pediatric board review course pediatric hematology/oncology

Pediatric Board Review CoursePediatric Hematology/Oncology

Kusum Viswanathan, MDVice Chair, Dept of Pediatrics

Director, Divn of Pediatric Hematology/OncologyBrookdale Univ Hospital and Medical Center

Case 1

6 week old term infant referred for anemia. No Sx Hb 7.5, Retic 2 %, Bili 3.5, Direct 0.5. Mother O+, Baby A -, Direct Coombs + Cord blood Hb 14.2 g/dL. Bilirubin 15mg/dL at 48 hours of life, recd photo Rx and d/c at 5 days.

Most likely explanation for the anemia is

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1. G 6 PD deficiency2. Hereditary

spherocytosis3. Physiologic anemia4. ABO incompatibilty5. Rh hemolytic

disease

Newborn -anemiaHemoglobin 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 :– hemoglobin 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

Newborn-ThrombocytopeniaA newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000.Differential diagnosis:– Production defects:

TAR, Megakaryocytic hypoplasia, Trisomy 13, 18.Wiskott-Aldrich (small plt, X-linked, eczema , SCT cure) Infections- viral, bacterial, Infiltration (Gauchers, Niemann Pick, Leukemia)

– Destruction: Allo-immune (iso-immune)- Platelet group incompatibiltyAuto-immune: Mat ITP, Drugs (thiazide, tolbutamide), SLEInfections: CMV, Rubella, herpes, DICLoss: Kasabach- Merritt syndrome (hemangiomas, DIC- Rx DIC and hemangioma with Steroids, interferon, VCR)

The treatment of choice for alloimune neonatal thrombocytopenia is:

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1. random platelet transfusion

2. IVIG3. Steroids4. Exchange

transfusion5. Washed maternal

platelets

Immune thrombocytopeniaAuto-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

Allo or 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

Kasabach- Merritt, TAR

15 months old girl presented in ER with h/o URI, and scattered petechiae and ecchymoses over the body and lower extremities. Physical exam normal, no hepatosplenomegaly. WBC-6,000, Hb 12.8, Plts-5,000, Diff: Normal Smear- The next step is to

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1. perform a bone marrow aspirate to confirm the diagnosis

2. Do a skeletal survey to rule out bony fractures

3. Start treatment with either IVIG or anti-D

4. Administer platelet transfusion

ITPUsually acute onset; immune mediated; post viralPeak 2-5 years of age, males=femalesSpontaneous bruises, petechiaePE –no lymphadenopathy (LN), hepatosplenomegaly.CBC- other cell lines normal, large plts on smearTreat if plt< 10,000 or wet ITP, avoid NSAIDS, AspirinTreat- IVIG best response, 48-72 hours; Side effects.– Anti-D (WInRho) Rh+ ,hemolysis, quick response– Steroids good response, SE, inexpensive, need BM

BM- Increased megakaryocytes, otherwise normal

Petechiae, HSP

PetechiaeITP- ThrombocytopeniaHemolytic Uremic Syndrome– Low plt ct, Hemolysis, high LDH, sick patient, Uremia,

microangiopathic hemolysis on smear.Henoch-Schonlein Purpura– Purpuric lesions on lower extremities and buttocks– Abdominal pain, arthritis. IgA deposition, normal plt ct.

ALL– Low plt ct, lymphadenopathy (LN), hepatosplenomegaly, other

cell lines affectedDrug induced- – Likely– By reducing production or increasing destruction

DIC

Platelet SizeNormal platelet 7-10 daysLarge 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, platelet dysfunction)

A 2 year old boy presents for evaluation of a chronic pruritic eruption. His medical history is remarkable for recurrent epistaxis, otitis media, and pneumonia. Physical examination reveals erythematous, slightly

scaling patches on the trunk and in the antecubital and popliteal fossae. Petechiae are present profusely. This is most suggestive of

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1. Acrodermatitis enteropathica

