Pediatric Board Review Course Pediatric Hematology/Oncology

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Pediatric Board Review CoursePediatric
Hematology/Oncology

• Kusum Viswanathan, MD
• Vice Chair, Dept of Pediatrics
• Brookdale Univ Hospital and Medical Center

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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

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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

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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)

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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 lt 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
• Mothers washed (PLA1 neg) platelets IVIG
  Ultrasound Steroids

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Kasabach- Merritt, TAR
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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

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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

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Petechiae, HSP
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ITP

• Usually acute onset immune mediated post viral
• Peak 2-5 years of age, malesfemales
• Spontaneous bruises, petechiae
• PE no lymphadenopathy (LN), hepatosplenomegaly.
• CBC- other cell lines normal, large plts on smear
• Treat if pltlt 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

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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)

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• 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

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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

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Thrombocytosis

• H- Hemorrhage, Hereditary Asplenia, Down
  myeloprol.
• I- Infections, Kawasaki, ImmuneGVH, 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

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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??

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Reticulocyte count

• Normal/Low- reduced production
• Iron deficiency anemia- MCV will be low
• ALL (leukemia)- other findings, LN, HSM
• Diamond Blackfan anemia- Us lt 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
  .

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Normal smear
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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

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Microcytic anemia
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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.

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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

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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

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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

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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??

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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

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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

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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

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Spherocytes

• Spherocytes
• Nucleated rbc
• Coombs-AIHA
• Osmotic fragility-HS

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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 girls present illness is
  infection with
• Coxsackie virus
• Epstein-Barr virus
• Hepatitis A virus
• Influenza A virus
• Parvovirus B19

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Newborn Screening

• You get a call from a frantic parent because she
  received a letter from the State regarding her
  babys 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

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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 gt75 .
• Start Penicillin daily and give until age 5.
  Prevention of pneumococcal infections.
• PPV (Pnu-23) age 2, 5
• Folic acid daily

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Sickle cell- Higher risk

• High WBC
• Low Hemoglobin
• Multiple episodes of dactylitis
• Low Hb F
• Associated Alpha thal trait- better clinical
  course

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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

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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?

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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

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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.

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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

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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 (CBFgt 200cm/sec)
• Reversal of CBF velocity is not sufficient to
  stop transfusion therapy. (STOP II)

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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)

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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.

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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.

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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

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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

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Neutropenia

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

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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, lt 3 years of age, skin and mucous membrane
  infections, Antibodies

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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

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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)

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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

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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.

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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)

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Coagulation cascade
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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

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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.

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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

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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

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Bleeding disorders

• Tests for bleeding
• Hemophilia A
• Hemophilia B
• Hemophilia C
• VW Disease

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Hemophilia

• Factor VIII deficiency (Hemophilia A)-85
• X-linked recessive, Carriers asymptomatic
• Severelt1, 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

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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

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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

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Von Willebrands 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-NRAs
• -Translocation- Ph chromosome t (922) 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 gt25 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
• ALLAML 41
• lt 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 lt 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 WBCgt 100,000 Secondary
  AML Myelodysplasia with AML

79
Hodgkins Lymphoma

• Bimodal age distribution first peak 20-30, again
  after age 50. Rare lt 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 (Burkitts)
• 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
Burkitts Lymphoma

• Endemic Burkitts
• African type, head and neck, jaw
• 95 chance of EBV
• Sporadic Burkitts
• 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 childs 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 gt 90 at 2 years
• UH lt 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 lt4 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 lt 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
  gt1.

96
Neuroblastoma

• Low risk
• Surgery alone gt95 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
Ewings 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
Ewings 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 lt 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 lt 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