Pediatric Board Review Course Pediatric Hematology

1. Pediatric Board Review CoursePediatric Hematology/Oncology Kusum Viswanathan, MD Vice Chair, Dept of Pediatrics Brookdale Univ Hospital and Medical Center

2. Case 1 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 spherocytes Most likely explanantion: Rh hemolytic disease G 6 PD deficiency Hereditary spherocytosis Physiologic anemia ABO incompatibilty

3. Newborn -anemia Hemoglobin at birth is 17 g/dl, MCV over 100. Falls to 11-12 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- repeat Hemorrhage, may not have had time to mount a retic response Acute hemorrhage- pallor and tachypnea Look at MCV- low MCV-suggestive of chronic feto-maternal hemorrhage Alpha Thalassemia trait. Kleihauer-Betke- Hb F resistance to acid elution

4. Newborn-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 incompatibilty Auto-immune: Mat ITP, Drugs (thiazide, tolbutamide), SLE Infections: CMV, Rubella, herpes, DIC Loss: Kasabach- Merritt syndrome (hemangiomas, DIC- Rx DIC and hemangioma with Steroids, interferon, VCR)

5. Immune thrombocytopenia Auto-immune: Pregnant women with ITP/Hx of ITP Passive 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 baby Iso-Immune: Normal platelet count in mother Similar to Rh disease; PL A1 antigen/ Zw a negative mother. 97% of population is PL A 1 positive Sensitization early in pregnancy Plt function defect because Anti-PL A1 interferes w/aggregation. Severe bleeding more likely; first born affected; Recovery in 2-3 weeks Mother’s washed (PLA1 neg) platelets; IVIG; Ultrasound; Steroids

6. Kasabach- Merritt, TAR

7. Older 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

8. Other causes Hemolytic Uremic Syndrome Hemolysis, sick patient, Uremia, microangiopathic Henoch-Schonlein Purpura Purpuric lesions on lower extremities and buttocks Abd pain, arthritis. IgA deposition ALL lymphadenopathy (LN), hepatosplenomegaly,other cell lines affected Drug induced- Likely By reducing production or increasing destruction

9. Petechiae, HSP

10. ITP Usually acute onset; immune mediated; post viral Peak 2-5 years of age, males=females Spontaneous bruises, petechiae PE –no lymphadenopathy (LN), hepatosplenomegaly. CBC- other cell lines normal, large plts on smear Treat if plt< 10,000 or wet ITP, avoid NSAIDS, Aspirin Treat- IVIG best response, 48-72 hours; Side effects. Anti-D (WInRho) Rh+ ,hemolysis, quick response Steroids good response, SE, inexpensive, need BM BM- Increased megakaryocytes, otherwise normal

11. Large platelets Normal platelet 7-10 days Large platelets: ITP May 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)

12. 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. Of the following, these findings are MOST suggestive of Acrodermatitis enteropathica Ataxia telangiectasia Atopic dermatitis Langerhans cell histiocytosis Wiskott-Aldrich syndrome

13. Platelet function defects Normal platelet number Glanzmann thrombasthenia AR, Abnormal aggregation Bleeding disorder, check h/o consanguinity Hermansky Pudlak Syndrome: AR, Decreased dense granules, In Puerto Ricans, Oculocutaneous albinism

14. Thrombocytosis H- Hemorrhage, Hereditary Asplenia, Down myeloprol. I- Infections, Kawasaki, Immune:GVH, Nephrotic syndrome P- Polycythemia vera, Myeloproliferative, Essential L- Leukemia (CML) A- Anemia,- Iron, Vit E, Sideroblastic T- Tumors E- Epinephrine, Steroids L- Lymphoma, Hodgkins E- Exercise, T- Trauma, Fractures S- Splenectomy

15. Anemia An 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, Anemia Reduced production Increased destruction Loss What else do you want??

16. Reticulocyte count Normal/Low- reduced production Iron deficiency anemia- MCV will be low ALL (leukemia)- other findings, LN, HSM Diamond 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 .