2. Ataxia telangiectasia

3. Atopic dermatitis4. Langerhans cell

histiocytosis5. Wiskott-Aldrich

syndrome

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Platelet function defects

Normal platelet numberGlanzmann thrombasthenia– AR, Abnormal aggregation– Bleeding disorder, check h/o consanguinity

Hermansky Pudlak Syndrome:– AR, Decreased dense granules– In Puerto Ricans– Oculocutaneous albinism

ThrombocytosisH- Hemorrhage, Hereditary Asplenia, Down myeloprol.I- Infections, Kawasaki, Immune:GVH, Nephrotic syndromeP- Polycythemia vera, Myeloproliferative, EssentialL- Leukemia (CML) A- Anemia,- Iron, Vit E, SideroblasticT- TumorsE- Epinephrine, SteroidsL- Lymphoma, HodgkinsE- Exercise, T- Trauma, FracturesS- Splenectomy

AnemiaAn 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??

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, recovers, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .

Aplastic Anemia

Congenital- Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, Amegakaryocytic thrombocytopenia– Fanconi’s anemia-AR, short stature, microcephaly, microphthalmia, epicanthal

folds, Café au lait, dangling thumbs, congenital dislocated hips. Chromosomal breakage increased by diepoxybutane (DEB) or mitomycin C. Hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors,

Acquired Infection- hepatitis, EBV,CMV, parvovirus B19, HIVDrug induced- Chloramphenicol Exposure to Toxins, RadiationAutoimmune disease such as lupusIdiopathic

Treatment- BM/Stem cell transplant

Normal smear

Microcytic anemia is a characteristic laboratory

abnormality of all listed diseases except

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1. Iron deficiency2. Lead poisoning3. Sickle cell

disease4. Thalassemia

trait

Microcytic anemia

Iron deficiencyLow MCV, low MCHC, low retic, RDW normal initially, will increase after treatment, Low Iron, Incr TIBC, Transferrin low, Ferritin lowCauses: 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.

Beta Thalassemia MinorQuantitative 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 or Delta- Increased Hb F and A2.Smear abnormalities significant even with MILD anemia.

AnemiaLow MCV, normal RDW, normal reticSmear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stipplingHb Electrophoresis: Increased Hb A2 and/or F.Normal iron studies, no response to iron

Beta Thalassemia MajorNo production of Beta chainsAutosomal recessive25 % chance with each pregnancyPre-natal testing for carriersChorionic villous sampling for diagnosisTransfusion dependent-allows for normal developmentPen Prophylaxis, Anti oxidantsSplenectomy after age 5Iron overload- inherent and transfusionNeed chelators

Thalassemia- Alpha

Reduced Alpha chains4 types- carried on 4 allelles. (xx/xx)One absent- Silent carrier (x-/xx)2 absent- Alpha Thal trait (xx/- - or x-/x-)3 absent- Hb H disease (x-/- -) Has 4 excess Beta chains)4 absent- Hydrops fetalis (- -/- -)NB period: Excess Gamma chains form Hb Barts- FAST moving Hb on Newborn screening

Megaloblastic anemiasVitamin B 12 or Folate deficiency (defective DNA synthesis)Defective maturation of other cell lines- leukopenia and/or ThrombocytopeniaHypersegmented neutrophils, large metamyelocytes and bandsCauses hyperhomocysteinemia. Dietary deficiency of vitamin B12 due to vegetarianism.Can occur in breast-fed infants of vitamin B12–deficient mothersSevere vitamin B12 deficiency - a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regressionUnderlying mechanisms– delayed myelination or demyelination of nerves– alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio– imbalance of neurotrophic and neurotoxic cytokines– accumulation of lactate in brain cells

Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12–deficient diets

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??

Reticulocyte count- Increased

Hemolysis– Intrinsic-

Membrane defects-Hereditary spherocytosis (HS)Enzyme-G 6 PD deficiencyHemoglobinopathies

– Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysis

Loss– Blood loss

QuestionA previously well African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL.

