1Pediatric Board Review Course Pediatric Hematology/Oncology Kusum Viswanathan, MDVice Chair, Dept of PediatricsDirector, Divn of Pediatric Hematology/OncologyBrookdale Univ Hospital and Medical Center
2Case 1 6 week old term infant referred for anemia. No Sx Hb 7.5, Retic 2 %, Bili 3.5, Direct 0.5.Mother O+, Baby A -, Direct Coombs +Cord blood Hb 14.2 g/dL. Bilirubin 15mg/dL at 48 hours of life, recd photo Rx and d/c at 5 days.
3Most likely explanation for the anemia is G 6 PD deficiencyHereditary spherocytosisPhysiologic anemiaABO incompatibiltyRh hemolytic disease
4Newborn -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 :hemoglobin 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
5Newborn-Thrombocytopenia A newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000.Differential diagnosis:Production defects:TAR, Megakaryocytic hypoplasia, Trisomy 13, 18.Wiskott-Aldrich (small plt, X-linked, eczema , SCT cure)Infections- viral, bacterial, Infiltration (Gauchers, Niemann Pick, Leukemia)Destruction:Allo-immune (iso-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)
6The treatment of choice for alloimune neonatal thrombocytopenia is: random platelet transfusionIVIGSteroidsExchange transfusionWashed maternal platelets
7Immune 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 babyAllo or Iso-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
915 months old girl presented in ER with h/o URI, and scattered petechiae and ecchymoses over the body and lower extremities. Physical exam normal, no hepatosplenomegaly. WBC-6,000, Hb 12.8, Plts-5,000, Diff: Normal Smear- The next step is toperform a bone marrow aspirate to confirm the diagnosisDo a skeletal survey to rule out bony fracturesStart treatment with either IVIG or anti-DAdminister platelet transfusion
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
12Petechiae ITP- Thrombocytopenia Hemolytic Uremic Syndrome Low plt ct, Hemolysis, high LDH, sick patient, Uremia, microangiopathic hemolysis on smear.Henoch-Schonlein PurpuraPurpuric lesions on lower extremities and buttocksAbdominal pain, arthritis. IgA deposition, normal plt ct.ALLLow plt ct, lymphadenopathy (LN), hepatosplenomegaly, other cell lines affectedDrug induced-LikelyBy reducing production or increasing destructionDIC
13Platelet Size 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, platelet dysfunction)
14Acrodermatitis enteropathica Ataxia telangiectasia Atopic dermatitis A 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. This is most suggestive ofAcrodermatitis enteropathicaAtaxia telangiectasiaAtopic dermatitisLangerhans cell histiocytosisWiskott-Aldrich syndrome6
15Platelet function defects Normal platelet numberGlanzmann thrombastheniaAR, Abnormal aggregationBleeding disorder, check h/o consanguinityHermansky Pudlak Syndrome:AR, Decreased dense granulesIn Puerto RicansOculocutaneous albinism
17AnemiaAn 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??
18Reticulocyte 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, recovers, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .
19Aplastic AnemiaCongenital- Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, Amegakaryocytic thrombocytopeniaFanconi’s anemia-AR, short stature, microcephaly, microphthalmia, epicanthal folds, Café au lait, dangling thumbs, congenital dislocated hips. Chromosomal breakage increased by diepoxybutane (DEB) or mitomycin C. Hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors,AcquiredInfection- hepatitis, EBV,CMV, parvovirus B19, HIVDrug induced- ChloramphenicolExposure to Toxins, RadiationAutoimmune disease such as lupusIdiopathicTreatment- BM/Stem cell transplant
23Iron deficiencyLow MCV, low MCHC, low retic, RDW 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.