17. Normal smear

18. Microcytic Anemia The 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 to A. administer intramuscular iron B. begin oral ferrous sulfate C. obtain serum iron levels D. refer for bone marrow evaluation E. transfuse with packed red blood cells

19. Microcytic anemia

20. Iron deficiency Low MCV, low MCHC, low retic, RDW will be normal initially, will increase after treatment, Low Iron, Incr TIBC, Transferrin low, Ferritin low Causes: Inadequate dietary intake Toddlers, too much milk, less solids, Breast fed need iron supplements poor absorption Blood loss: Menstrual, GI tract, Meckels, Epistaxis D/D: Thalassemia trait- MCV much lower in prop to anemia, Anemia of chronic disease- low Fe, low TIBC, normal/high Ferritin.

21. Thalassemia Minor Quantitative defect in globin chains Reduced production of Beta chains Hb electrophoresis Hb A- 2 Alpha, 2 Beta Hb F- 2 Alpha, 2 Gamma Hb A2- 2 Alpha, 2 Delta Excess Alpha combines with Gamma, Delta- Increased Hb F and A 2. Smear abnormalities significant even with MILD anemia. Anemia Low MCV, normal RDW, normal retic Smear shows anisopoikulocytosis, target cells, microcytes, misshapen cells, basophilic stippling Hb Electrophoresis: Increased Hb A2 and/or F. Normal iron studies, no response to iron

22. Thalassemia Major No production of Beta chains Autosomal recessive 25 % chance with each pregnancy Pre natal testing for carriers Chorionic villous sampling for diagnosis Transfusion dependent-allows for normal development Pen Prophylaxis, Anti oxidants Splenectomy after age 5 Iron overload- inherent and transfusion Need chelators

23. Thalassemia- 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

24. Case 3 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??

25. Reticulocyte count- Increased Hemolysis Intrinsic- Membrane defects-Hereditary spherocytosis (HS) Enzyme-G 6 PD deficiency Hemoglobinopathies Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysis Loss Blood loss

26. Hemolytic anemia History; Recent infection, drug exposure, illness, dark urine, anorexia, fatigue, pallor Family h/o gallstones, splenectomy Physical Examination: Pallor, Tachycardia, Tachypnea, Splenomegaly. Peripheral smear: Blisters, spherocytes

27. G-6PD deficiency A 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 is Hereditary spherocytosis Sickle cell disease Hepatitis G6PD deficiency Avoid certain medications (Sulfas), Fava beans in Mediterranean. Seen in African American- avoid moth balls. Blister cells Bite cells Blister cells Bite cells

28. Spherocytes Spherocytes Nucleated rbc Coombs-AIHA Osmotic fragility-HS

29. HS- with severe anemiaAll 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 with Coxsackie virus Epstein-Barr virus Hepatitis A virus Influenza A virus Parvovirus B19

30. Newborn Screening You 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 trait FSC- SC disease FAS- Sickle cell trait FAC- Hb C trait FAE- Hb E trait FE - Hb EE disease, E-Thal

31. Sickle cell Hemolysis- life span 20-50 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, 5 Folic acid daily

32. Sickle cell- Higher risk High WBC Low Hemoglobin Multiple episodes of dactylitis Low Hb F Associated Alpha thal trait- better clinical course

33. Sickle cell crises Vaso-occlusive crisis-dactylitis, long bones, back, chest. Trt. Pain meds, hydration. Aplastic crisis: low Hb, low retic, Sec to Parvovirus infection. Splenic sequestration crisis: spleen palpation Hyperhemolytic crisis

34. Case 12 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?

35. Sickle cell Acute Chest Syndrome New infiltrate on X-ray, fever, chest pain, back pain, hypoxia. Due to infarction, infection, BM fat embolism Treat: Antibiotics to cover pneumococcus, Mycoplasma, Chlamydia, Bronchodilator, Oxygen, Incentive spirometry, transfusion, Steroids (controversial). Avoid overhydration

36. Pulmonary Hypertension Prevalence of pulmonary HT in SCD from 20-40 %. 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 2004 -N Engl J Med Feb 2004.