SMEAR

An African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. The most likely

diagnosis is

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1. Hereditary spherocytosis

2. Sickle cell disease

3. Hepatitis4. G6PD deficiency

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Hemolytic anemia

History; Recent infection, drug exposure, illness, dark urine, anorexia, fatigue, pallorFamily h/o gallstones, splenectomyPhysical Examination: Pallor, tachycardia, tachypnea, splenomegaly.Peripheral smear: Blisters, spherocytes

Children with congenital spherocytosis have all of the listed conditions except:

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1. positive Direct Coombs 2. splenomegaly,

gallbladder stones 3. abnormalities in spectrin

and /or ankyrin4. increased MCHC5. abnormal osmotic

fragility test.

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Spherocytes

SpherocytesNucleated rbcCoombs-AIHAOsmotic fragility-HS

HS- with severe anemia

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– Parvovirus B19– Epstein-Barr virus– Hepatitis A virus– Influenza A virus

HS- with severe anemia

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1. Coxsackie virus2. Parvovirus B193. Epstein-Barr

virus4. Hepatitis A virus5. Influenza A virus

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Newborn ScreeningYou get a call from a frantic parent because she received a letter from the State regarding her baby’s test results on NBS.FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH.FSA- Sickle B+ thal, Sickle cell traitFSC- SC diseaseFAS- Sickle cell traitFAC- Hb C traitFAE- Hb E traitFE - Hb EE disease, E-Thal

Sickle cellHemolysis- 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, 5Meningococcal vaccineFolic acid daily

The mother of a 10 month old baby with SS disease asks you about prognostic indicators. All of the following indicate likelihood of more

severe disease except:

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1. High WBC2. Associated alpha

thalassemia trait3. Low hemoglobin4. Repeated

episodes of dactylitis

Sickle cell crisesVaso-occlusive crisis-dactylitis, long bones, back, chest. Trt. Pain meds, hydration.Aplastic crisis: low Hb, low retic, Secondary to Parvovirus infection.Splenic sequestration crisis: spleen palpationHyperhemolytic crisis

Sickle cell Acute Chest Syndrome

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

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.

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

According to the STOP protocols, all children with abnormal TCD require enrollment in hypertransfusion

protocol till (choose one)

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1. Repeat TCD is normal

2. Continue indefinitely

3. the child reaches 18 years

4. MRA/MRI are reported normal

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Sickle cell and StrokeAffects 10 % of patientsInfarctive 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)

Sickle cell and TransfusionsTransfusion indications:– Acute anemia (Aplastic, Hyperhemolytic, Sequestration)– Hypoxia (ACS, chronic lung disease, Pulmonary hypertension)– Stroke and stroke prevention– Intractable pain, pre-operative preparation

Types of transfusions– Intermittent– Chronic simple– Exchange (Partial, Total, Erythrocytapheresis)– Hypertransfusion (transfusions in an effort to prevent patient

from producing their own red cells)

Which of the complications of sickle cell disease is more common in SC patients compared to SS disease

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1. Sickle retinopathy 2. Ischemic stroke3. Acute Chest

syndrome4. Pulmonary

Hypertension5. Leg ulcers

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Iron overloadOne unit -200mg IronNo physiologic way of removal 10-20 transfusionsDesferioxamine available. Can be given IV or subq infusion or subq shots.Compliance an issue.December 2005- Oral chelator available (Deferasirox)- FDA approved.

Sickle cell and Hydoxyurea

FDA approved for adultsStudies in children demonstrated efficacy and safety.Increases hemoglobin F levelIncreases hemoglobinDecreases WBC – ancillary effectHydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, acute chest syndrome.