24Beta Thalassemia Minor Quantitative defect in globin chainsReduced production of Beta chainsHb electrophoresisHb A- 2 Alpha, 2 BetaHb F- 2 Alpha, 2 GammaHb A2- 2 Alpha, 2 DeltaExcess Alpha combines with Gamma or Delta- Increased Hb F and A2.Smear abnormalities significant even with MILD anemia.AnemiaLow MCV, normal RDW, normal reticSmear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stipplingHb Electrophoresis: Increased Hb A2 and/or F.Normal iron studies, no response to iron
25Beta Thalassemia Major No production of Beta chainsAutosomal recessive25 % 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
26Thalassemia- Alpha Reduced Alpha chains 4 types- carried on 4 allelles. (xx/xx)One absent- Silent carrier (x-/xx)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 chains form Hb Barts- FAST moving Hb on Newborn screening
27Megaloblastic anemias Vitamin B 12 or Folate deficiency (defective DNA synthesis)Defective maturation of other cell lines- leukopenia and/or ThrombocytopeniaHypersegmented neutrophils, large metamyelocytes and bandsCauses hyperhomocysteinemia.Dietary deficiency of vitamin B12 due to vegetarianism.Can occur in breast-fed infants of vitamin B12–deficient mothersSevere vitamin B12 deficiency - a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regressionUnderlying mechanismsdelayed myelination or demyelination of nervesalteration in the S-adenosylmethionine:S-adenosylhomocysteine ratioimbalance of neurotrophic and neurotoxic cytokinesaccumulation of lactate in brain cellsElevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12–deficient diets
28Case3 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??
29Reticulocyte count- Increased HemolysisIntrinsic-Membrane defects-Hereditary spherocytosis (HS)Enzyme-G 6 PD deficiencyHemoglobinopathiesExtrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysisLossBlood loss
30QuestionA previously well 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.SMEAR
31Hereditary spherocytosis Sickle cell disease Hepatitis G6PD deficiency An 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 deficiency6
33Children with congenital spherocytosis have all of the listed conditions except: positive Direct Coombssplenomegaly, gallbladder stonesabnormalities in spectrin and /or ankyrinincreased MCHCabnormal osmotic fragility test.6
35HS- with severe anemiaA 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 virusParvovirus B19Epstein-Barr virusHepatitis A virusInfluenza A virus
36HS- with severe anemia Coxsackie virus Parvovirus B19 Epstein-Barr virusHepatitis A virusInfluenza A virus6
37Newborn 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
38Sickle 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, 5Meningococcal vaccineFolic acid daily
39Associated alpha thalassemia trait Low hemoglobin The mother of a 10 month old baby with SS disease asks you about prognostic indicators. All of the following indicate likelihood of more severe disease except:High WBCAssociated alpha thalassemia traitLow hemoglobinRepeated episodes of dactylitis
41Sickle 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
42Pulmonary 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.
43TCD- 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
44Continue indefinitely the child reaches 18 years According to the STOP protocols, all children with abnormal TCD require enrollment in hypertransfusion protocol till (choose one)Repeat TCD is normalContinue indefinitelythe child reaches 18 yearsMRA/MRI are reported normal6
45Sickle 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)
46Sickle cell and Transfusions Transfusion indications:Acute anemia (Aplastic, Hyperhemolytic, Sequestration)Hypoxia (ACS, chronic lung disease, Pulmonary hypertension)Stroke and stroke preventionIntractable pain, pre-operative preparationTypes of transfusionsIntermittentChronic simpleExchange (Partial, Total, Erythrocytapheresis)Hypertransfusion (transfusions in an effort to prevent patient from producing their own red cells)
47Pulmonary Hypertension Leg ulcers Which of the complications of sickle cell disease is more common in SC patients compared to SS diseaseSickle retinopathyIschemic strokeAcute Chest syndromePulmonary HypertensionLeg ulcers6
48Iron 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.
49Sickle 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.
50Other 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
51Refer to a hematologist Repeat CBC in 1-2 weeks A 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. Most appropriate step is tAmoxicillin for 10 daysG- CSF for 10 days.BM aspirateRefer to a hematologistRepeat CBC in 1-2 weeks6
52Neutropenia 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.
53Neutropenia Auto-Immune neutropenia Schwachman-Diamond Syndrome Self limited, G CSF only if necessaryMild infectionsSchwachman-Diamond SyndromeAR, Exocrine pancreatic failure, short stature, recurrent infections, metaphyseal dysostoses.G-CSF, Risk of myelodysplasia and AML, BMT curativeChronic benign Neutropenia??AI, < 3 years of age, ANC < 200,skin and mucous membrane infections, Normal marrow, AntibodiesEthnic neutropenia- (Benign familial)-AADrug Induced- Procainamide, Anti-thyroid, Sulfasalazine.
