein S.Venous thromboembolism, Neonatal purpura fulminans, Warfarin-induced skin necrosis.
64Hypercoagulable states G20210A Prothrombin mutationIncrease in the prothrombin, a precursor of thrombinVitamin K-dependent protein which is synthesized in the liverHeterozygous carriers have an increased risk of deep vein and cerebral vein thrombosis.Antithrombin (AT, formerly called AT III)vitamin K-independent glycoprotein that is a major inhibitor of thrombin and factors Xa and IXa.In the presence of heparin, thrombin or factor Xa is rapidly inactivated by AT; this is referred to as the heparin cofactor activity of AT.
65TransfusionA 4-year-old boy develops massive bleeding following a tonsillectomy. A transfusion is indicated, but his parents are extremely concerned about the risk of a transfusion-mediated infection. They want to know what tests are performed on donated units of blood before they consent to the procedure.Of the following, your discussion is MOST likely to include the statement thatA. all units are tested only for hepatitis B and CB. all units are tested only for human immuno-deficiency virus (HIV)C. all units are tested for HIV, hepatitis B, and hepatitis CD. all units are tested for HIV, hepatitis B, hepatitis C, sickle cell trait, cytomegalovirus, and Epstein-Barr virusE. only units obtained from donors who have one or more risk factors are screened for HIV
66Transfusion- Notes CMV negative- give leukocyte reduced. Irradiated products- To prevent GVHDWashed cellsPhenotype matchedTo prevent allo-immunizationSickle negative
68Cancer in Children Leukemias, Brain tumors, Lymphomas 2nd leading cause of death 1-14yrs12,400 cases per yearProto-Oncogenes imp for function-Activated-Amplification --n-myc-Point mutation-NRA’s-Translocation- Ph chromosome t (9:22); BCR-ABL
69Case18 month old comes to the clinic with complaints of pallor. No fever, appetite change, wt loss. P/E Pale, HR 110/min, No HSM, bruise left buttock, arms and abdomen.MOST likely diagnosisALLChild abuseITPIron deficiency anemiaTEC (Transient erythroblastopenia of childhood)
70ALL (Acute Lymphoblastic leukemia) This suggests 2 cell lines are affected. Consider ALL, viral infections, aplastic anemia, myelofibrosis, neuroblastoma.Child abuse: unlikely to have pallor unless massive traumaITP: can have mild anemia, but here, the HR suggests significant anemiaIron def and TEC: No bruising
71A 6-year-old girl has had diffuse aching in her arms, legs, and back for more than 2 weeks. Results of laboratory tests include hemoglobin, 9.4 g/dL; white blood cell count, 5,600/mm³ with no abnormal cells noted on smear; and platelet count, 106,000/mm³. Radiographs of long bones reveal osteolytic lesions and radiolucent metaphyseal growth arrest lines.Of the following, the MOST likely cause of these findings isA. acute lymphoblastic leukemiaB. aplastic anemiaC. Gaucher diseaseD. lead poisoningE. multifocal osteomyelitis
72ALL (Acute Lymphoblastic leukemia) Can present with generalized bone painBruising, nose bleedsUnusual fevers, infectionLymphadenopathy, hepatosplenomegaly
73ALL (Acute Lymphoblastic leukemia) Abnormal to see blasts in the peripheral smearDiagnosis: >25 % blasts in the BM.Normal marrow has 5 % blastsSingle most common childhood cancer (29% of all childhood cancers); cases per yearPeak age 2-5 yearsMore likely in Trisomy 21, Ataxia-Telangiectasia, Bloom syndrome, Fanconi anemia.