37. TCD- 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

38. Sickle 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)

39. Sickle cell and Transfusions Transfusion indications: Acute anemia (Aplastic, Hyperhemolytic, Sequestration) Hypoxia (ACS, chronic lung disease, Pulmonary hypertension) Stroke and stroke prevention Intractable pain, pre-operative Types of transfusions Intermittent Chronic simple Exchange (Partial, Total, Erythrocytapheresis) Hypertransfusion (transfusions in an effort to prevent patient from producing their own red cells)

40. Iron overload One unit -200mg Iron No physiologic way of removal 10-20 transfusions Desferioxamine available. Can be given IV or subq infusion or subq shots. Compliance an issue. December 2005- Oral chelator available (Deferasirox)- FDA approved.

41. Sickle cell and Hydoxyurea FDA approved for adults Studies in children demonstrated efficacy and safety. Increases hemoglobin F level Increases hemoglobin Decreases WBC – ancillary effect Hydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, Acute chest syndrome.

42. Other important points Median life expectancy: Males 42 years, females 48 years Improvement related to Penicillin, immunizations, education. Bone marrow transplant (BMT) is a cure Cord blood storage

43. Case 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. The most appropriate management would be: Amoxicillin for 10 days G- CSF for 10 days. BM aspirate Refer to a hematologist Repeat CBC in 1-2 weeks

44. Neutropenia Severe neutropenia ANC < 500/mm3 Viral infection(hepatitis, Influenza, Measles, Rubella, RSV, EBV)- No Rx. Cyclic neutropenia Sporadic Autosomal dominant disorder 21 day intervals, nadir < 200/uL G CSF treatment Severe Congenital Neutropenia (Kostmann) AR, ANC< 200, BM arrest, high dose G CSF, risk of malignancy (MDS/AML) and sepsis. BMT cure.

45. Neutropenia AutoImmune neutropenia Self limited, G CSF only if necessary Mild infections Schwachman-Diamond Syndrome AR, Exocrine pancreatic failure, short stature, recurrent infections, mataphyseal dysostoses. G-CSF, Risk of myelodysplasia and AML, BMT curative Chronic benign Neutropenia ??AI, < 3 years of age, skin and mucous membrane infections, Antibodies

46. Case A 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 is A. chronic benign neutropenia B. cyclic neutropenia C. Schwachman-Diamond syndrome D. severe congenital neutropenia E.. transient viral bone marrow suppression

47. Approach to a bleeding patient History: h/o trauma, H/o similar episodes h/o bruising, h/o surgery in the past h/o circumcision, bleeding from the umbilical stump ,delayed wound healing Time of onset (Acute/chronic), any challenges eg. trauma, surgery or menstruation Overall health ( well/sick); Evidence of shock. bleeding disorders in the family (maternal uncles and aunts, grandparents)

48. Abnormal Bleeding Epistaxis 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

49. Case 13 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.

50. Bleeding patient Physical Examination: Type of bleeding: Superficial or deep Bruises, Petechiae Epistaxis, Gum bleeding, Excessive menstrual bleeding Site of bleeding Bleeding into the joints and soft tissues Look for evidence of shock Medication history (Aspirin, NSAIDS)

51. Coagulation cascade

52. Lab studies(What do they measure?) CBC and Peripheral smear PT, INR and PTT PT - Factor VII, common pathway PTT- Factor VIII, IX, XI, common pathway Mixing studies (Inhibitors and deficiency) Specific coagulation factor assays Fibrinogen

53. Circulating anticoagulant Mixing study If 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.

54. Factor XIII and VII deficiency Factor XIII Rare Autosomal Recessive If all tests are normal: PT, PTT, Platelet count and function, VW tests all normal. Think of doing Factor XIII assay for deficiency Bleeding after umbilical stump separation Abnormal clot solubility in 5M Urea Factor VII Intracranial hemorrhage Rare, homozygous state Prolonged PT, n PTT Treatment with Recombinant F VII

55. Case A 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 is A. disseminated intravascular coagulation B. factor VIII deficiency hemophilia C. immune thrombocytopenic purpura D. neonatal alloimmune thrombocytopenia E. von Willebrand disease

56. Bleeding disorders Tests for bleeding Hemophilia A Hemophilia B Hemophilia C VW Disease

57. Hemophilia Factor VIII deficiency (Hemophilia A)-85% X-linked recessive, Carriers asymptomatic Severe<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