54CaseA 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
55All of the following are true in CGD (Chronic granulomatous disease) except Neurophils cannot destroy catalase positive organismsUnable to secrete Hydrogen peroxidePneumonia, Underweight, recurrent infectionsNitroblue Tetrazolium test is for diagnosisHave abnormal chemotaxis
56Approach 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)
57Abnormal BleedingEpistaxis unrelieved by 15 minutes of pressure, both nostrils, requiring an ER visit, documented drop of hemoglobin.Menstrual periods( amount, pads, duration)Bleeding after procedures (circumcision, dental extractions, T and A-delayed bleed)Ecchymoses/bruising inconsistent with the degree of trauma
58Bleeding 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)
60Lab studies (What do they measure?) CBC and Peripheral smearPT, INR and PTTPT - Factor VII, common pathwayPTT- Factor VIII, IX, XI, XII, common pathwayMixing studies (Inhibitors and deficiency)Specific coagulation factor assaysFibrinogen
61Circulating 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.
62Factor 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
63A healthy 2-day-old boy born at term undergoes circumcision A healthy 2-day-old boy born at term undergoes circumcision. Bleeding noted at the site 10 hours after the procedure and increased steadily over the past 4 hours. Findings on exam are unremarkable except for bleeding along 2 to 3 mm of the surgical site; no petechiae or purpura.Disseminated intravascular coagulationFactor VIII deficiency hemophiliaImmune thrombocytopenic purpuraNeonatal alloimmune thrombocytopeniaVon Willebrand disease6
64Bleeding disorders Tests for bleeding Hemophilia A Hemophilia B Hemophilia CVW Disease
65Hemophilia Factor VIII deficiency (Hemophilia A)-85% X-linked recessive, Carriers asymptomaticSevere<1%, Moderate 1-5, Mild 6-30 %Treat Recombinant Factor VIII 1unit/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
66A patient with Hemophilia A has asked you about the possibility of his children being affected by the disease. The partner is normal.There is a 50 % chance that his sons will have the disease.There is a 50 % chance that his daughters will be carriersThere is a 100 % chance that his sons will have the diseaseThere is a 100 % chance that his daughters will be carriers6
67Case13 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:
68Von 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
69Thrombophilia- 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
70The most common cause of familial predisposition to thrombosis is Hemophilia antibodiesProtein C deficiencyProtein S deficiencyFactor V Leiden mutationAntithrombin III deficiency6
71Causes 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
72Hypercoagulable 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.
73Hypercoagulable 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.
74TransfusionA 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 that
75your discussion is MOST likely to include the statement that all units are tested only for hepatitis B and Call units are tested only for human immuno-deficiency virus (HIV)all units are tested for HIV, hepatitis B, and hepatitis Call units are tested for HIV, hepatitis B, hepatitis C, sickle cell trait, cytomegalovirus, and Epstein-Barr virusonly units obtained from donors who have one or more risk factors are screened for HIV, all units are tested only for hepatitis B and C6
76Transfusion- Notes CMV negative- give leukocyte reduced. Irradiated products- To prevent GVHDWashed cells- To reduce febrile reactionsPhenotype matchedTo prevent allo-immunizationSickle negative- In sickle cell patients, neonates
78Cancer 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
79acute lymphoblastic leukemia Aplastic anemia Gaucher disease A 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.acute lymphoblastic leukemiaAplastic anemiaGaucher diseaselead poisoningMultifocal osteomyelitis6
80ALL (Acute Lymphoblastic leukemia) Can present with generalized bone painBruising, nose bleedsUnusual fevers, infectionLymphadenopathy, hepatosplenomegaly
81ALL (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.
83ALL- 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
84Down 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 newborn 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)
85Acute 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
86Acute 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
87All statements about Hodgkin’s disease are true except Has a better prognosis than Non HodgkinsCan progress to acute leukemiaFever, night sweats, wt loss are used for stagingHas a bimodal age distribution6
88Hodgkin’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.
89Non 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)
90Burkitt’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 %.
91Case5 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.
92Medulloblastoma - 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.
93Brain 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 decelerationAssociations with Inherited Genetic disorders:Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau disease, Li-Fraumeni (glioma), Turcot syndrome
94Wilms 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.