74ALL TreatmentInduction: 4-6 weeks, 95 % remission; Vincristine, Corticosteroids, L-Asparaginase and AnthracyclineConsolidation /delayed Intensification:6-12 months; rotating drugs.Maintenance : Daily oral 6-MP, weekly MTX, Monthly pulses of Vincristine and Steroid.CNS prophylaxis: Intrathecal chemoCNS Therapy: RT + Int Systemic chemoTesticular disease: RT
75ALL- Prognosis Prognosis: WBC, Age, Cytogenetics good if hyperdiploidy, trisomy 4,10,t (12,21)Bad if Philadelphia chr t (9,22),t(4,11), t(8,14)Immunophenotype: Pre-B, B, TEarly response, Minimal residual disease (MRD)Standard risk: 85 % survivalHigh risk: 65 % survivalVery low risk: 90% survivalInfants: 50 % survivalEarly relapse is a poor sign
76Down Syndrome and Leukemia 10-20 fold increaseALL:AML 4:1< 2 years: M7 AMLDS: 400 fold Increase in M7 AMLSuperior response to Rx of AMLTransient Myeloproliferative disorder in NB which resolves within 3 months.No clonal cytogenetic abnormality.Rx : Exchange or low dose cytoreduction.Higher chance of M 7 AML. (30% in some reports)
77Acute Myeloid Leukemia (AML) 20 % of all leukemiasIncreased incidence in < 1 year of ageHigher incidence:Downs, Fanconi, Bloom, DBA, Kostmann, Neurofibromatosis I, Schwachman-DiamondSx: Fever, bleeding, pallor, anorexia, fatigue, Bone/Jt pain, LN, GI Sx.Chloromas (green) – solid collection in bone/soft tissuesTypes: M0-M7, commonest M2M7- Downs syndrome
78Acute Myeloid Leukemia (AML) Treatment:Remission Induction, Consolidation, MaintBMT (matched sib donor) after remission.ATRA (form of Vit A-transretinoic acid) in APMLResults:HLA matched donor: 65 % EFSNo donor %Prognostic features:Favorable: t(8,21), inv(16); Early remission;FAB M4 with eosinophiliaUnfavorable: Monosomy 7; WBC> 100,000; Secondary AML; Myelodysplasia with AML
79Hodgkin’s LymphomaBimodal age distribution: first peak 20-30, again after age 50. Rare < 5 years.5 % of all malignancies; 40 % of lymphomas,Sx: Painless adenopathy, 1/3 have “B” symptoms( fever, night sweats, wt loss)Pathology: Reed-Sternberg cell (large cell with multilobed nuclei); B-cell, 4 subtypes.Rx: based on stage; Staging depends upon one side or both sides of the diaphragm. Stage !-2, EFS %, Stage 3-4; 75 % EFS.Second malignancy in patients who have recd combination chemo and RT-- Leukemia, NHL, Breast cancer.
80Non Hodgkins Lymphoma Most common lymphoma in childhood 10-15 % of all cancers (after leukemia, Brain tumor)50 % of all cancers in Africa (Burkitt’s)More in males, CaucasiansCommon in immunodeficiencies (SCID, Wiskott-Aldrich syndrome, HIV, following stem cell transplant.Types:small, non-cleaved 40 % (B cell)Lymphoblastic lymphoma 30 % (T cells)Large cell 20 % (B, T, indeterminate)Sites: Abdomen, mediastinum, head and neckMajority are high gradeChromosomal translocations involve c-myc oncogene (chr 8)
81Burkitt’s Lymphoma Endemic Burkitt’s Sporadic Burkitt’s African type, head and neck, jaw95 % chance of EBVSporadic Burkitt’sAbdomen15-20 % chance of EBVTreatment- Early diagnosis, surgery, chemotherapy, Tumor lysis, Treatment based on stage and histology.Immunotherapy: Anti-CD 20 monoclonal antibody; (Rituximab)Prognosis: Stage Overall 70 % cure rate, early 85 %.
82Case5 yr old boy with progressive vomiting, headache, unsteady gait and diplopia for 4 weeks. MRI shows a contrast enhancing tumor in the 4th ventricle with obstructive hydrocephalus.
83Medulloblastoma - most common CNS tumor Trt: Resection, Craniospinal RT, Chemo for incompletely resected tumor and infants to permit smaller RT dose and recurrence.Prognosis: Age, large size, degree of resection, dissemination, histology.
84Brain Tumors 20% of all malignancies in children Age 3-7 years Most often infratentorialcerebellar and hemispheric astrocytoma, medulloblastoma, brain stem gliomas, Craniopharyngiomas.Sx: Persistent vomiting, headache, gait imbalance, diplopia, ataxia, vision loss, school deterioration, growth decelerationInherited Genetic disorders Associated:Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau disease, Li-Fraumeni (glioma), Turcot syndrome
85A 13 year old female comes with complaints of headache off and on for the past 2 months. Of significance, is that her shoe size has not changed for the past 3 years. She is Tanner stage 1.CT Scan shows a midline calcification in the brain.What do you think is the diagnosis?