Other important points

Median life expectancy:– Males 42 years, females 48 years

Improvement related to Penicillin, immunizations, education.Bone marrow transplant (BMT) is a cureCord blood storage

A healthy 5 year old boy has a 2 day hx of fever, P/E normal, No hepatosplenomegaly, LN, no focus of infection. CBC WBC 3, Neutrophils 25 %, Hb 12,

Platelet 200X109/L, ANC 750. Most appropriate step is t

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1. Amoxicillin for 10 days

2. G- CSF for 10 days.3. BM aspirate4. Refer to a

hematologist5. Repeat CBC in 1-2

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NeutropeniaSevere 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.

NeutropeniaAuto-Immune neutropenia– Self limited, G CSF only if necessary– Mild infections

Schwachman-Diamond Syndrome– AR, Exocrine pancreatic failure, short stature, recurrent

infections, metaphyseal dysostoses.– G-CSF, Risk of myelodysplasia and AML, BMT curative

Chronic benign Neutropenia– ??AI, < 3 years of age, ANC < 200,skin and mucous membrane

infections, Normal marrow, AntibodiesEthnic neutropenia- (Benign familial)-AADrug Induced- Procainamide, Anti-thyroid, Sulfasalazine.

CaseA 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 neutropeniaB. cyclic neutropeniaC. Schwachman-Diamond syndromeD. severe congenital neutropeniaE.. transient viral bone marrow suppression

All of the following are true in CGD (Chronic granulomatous disease) except

Neurophils cannot destroy catalase positive organismsUnable to secrete Hydrogen peroxidePneumonia, Underweight, recurrent infectionsNitroblue Tetrazolium test is for diagnosisHave abnormal chemotaxis

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)

Abnormal Bleeding

Epistaxis unrelieved by 15 minutes of pressure, both nostrils, requiring an ER visit, documented drop of hemoglobin. Menstrual periods( amount, pads, duration) Bleeding after procedures (circumcision, dental extractions, T and A-delayed bleed)Ecchymoses/bruising inconsistent with the degree of trauma

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)

Coagulation cascade

Lab studies(What do they measure?)

CBC and Peripheral smearPT, INR and PTT– PT - Factor VII, common pathway– PTT- Factor VIII, IX, XI, XII, common pathway

Mixing studies (Inhibitors and deficiency)Specific coagulation factor assaysFibrinogen

Circulating anticoagulant

Mixing studyIf PT or PTT is prolonged, ask for a mixing study.Mix patient plasma with equal amount of normal plasma, the test will normalize if the abnormal result is because of a deficiency in factor. If there is an anticoagulant, it will not normalize or even if it does, it will become abnormal again after incubation.

Factor XIII and VII deficiencyFactor XIII

Rare Autosomal RecessiveIf 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 separationAbnormal clot solubility in 5M Urea

Factor VIIIntracranial hemorrhageRare, homozygous stateProlonged PT, n PTTTreatment with Recombinant F VII

A healthy 2-day-old boy born at term undergoes circumcision. Bleeding noted at the site 10 hours after the procedure and

increased steadily over the past 4 hours. Findings on exam are unremarkable except for bleeding along 2 to 3 mm of the surgical

site; no petechiae or purpura.

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1. Disseminated intravascular coagulation

2. Factor VIII deficiency hemophilia

3. Immune thrombocytopenic purpura

4. Neonatal alloimmune thrombocytopenia

5. Von Willebrand disease

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Bleeding disorders

Tests for bleedingHemophilia AHemophilia BHemophilia CVW Disease

Hemophilia

Factor VIII deficiency (Hemophilia A)-85%– X-linked recessive, Carriers asymptomatic– Severe<1%, Moderate 1-5, Mild 6-30 %– Treat Recombinant Factor VIII 1unit/kg raises factor

level by 2 %. Half life 12 hrs. DDAVP for mild cases.– Joint bleeds need100%, muscle bleeds 50 %.– 30 % develop inhibitors after infusions with

concentrate (Approx 50 infusions)Factor IX deficiency (Hemophilia B)– X-linked recessive, less common

A patient with Hemophilia A has asked you about the possibility of his children being affected by the

disease. The partner is normal.

