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Pediatric Board Review Course Pediatric HematologyOncology

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Title: Pediatric Board Review Course Pediatric HematologyOncology


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 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

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, 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

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, 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

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 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
    .

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 girls 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
    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

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 gt75 .
  • 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 (CBFgt 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 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.

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, lt 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
  • 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

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 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
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