86Observe the relatively homogeneous and cystic mass arising from the sella turcica and extending superiorly and posteriorly with compression of normal regional structures. Note that the lesion is sharply demarcated and smoothly contoured. Craniopharygioma
87Wilms TumorAn 18-month-old girl is being evaluated because her mother thinks her abdomen seems “full.” Physical examination reveals an abdominal mass. Ultrasonography identifies a solid renal mass. At surgery, a stage I Wilms tumor is found.This child’s chance of 4-year survival is CLOSEST to:A. 30%B. 45%C. 60%D. 75%E. 95%
89Wilms Tumor Associations: WAGR (Wilms, Aniridia, GU anomalies, MR) Beckwith-Weidemann syndrome- organomegaly, Hemihypertrophy, omphalocoele)(chr 11p15.5 gene deletion)3-5 % risk of WT (general population 8.5/mill)Denys-Drash: Pseudohermaphroditism, nephropathyPerlman syndrome: Macrocephaly, macrosomiaDo US , UA q 3-4 months
90Wilms Tumor Histology: favorable(FH) vs unfavorable (UH) Staging: I-local, II-excised, III-residual, IV-metastases, V -bilateralTreatment: Nephrectomy, Chemo-all, St I-II-2 drugs-18 weeks, St III-IV- 3 drugs+ RTPrognosis:FH: > 90% at 2 yearsUH: < 60% at 2 years
91QuestionA 9 year old previously healthy girl manifests progressive painless proptosis and decreased visual acuity of the left eye during a 2 month period. The most likely diagnosis isPseudotumor of the orbitTrichinosisRetinoblastomaRhabdomyosarcomaOrbital cellulitis
92Rhabdomyosarcoma 7 % of all childhood cancers Painless non tender mass, 60% under age 6Sites: head & neck, GU, Extremities, mets lungs.Majority sporadic, associations: B-W, Li Fraumeni, NF 1Types:Embryonal 70%, better prognosisAlveolar 30 %, trunk, worse prognosisTreatment: Surgery, Chemo, local control RTResults:85 % good risk30 % metastatic disease
93MassThe mother of a 22-month-old boy reports that he has been fussy and tired. Findings on physical examination confirm the presence of a nontender rt upper quadrant mass. Bilateral periorbital ecchymoses also are noted.Of the following, the MOST likely cause for these findings isA. multicystic kidney diseaseB. neuroblastomaC. non-Hodgkin lymphomaD. HepatoblastomaE. Wilms tumor
94NeuroblastomaThe mother of a 22-month-old boy reports that he has been fussy and tired. Findings on physical examination confirm the presence of a nontender left upper quadrant mass. Bilateral periorbital ecchymoses also are noted.Of the following, the MOST likely cause for these findings isA. multicystic kidney diseaseB. neuroblastomaC. non-Hodgkin lymphomaD. HepatoblastomaE. Wilms tumor
95Neuroblastoma Most common extra-cranial solid tumor Most common cancer in the first year of lifeFrequent in <4 years, 97 % by 10 yearsMost commonly diagnosed as Stage III or IVDx: biopsy or BM plus urine for VMA, HVAMetastatic- orbital discoloration, bone painPrognosis: StageBetter in age < 1 year, low stage, Shimada classification (histology), high DNA index.Worse with N-myc oncogene amplification and tumor diploidy (DNA index 1), Higher LDH, Ferritin, age >1.
96Neuroblastoma Low risk: Intermediate risk: High risk: Surgery alone; >95 % 5 year survivalIntermediate risk:Surgery and Chemo; % 5 year survivalHigh risk:Induction chemo, surgery, Chemo with autologous transplant, RT, Biologic therapy30 % 5 year survivalStage IVs-Localized Prim tumor with spread to skin, liver and/or bone marrow- Minimal therapy.
97A 16 year old male comes in because he fell in the supermarket. P/E shows a small painless mass on the medial aspect of the knee.X ray shows a fracture and a lytic sunburst pattern. (periosteal elevation)What is your diagnosis?What would you do next?
99Osteogenic Sarcoma MRI, Bone scan, Biopsy, CT Chest. Peak incidence- 2nd decadePredisposition: Hereditary retinoblastomas, Li-Fraumeni, Pagets, RT, Alkylating agents60 % near the knee (Metaphyses of long bones)History of fall, pain common Sx, mass, no systemic Sx.Treatment: Open biopsy, Sperm banking, Neo-adjuvant Chemotherapy, limb preserving surgery.
100A 16 year old Caucasian female comes with complaints of chest pain and difficulty breathing for the past one week. She has had fever, wt loss over the last 2 months. She has reduced air entry and CXR shows a moth eaten appearance of one of the ribs and a pleural effusion.Biopsy is done and is consistent with Ewings Sarcoma.