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1. There is a 50 % chance that his sons will have the disease.

2. There is a 50 % chance that his daughters will be carriers

3. There is a 100 % chance that his sons will have the disease

4. There is a 100 % chance that his daughters will be carriers

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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 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:

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

Thrombophilia- CaseA 14 year old male presents with chest pain and difficulty breathing. He notes that his right calf has been swollen for the last 3 days and he has difficulty placing his foot on the ground. P/E Pain on dorsiflexion, Air entry reduced. CXR and EKG are normal. VQ scan shows a filling defect and a diagnosis of DVT and pulmonary embolism is made.What are the important questions on history?– History of DVT in family members– H/o recurrent late miscarriages in mother and her sisters.– H/o trauma and precipitating factors

The most common cause of familial predisposition to thrombosis is

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1. Hemophilia antibodies

2. Protein C deficiency3. Protein S deficiency4. Factor V Leiden

mutation5. Antithrombin III

deficiency

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Causes

Factor V Leiden (Activated Protein C resistance)Prothrombin G 20210A gene mutation Protein C deficiency and activityProtein S deficiency and activity.Anti thrombin III deficiency and activity.HyperhomocystenemiaAntiphospholipid syndromeRare disorders-Dysfibrinogenemia

Hypercoagulable statesFactor 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.

Hypercoagulable statesG20210A 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.

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

your discussion is MOST likely to include the statement that

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1. all units are tested only for hepatitis B and C

2. all units are tested only for human immuno-deficiency virus (HIV)

3. all units are tested for HIV, hepatitis B, and hepatitis C

4. all units are tested for HIV, hepatitis B, hepatitis C, sickle cell trait, cytomegalovirus, and Epstein-Barr virus

5. only units obtained from donors who have one or more risk factors are screened for HIV, all units are tested only for hepatitis B and C

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Transfusion- Notes

CMV negative- give leukocyte reduced.Irradiated products- To prevent GVHDWashed cells- To reduce febrile reactionsPhenotype matched– To prevent allo-immunization

Sickle negative- In sickle cell patients, neonates

CANCER IN CHILDREN

Distribution-All agesChildhood Cancer Distribution Leukemia

Lymphoma

Brain Tumor

Soft tissue sarcoma

Germ call

Bone

Neuroblastoma

Renal

Retino

Hepato

Carcinoma

Other

Cancer in Children

Leukemias, Brain tumors, Lymphomas2nd leading cause of death 1-14yrs12,400 cases per year

Proto-Oncogenes imp for function-Activated

-Amplification --n-myc-Point mutation-NRA’s-Translocation- Ph chromosome t (9:22);

BCR-ABL

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.

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1. acute lymphoblastic leukemia

2. Aplastic anemia3. Gaucher disease4. lead poisoning5. Multifocal

osteomyelitis

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ALL (Acute Lymphoblastic leukemia)Can present with generalized bone painBruising, nose bleedsUnusual fevers, infectionLymphadenopathy, hepatosplenomegaly

ALL (Acute Lymphoblastic leukemia)Abnormal to see blasts in the peripheral smearDiagnosis: >25 % blasts in the BM.Normal marrow has < 5 % blastsSingle most common childhood cancer (29% of all childhood cancers); 2500-3500 cases per yearPeak age 2-5 yearsMore likely in Trisomy 21, Ataxia-Telangiectasia, Bloom syndrome, Fanconi anemia.