58. Hemophilia A 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 carriers c. There is a 100 % chance that his sons will have the disease d. There is a 100 % chance that his daughters will be carriers

59. Answer was dCase 13 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:

60. Von Willebrand’s Disease1-2 % of population Type I - 80 % of cases; Quantitative defect, Autosomal dominant (AD) Type 2 - 15-20 %, Qualitative defect 2A, 2b (thrombocytopenia), 2M, 2N (AR) Type 3 - Severe (similar to hemophilia A) Autosomal recessive (AR) DDAVP- Releases VWF from endothelial cells and stabilizes Factor VIII SE: Water retention, Tachyphylaxis, hyponatremia. For mild Hemophilia, Type I VWD, 2 Contra-indicated in Type 2B Plasma derived VWF containing concentrates

61. Thrombophilia- Case A 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 members H/o recurrent late miscarriages in mother and her sisters. H/o trauma and precipitating factors

62. Causes Factor V Leiden (Activated Protein C resistance) Prothrombin G 20210A gene mutation Protein C deficiency and activity Protein S deficiency and activity. Anti thrombin III deficiency and activity. Hyperhomocystenemia Antiphospholipid syndrome Rare disorders-Dysfibrinogenemia

63. Hypercoagulable states Factor V Leiden- 40-50 % cases Abnormal 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 thrombosis Homozygotes 1% Protein C- Vit K dependent, produced in liver Activated PC inactivates coagulation factors Va and VIIIa, The inhibitory effect is enhanced by Protein S. Venous thromboembolism, Neonatal purpura fulminans, Warfarin-induced skin necrosis.

64. Hypercoagulable states G20210A Prothrombin mutation Increase in the prothrombin, a precursor of thrombin Vitamin K-dependent protein which is synthesized in the liver Heterozygous 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.

65. Transfusion A 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 A. all units are tested only for hepatitis B and C B. all units are tested only for human immuno-deficiency virus (HIV) C. all units are tested for HIV, hepatitis B, and hepatitis C D. all units are tested for HIV, hepatitis B, hepatitis C, sickle cell trait, cytomegalovirus, and Epstein-Barr virus E. only units obtained from donors who have one or more risk factors are screened for HIV

66. Transfusion- Notes CMV negative- give leukocyte reduced. Irradiated products- To prevent GVHD Washed cells Phenotype matched To prevent allo-immunization Sickle negative

67. CANCER IN CHILDREN Distribution-All ages

68. Cancer in Children Leukemias, Brain tumors, Lymphomas 2nd leading cause of death 1-14yrs 12,400 cases per year Proto-Oncogenes imp for function-Activated -Amplification --n-myc -Point mutation-NRA’s -Translocation- Ph chromosome t (9:22); BCR-ABL

69. Case 18 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 diagnosis ALL Child abuse ITP Iron deficiency anemia TEC (Transient erythroblastopenia of childhood)

70. ALL (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 trauma ITP: can have mild anemia, but here, the HR suggests significant anemia Iron def and TEC: No bruising

71. 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. Of the following, the MOST likely cause of these findings is A. acute lymphoblastic leukemia B. aplastic anemia C. Gaucher disease D. lead poisoning E. multifocal osteomyelitis

72. ALL (Acute Lymphoblastic leukemia) Can present with generalized bone pain Bruising, nose bleeds Unusual fevers, infection Lymphadenopathy, hepatosplenomegaly

73. ALL (Acute Lymphoblastic leukemia) Abnormal to see blasts in the peripheral smear Diagnosis: >25 % blasts in the BM. Normal marrow has 5 % blasts Single most common childhood cancer (29% of all childhood cancers); 2500-3500 cases per year Peak age 2-5 years More likely in Trisomy 21, Ataxia-Telangiectasia, Bloom syndrome, Fanconi anemia.