101Ewing’s SarcomaSeen in Axial bones, flat bones and long bones. 20 % in soft tissue.Caucasians, Onion skin appearance, Diaphysis affected.MRI, CT Chest, Bone scan, Biopsy, BM aspirate and biopsy( Anemia).Unique marker: t(11,22) most casesPNET: Ewing like tumor with neural differentiationTreatment:Surgery, RT, Neoadjuvant Chemo,
103Retinoblastoma Presentation: Unilateral 75 % (could be hereditary/non) Leukocoria (cats eye reflex),Dilated pupil, esotropia, strabismusUnilateral 75 % (could be hereditary/non)60 % unilateral and non hereditary15 % unilateral and hereditary (RB1 mutation)Bilateral 25 %25 % are bilateral and hereditary, have RB1 mutationEarlier age, 11mos, Can develop in each eye separatelyHigher incidence of sarcoma, melanoma, brain tumors.10 % of retinoblastoma cases have family history.But child of parent with the RB1 gene (Chromosome 13q) has a 45 % chance of developing the tumor.
105Tumor lysis syndromeA 12 year old girl with ALL has been started on Chemotherapy. She had a WBC of 82,000, Hb 9gm, Platelet count of 45,000. Within 12 hours, she develops findings typical of tumor lysis syndrome:Which one of the following depicts itK high, P high, LDH normal, Na highK high, P nl, LDH high, Na nlK nl, P high, LDH high, Na highK nl, P nl, LDH high, Na nlK high, P high, LDH high, Na nl.
106Tumor lysis syndrome 5. Rapid destruction of cancer cells. Release of intracellular ions, also Uric acid, can cause tubular obstruction and damage.Treatment: Allopurinol or Rasburicase early, Hydration, alkalinization, diuretic therapy,
108Fever, Neutropenia Single most important risk factor: ANC Organisms: Gram negative, Staph epi in catheter patientsMedication: Broad spectrum 3rd generation antibioticsAnti-fungal after 4 daysExamine patient thoroughly
109Late effectsA 16-year-old girl, diagnosed at 8 years of age as having Hodgkins disease, completed therapy with Involved field RT and chemotherapy. She now develops petechiae, purpura, LN, HSM. Lab include: plt 12,000/mm³; Hb 8.0 gm/dL; and WBC 13,000/mm³.The MOST likely explanation for these findings isA. acute myeloid leukemia as a second malignancyB. disseminated varicellaC. drug-induced immune thrombocytopenic purpuraD. late-onset aplastic anemia due to chemotherapyE. viral-induced immune thrombocytopenic purpura
110Late effectsYou are evaluating a 9 year old child for short stature. She was treated at 3 yrs of age for ALL, received cranial RT. Her height is < 5th percentile and she is Tanner stage I. Of the following , the test MOST likely to be abnormal is measurement ofEstradiolFollicle stimulating hormoneGonadotropin releasing hormoneGrowth hormoneThyroid stimulating hormone
111Late effects of cancer therapy Hypothalamic pituitary axis is impaired; central hypothyroid and Adrenal insuff.RT doses higher in brain tumorGH is dose sensitive to the effects of RTAge related: < 5 years susceptiblePanhypopit with higher dosesovarian failure with RT
112ChemotherapyA 16 year old boy is receiving chemo for rhabdomyosarcoma. The treatment involves one year of repeated cycles of Vincristine, Actinimycin-D and Cyclophosphamide.The most likely endocrinologic late effect of this therapy isGrowth hormone deficiencyHypothyroidismImpotenceInfertilityOsteoporosis
113Chemotherapy effects Infertility Chemotherapy with alkylating agents Females,less effects than males; normal puberty, early menopause.Males; irreversible gonadal toxicity and sterility with azospermia. Puberty usually not affected (leydig cells)
114TransplantThe most consistent finding observed in nearly all large cooperative group studies that have tested matched family donor hematopoietic stem cell transplantation (HSCT) for children with AML is:HSCT reduces disease-free survivalHSCT improves disease-free survivalHSCT improves event-free survivalHSCT improves overall survival
115TransplantThe most common reason for the failure of hematopoietic stem cell transplantation is:Veno-occlusive disease of the liverDisease recurrenceInfectionGraft vs. host diseaseGraft rejection
116GVHD ( Graft vs Host disease) True statements include all except:It is the reaction of the donor lymphocytes against the host.Acute GVHD starts within the first 100 days and chronic is after 100 days.Affects the skin, liver and GI tractIrradiation of blood products does not helpComplete HLA matching prevents GVHD
117Germ cell tumors 2-3 % of Pediatric malignancies Teratomas arise from endoderm, ectoderm and mesodermMarkers:Endodermal sinus tumors –Alpha feto proteinEmbryonal Ca, Choriocarcinoma- HCGMature teratomas- excision onlyImmature Teratomas: Surgery + Chemo
118Other topics- do readHistiocytosisStorage disorders