95Wilms 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
96Congenital anomalies associated with Wilms’ tumor include all of the following except PolydactylyAniridiaHemihypertrophyCryptorchidismDenys-Drash syndrome6
97Wilms 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 Ultrasound, Urinalysis q 3-4 monthsChest Xray needs to be followed
98Pseudotumor of the orbit Trichinosis Retinoblastoma Rhabdomyosarcoma A 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 cellulitis6
99Rhabdomyosarcoma 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
100MassThe 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
101All statements are true about Neuroblastoma except: Most common extra-cranial solid tumorPrognosis better with N-myc oncogene amplification and tumor diploidy (DNA index 1)Most common cancer in the first year of lifeFrequent in <4 years, 97 % cases by 10 yearsMost commonly diagnosed as Stage III or IV6
102Neuroblastoma 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 primary tumor with spread to skin, liver and/or bone marrow- Minimal therapy.
103A 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?
105Osteogenic 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 symptom, mass, no systemic symptoms.Treatment: Open biopsy, Sperm banking, Neo-adjuvant Chemotherapy, limb preserving surgery.
106A 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
107Ewing’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,
109Retinoblastoma 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.
111A child with ALL was started on Chemotherapy A child with ALL was started on Chemotherapy. She had a WBC 82,000, Hb 9gm, plt ct 45,000. She develops tumor lysis syndrome: Which one depicts Tumor lysisK high, P high, LDH normal, Na highK high, P normal, LDH high, Na nlK normal, P high, LDH high, Na highK normal, P normal, LDH high, Na normalK high, P high, LDH high, Na normal.6
112Tumor lysis syndrome 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.
113Spinal cord compression Local tumor extension or metastasisLymphomas, neuroblastoma, soft tissue sarcomasPresentation: back pain worse with movement, neck flexion, straight leg raising, valsalvaWeakness; partial/complete paralysis, IncontinenceDiagnosis: Clinical / Spinal MRITherapy: Urgent treatment to relieve pressure and prevent permanent neurologic damage.Neurology/Neurosurgery consultHigh dose dexamethasoneEmergency radiation therapyLaminectomy
114Superior Vena Cava Syndrome Mass lesion obstructs flow through the SVCSx due to engorgement of collateral veins of thorax, neck and headDyspnea, edema of face, neck, upper extremitiesPeriorbital edema, conj edema (itchy eyes)Dysphagia,resp distress, vocal cord paralysisTracheal compression: resp distress, wheezingNHL, Tcell ALL, Lymphoma, TeratomaSecondary cause: occluded central venous catheterTry to get a diagnosis before therapy
116Fever, 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
11716-year-old girl, completed therapy at age 8 for Hodgkins disease with Involved field RT and chemo. She now develops petechiae, purpura, lymphadenopathy and hepatosplenomegaly.Lab include: plt 12,000,Hb 8.0 gm/dL; and WBC 13,000/mm³acute myeloid leukemia as a second malignancydisseminated varicelladrug-induced ITPlate-onset aplastic anemia due to chemotherapyviral-induced ITP6
118Follicle stimulating hormone Gonadotropin releasing hormone You 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. Most likely to have an abnormal test ofGrowth hormoneEstradiolFollicle stimulating hormoneGonadotropin releasing hormoneThyroid stimulating hormone6
119Late 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 susceptiblePanhypopituitarism with higher dosesovarian failure with RT
120Growth hormone deficiency Hypothyroidism Impotence Infertility A 16 year old boy is receiving chemo for rhabdomyosarcoma with a year of cycles of Vincristine, Actinimycin-D and Cyclophosphamide. Most likely endocrinologic late effect of this therapyGrowth hormone deficiencyHypothyroidismImpotenceInfertilityOsteoporosis6
121Chemotherapy effects Chemotherapy with alkylating agents Females: less effects than malesnormal pubertyearly menopauseMales:irreversible gonadal toxicitysterility with azospermiaPuberty usually not affected (leydig cells)
122The most common reason for the failure of hematopoietic stem cell transplantation is Veno-occlusive disease of the liverDisease recurrenceInfectionGraft vs. host diseaseGraft rejection6
123GVHD ( Graft vs Host disease): All are true 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 GVHD6
124Germ 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
125Other topics- do readHistiocytosisStorage disorders