74. ALL Treatment Induction: 4-6 weeks, 95 % remission; Vincristine, Corticosteroids, L-Asparaginase and Anthracycline Consolidation /delayed Intensification: 6-12 months; rotating drugs. Maintenance : Daily oral 6-MP, weekly MTX, Monthly pulses of Vincristine and Steroid. CNS prophylaxis: Intrathecal chemo CNS Therapy: RT + Int Systemic chemo Testicular disease: RT

75. ALL- 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, T Early response, Minimal residual disease (MRD) Standard risk: 85 % survival High risk: 65 % survival Very low risk: 90% survival Infants: 50 % survival Early relapse is a poor sign

76. Down Syndrome and Leukemia 10-20 fold increase ALL:AML 4:1 < 2 years: M7 AML DS: 400 fold Increase in M7 AML Superior response to Rx of AML Transient 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)

77. Acute Myeloid Leukemia (AML) 20 % of all leukemias Increased incidence in < 1 year of age Higher incidence: Downs, Fanconi, Bloom, DBA, Kostmann, Neurofibromatosis I, Schwachman-Diamond Sx: Fever, bleeding, pallor, anorexia, fatigue, Bone/Jt pain, LN, GI Sx. Chloromas (green) – solid collection in bone/soft tissues Types: M0-M7, commonest M2 M7- Downs syndrome

78. Acute Myeloid Leukemia (AML) Treatment: Remission Induction, Consolidation, Maint BMT (matched sib donor) after remission. ATRA (form of Vit A-transretinoic acid) in APML Results: HLA matched donor: 65 % EFS No donor 40-50 % Prognostic features: Favorable: t(8,21), inv(16); Early remission; FAB M4 with eosinophilia Unfavorable: Monosomy 7; WBC> 100,000; Secondary AML; Myelodysplasia with AML

79. Hodgkin’s Lymphoma Bimodal 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 85-90 %, Stage 3-4; 75 % EFS. Second malignancy in patients who have recd combination chemo and RT-- Leukemia, NHL, Breast cancer.

80. Non 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, Caucasians Common 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 neck Majority are high grade Chromosomal translocations involve c-myc oncogene (chr 8)

81. Burkitt’s Lymphoma Endemic Burkitt’s African type, head and neck, jaw 95 % chance of EBV Sporadic Burkitt’s Abdomen 15-20 % chance of EBV Treatment- 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 %.

82. Case 5 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.

83. Medulloblastoma - 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.

84. Brain Tumors 20% of all malignancies in children Age 3-7 years Most often infratentorial cerebellar and hemispheric astrocytoma, medulloblastoma, brain stem gliomas, Craniopharyngiomas. Sx: Persistent vomiting, headache, gait imbalance, diplopia, ataxia, vision loss, school deterioration, growth deceleration Inherited Genetic disorders Associated: Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau disease, Li-Fraumeni (glioma), Turcot syndrome

85. A 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?

86. Observe 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

87. Wilms Tumor An 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%

88. CT Scan -Wilms Tumor

89. Wilms 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, nephropathy Perlman syndrome: Macrocephaly, macrosomia Do US , UA q 3-4 months

90. Wilms Tumor Histology: favorable(FH) vs unfavorable (UH) Staging: I-local, II-excised, III-residual, IV-metastases, V -bilateral Treatment: Nephrectomy, Chemo-all, St I-II-2 drugs-18 weeks, St III-IV- 3 drugs+ RT Prognosis: FH: > 90% at 2 years UH: < 60% at 2 years

91. Question 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 is Pseudotumor of the orbit Trichinosis Retinoblastoma Rhabdomyosarcoma Orbital cellulitis

92. Rhabdomyosarcoma 7 % of all childhood cancers Painless non tender mass, 60% under age 6 Sites: head & neck, GU, Extremities, mets lungs. Majority sporadic, associations: B-W, Li Fraumeni, NF 1 Types: Embryonal 70%, better prognosis Alveolar 30 %, trunk, worse prognosis Treatment: Surgery, Chemo, local control RT Results: 85 % good risk 30 % metastatic disease

93. Mass The 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 is A. multicystic kidney disease B. neuroblastoma C. non-Hodgkin lymphoma D. Hepatoblastoma E. Wilms tumor

94. Neuroblastoma The 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 is A. multicystic kidney disease B. neuroblastoma C. non-Hodgkin lymphoma D. Hepatoblastoma E. Wilms tumor

95. Neuroblastoma Most common extra-cranial solid tumor Most common cancer in the first year of life Frequent in <4 years, 97 % by 10 years Most commonly diagnosed as Stage III or IV Dx: biopsy or BM plus urine for VMA, HVA Metastatic- orbital discoloration, bone pain Prognosis: Stage Better 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.