ALL TreatmentInduction: 4-6 weeks, 95 % remission; Vincristine, Corticosteroids, L-Asparaginase and AnthracyclineConsolidation /delayed Intensification: 6-12 months; rotating drugs.Maintenance : Daily oral 6-MP, weekly MTX, Monthly pulses of Vincristine and Steroid.CNS prophylaxis: Intrathecal chemoCNS Therapy: RT + Intensive systemic chemoTesticular disease: RT

ALL- PrognosisPrognosis: WBC, Age, Cytogenetics – good if hyperdiploidy, trisomy 4,10,t (12,21)– Bad if Philadelphia chr t (9,22),t(4,11), t(8,14)

Immunophenotype: Pre-B, B, TEarly response, Minimal residual disease (MRD)Standard risk: 85 % survivalHigh risk: 65 % survivalVery low risk: 90% survivalInfants: 50 % survivalEarly relapse is a poor sign

Down Syndrome and Leukemia10-20 fold increaseALL : AML= 4 :1< 2 years: M7 AMLDS: 400 fold Increase in M7 AMLSuperior response to Rx of AMLTransient Myeloproliferative disorder in newborn which resolves within 3 months. – No clonal cytogenetic abnormality.

Rx : Exchange or low dose cytoreduction. Higher chance of M 7 AML. (30% in some reports)

Acute Myeloid Leukemia (AML)20 % of all leukemiasIncreased incidence in < 1 year of ageHigher incidence:– Downs, Fanconi, Bloom, DBA, Kostmann,

Neurofibromatosis I, Schwachman-DiamondSx: Fever, bleeding, pallor, anorexia, fatigue, Bone/Jt pain, LN, GI Sx.Chloromas (green) – solid collection in bone/soft tissuesTypes: M0-M7, commonest M2M7- Downs syndrome

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

All statements about Hodgkin’s disease are true except

0%0%0%0%

1 2 3 4

1. Has a better prognosis than Non Hodgkins

2. Can progress to acute leukemia

3. Fever, night sweats, wt loss are used for staging

4. Has a bimodal age distribution

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Hodgkin’s LymphomaBimodal age distribution: first peak 20-30, again after age 50. Rare < 5 years.5 % of all malignancies; 40 % of lymphomas, Sx: Painless adenopathy, 1/3 have “B” symptoms( fever, night sweats, wt loss)Pathology: Reed-Sternberg cell (large cell with multilobed nuclei); B-cell, 4 subtypes.Rx: based on stage; Staging depends upon one side or both sides of the diaphragm. Stage !-2, EFS 85-90 %, Stage 3-4; 75 % EFS.Second malignancy in patients who have recd combination chemo and RT-- Leukemia, NHL, Breast cancer.

Non Hodgkins LymphomaMost common lymphoma in childhood10-15 % of all cancers (after leukemia, Brain tumor)50 % of all cancers in Africa (Burkitt’s)More in males, CaucasiansCommon in immunodeficiencies (SCID, Wiskott-Aldrich syndrome, HIV, following stem cell transplant.Types: – small, non-cleaved 40 % (B cell)– Lymphoblastic lymphoma 30 % (T cells)– Large cell 20 % (B, T, indeterminate)

Sites: Abdomen, mediastinum, head and neckMajority are high gradeChromosomal translocations involve c-myc oncogene (chr 8)

Burkitt’s LymphomaEndemic 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 %.

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.

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.

Brain Tumors20% of all malignancies in childrenAge 3-7 yearsMost often infratentorial– cerebellar and hemispheric astrocytoma, medulloblastoma,

brain stem gliomas, Craniopharyngiomas.Sx: Persistent vomiting, headache, gait imbalance, diplopia, ataxia, vision loss, school deterioration, growth decelerationAssociations with Inherited Genetic disorders:– Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau

disease, Li-Fraumeni (glioma), Turcot syndrome

Wilms TumorAn 18-month-old girl is being evaluated because her mother thinks her abdomen seems “full.” Physical examination reveals an abdominal mass. Ultrasonography identifies a solid renal mass. At surgery, a stage I Wilms tumor is found.