96. Neuroblastoma Low risk: Surgery alone; >95 % 5 year survival Intermediate risk: Surgery and Chemo; 80-90 % 5 year survival High risk: Induction chemo, surgery, Chemo with autologous transplant, RT, Biologic therapy 30 % 5 year survival Stage IVs-Localized Prim tumor with spread to skin, liver and/or bone marrow- Minimal therapy.

97. A 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?

98. Osteogenic Sarcoma- X ray and MRI

99. Osteogenic Sarcoma MRI, Bone scan, Biopsy, CT Chest. Peak incidence- 2nd decade Predisposition: Hereditary retinoblastomas, Li-Fraumeni, Pagets, RT, Alkylating agents 60 % 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.

100. A 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.

101. Ewing’s Sarcoma Seen 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 cases PNET: Ewing like tumor with neural differentiation Treatment: Surgery, RT, Neoadjuvant Chemo,

102. Ewing’s Sarcoma

103. Retinoblastoma Presentation: Leukocoria (cats eye reflex),Dilated pupil, esotropia, strabismus Unilateral 75 % (could be hereditary/non) 60 % unilateral and non hereditary 15 % unilateral and hereditary (RB1 mutation) Bilateral 25 % 25 % are bilateral and hereditary, have RB1 mutation Earlier age, 11mos, Can develop in each eye separately Higher 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.

104. Retinobalstoma

105. Tumor lysis syndrome A 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 it K high, P high, LDH normal, Na high K high, P nl, LDH high, Na nl K nl, P high, LDH high, Na high K nl, P nl, LDH high, Na nl K high, P high, LDH high, Na nl.

106. Tumor 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,

107. Chemotherapy-Side effects Anthracyclines: Cardiomyopathy Vincristine: foot drop, neurological Cisplatinum: kidney, deafness Methotrexate, 6MP: Liver toxicity Bleomycin: Pulmonary fibrosis Asparaginase: Pancreatitis Cyclophosphamaide: Hemorrhagic cystitis (MESNA, Uroprotector)

108. Fever, Neutropenia Single most important risk factor: ANC Organisms: Gram negative, Staph epi in catheter patients Medication: Broad spectrum 3rd generation antibiotics Anti-fungal after 4 days Examine patient thoroughly

109. Late effects A 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 is A. acute myeloid leukemia as a second malignancy B. disseminated varicella C. drug-induced immune thrombocytopenic purpura D. late-onset aplastic anemia due to chemotherapy E. viral-induced immune thrombocytopenic purpura

110. Late effects 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. Of the following , the test MOST likely to be abnormal is measurement of Estradiol Follicle stimulating hormone Gonadotropin releasing hormone Growth hormone Thyroid stimulating hormone

111. Late effects of cancer therapy RT: Hypothalamic pituitary axis is impaired; central hypothyroid and Adrenal insuff. RT doses higher in brain tumor GH is dose sensitive to the effects of RT Age related: < 5 years susceptible Panhypopit with higher doses ovarian failure with RT

112. Chemotherapy A 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 is Growth hormone deficiency Hypothyroidism Impotence Infertility Osteoporosis

113. Chemotherapy 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)

114. Transplant The 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 survival HSCT improves disease-free survival HSCT improves event-free survival HSCT improves overall survival

115. Transplant The most common reason for the failure of hematopoietic stem cell transplantation is: Veno-occlusive disease of the liver Disease recurrence Infection Graft vs. host disease Graft rejection

116. GVHD ( 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 tract Irradiation of blood products does not help Complete HLA matching prevents GVHD

117. Germ cell tumors 2-3 % of Pediatric malignancies Teratomas arise from endoderm, ectoderm and mesoderm Markers: Endodermal sinus tumors –Alpha feto protein Embryonal Ca, Choriocarcinoma- HCG Mature teratomas- excision only Immature Teratomas: Surgery + Chemo

118. Other topics- do read Histiocytosis Storage disorders

119. GOOD LUCK