Wilms Tumor

Histology: favorable(FH) vs unfavorable (UH)Staging: I-local, II-excised, III-residual, IV-metastases, V -bilateralTreatment: Nephrectomy, Chemo-all, St I-II-2 drugs-18 weeks, St III-IV- 3 drugs+ RTPrognosis: – FH: > 90% at 2 years– UH: < 60% at 2 years

Congenital anomalies associated with Wilms’ tumor include all of the following

except

1 2 3 4 5

0% 0% 0%0%0%

1. Polydactyly2. Aniridia3. Hemihypertrophy4. Cryptorchidism5. Denys-Drash

syndrome

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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 Ultrasound, Urinalysis q 3-4 monthsChest Xray needs to be followed

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

1 2 3 4 5

0% 0% 0%0%0%

1. Pseudotumor of the orbit

2. Trichinosis3. Retinoblastoma4. Rhabdomyosarco

ma5. Orbital cellulitis

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Rhabdomyosarcoma7 % of all childhood cancersPainless non tender mass, 60% under age 6Sites: head & neck, GU, Extremities, mets lungs.Majority sporadic, associations: B-W, Li Fraumeni, NF 1Types:– Embryonal 70%, better prognosis– Alveolar 30 %, trunk, worse prognosis

Treatment: Surgery, Chemo, local control RTResults: – 85 % good risk– 30 % metastatic disease

MassThe mother of a 22-month-old boy reports that he has been fussy and tired. Findings on physical examination confirm the presence of a nontender rt upper quadrant mass. Bilateral periorbital ecchymoses also are noted.Of the following, the MOST likely cause for these findings isA. multicystic kidney diseaseB. neuroblastomaC. non-Hodgkin lymphomaD. HepatoblastomaE. Wilms tumor

All statements are true about Neuroblastoma except:

1 2 3 4 5

0% 0% 0%0%0%

1. Most common extra-cranial solid tumor

2. Prognosis better with N-myc oncogene amplification and tumor diploidy (DNA index 1)

3. Most common cancer in the first year of life

4. Frequent in <4 years, 97 % cases by 10 years

5. Most commonly diagnosed as Stage III or IV

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NeuroblastomaLow 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 primary tumor with spread to skin, liver and/or bone marrow- Minimal therapy.

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?

Osteogenic Sarcoma- X ray and MRI

Osteogenic SarcomaMRI, Bone scan, Biopsy, CT Chest. Peak incidence- 2nd decadePredisposition: Hereditary retinoblastomas, Li-Fraumeni, Pagets, RT, Alkylating agents60 % near the knee (Metaphyses of long bones)History of fall, pain common symptom, mass, no systemic symptoms.Treatment: Open biopsy, Sperm banking, Neo-adjuvant Chemotherapy, limb preserving surgery.

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

Ewing’s SarcomaSeen in Axial bones, flat bones and long bones. 20 % in soft tissue.Caucasians, Onion skin appearance, Diaphysis affected.MRI, CT Chest, Bone scan, Biopsy, BM aspirate and biopsy( Anemia).Unique marker: t(11,22) most casesPNET: Ewing like tumor with neural differentiationTreatment:– Surgery, RT, Neoadjuvant Chemo,

Ewing’s Sarcoma

RetinoblastomaPresentation:– 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.

Retinobalstoma

A child with ALL was started on Chemotherapy. She had a WBC 82,000, Hb 9gm, plt ct 45,000. She develops tumor lysis syndrome: Which one depicts Tumor lysis

1 2 3 4 5

0% 0% 0%0%0%

1. K high, P high, LDH normal, Na high

2. K high, P normal, LDH high, Na nl

3. K normal, P high, LDH high, Na high

4. K normal, P normal, LDH high,

Na normal5. K high, P high,

LDH high, Na normal.

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Tumor lysis syndrome

Rapid destruction of cancer cells.Release of intracellular ions, also Uric acid, can cause tubular obstruction and damage.Treatment: Allopurinol or Rasburicase early, hydration, alkalinization, diuretic therapy.

Spinal cord compressionLocal tumor extension or metastasisLymphomas, neuroblastoma, soft tissue sarcomasPresentation: back pain worse with movement, neck flexion, straight leg raising, valsalva– Weakness; partial/complete paralysis, Incontinence

Diagnosis: Clinical / Spinal MRITherapy: Urgent treatment to relieve pressure and prevent permanent neurologic damage. – Neurology/Neurosurgery consult– High dose dexamethasone– Emergency radiation therapy– Laminectomy

Superior Vena Cava SyndromeMass lesion obstructs flow through the SVCSx due to engorgement of collateral veins of thorax, neck and head– Dyspnea, edema of face, neck, upper extremities– Periorbital edema, conj edema (itchy eyes)– Dysphagia,resp distress, vocal cord paralysis

Tracheal compression: resp distress, wheezingNHL, Tcell ALL, Lymphoma, TeratomaSecondary cause: occluded central venous catheterTry to get a diagnosis before therapy

Chemotherapy-Side effects

Anthracyclines: CardiomyopathyVincristine: foot drop, neurologicalCisplatinum: kidney, deafnessMethotrexate, 6MP: Liver toxicityBleomycin: Pulmonary fibrosisAsparaginase: PancreatitisCyclophosphamaide: Hemorrhagic cystitis– (MESNA, Uroprotector)

Fever, Neutropenia

Single most important risk factor: ANCOrganisms: Gram negative, Staph epi in catheter patientsMedication: Broad spectrum 3rd generation antibioticsAnti-fungal after 4 daysExamine patient thoroughly

16-year-old girl, completed therapy at age 8 for Hodgkins disease with Involved field RT and chemo. She now develops petechiae, purpura, lymphadenopathy and

hepatosplenomegaly.Lab include: plt 12,000,Hb 8.0 gm/dL; and WBC 13,000/mm³

1 2 3 4 5

0% 0% 0%0%0%

1. acute myeloid leukemia as a second malignancy

2. disseminated varicella3. drug-induced ITP4. late-onset aplastic

anemia due to chemotherapy

5. viral-induced ITP

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You are evaluating a 9 year old child for short stature. She was treated at 3 yrs of age for ALL, received cranial RT. Her height is < 5th percentile and she is Tanner stage I.

Most likely to have an abnormal test of

1 2 3 4 5

0% 0% 0%0%0%

1. Growth hormone 2. Estradiol3. Follicle stimulating

hormone4. Gonadotropin

releasing hormone5. Thyroid stimulating

hormone

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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 Panhypopituitarism with higher doses ovarian failure with RT

A 16 year old boy is receiving chemo for rhabdomyosarcoma with a year of cycles of

Vincristine, Actinimycin-D and Cyclophosphamide. Most likely endocrinologic late effect of this therapy

1 2 3 4 5

0% 0% 0%0%0%

1. Growth hormone deficiency

2. Hypothyroidism3. Impotence4. Infertility5. Osteoporosis

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Chemotherapy effects

Chemotherapy with alkylating agents Females:

less effects than males normal puberty early menopause

Males:irreversible gonadal toxicitysterility with azospermiaPuberty usually not affected (leydig

cells)

The most common reason for the failure of hematopoietic stem cell transplantation is

1 2 3 4 5

0% 0% 0%0%0%

1. Veno-occlusive disease of the liver

2. Disease recurrence

3. Infection4. Graft vs. host

disease5. Graft rejection

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GVHD ( Graft vs Host disease): All are true except

1 2 3 4 5

0% 0% 0%0%0%

1. It is the reaction of the donor lymphocytes against the host.

2. Acute GVHD starts within the first 100 days and chronic is after 100 days.

3. Affects the skin, liver and GI tract

4. Irradiation of blood products does not help

5. Complete HLA matching prevents GVHD

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Germ cell tumors

2-3 % of Pediatric malignanciesTeratomas arise from endoderm, ectoderm and mesodermMarkers:– Endodermal sinus tumors –Alpha feto protein– Embryonal Ca, Choriocarcinoma- HCG

Mature teratomas- excision onlyImmature Teratomas: Surgery + Chemo

Other topics- do read

HistiocytosisStorage disorders

GOOD LUCK