Presentation on theme: "Pediatric Board Review Course Pediatric Hematology/Oncology Kusum Viswanathan, MD Vice Chair, Dept of Pediatrics Director, Divn of Pediatric Hematology/Oncology."— Presentation transcript:
Pediatric Board Review Course Pediatric Hematology/Oncology Kusum Viswanathan, MD Vice Chair, Dept of Pediatrics Director, Divn of Pediatric Hematology/Oncology Brookdale 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 + 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. 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 1. G 6 PD deficiency 2. Hereditary spherocytosis 3. Physiologic anemia 4. ABO incompatibilty 5. Rh hemolytic disease
Newborn -anemia Hemoglobin at birth is 17 g/dl, MCV over 100. Falls to by 6 weeks of age- nadir. Erythropoietin production shifts from liver to kidneys and reduces because of increase in PaO2. Anemia at birth could be : –hemoglobin not have equilibrated- 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. Alpha Thalassemia trait. –Kleihauer-Betke- Hb F resistance to acid elution
Newborn-Thrombocytopenia A newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000. Differential diagnosis: –Production defects: TAR, Megakaryocytic hypoplasia, Trisomy 13, 18. Wiskott-Aldrich (small plt, X-linked, eczema, SCT cure) Infections- viral, bacterial, Infiltration (Gauchers, Niemann Pick, Leukemia) –Destruction: Allo-immune (iso-immune)- Platelet group 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)
The treatment of choice for alloimune neonatal thrombocytopenia is: 1. random platelet transfusion 2. IVIG 3. Steroids 4. Exchange transfusion 5. Washed maternal platelets
Immune thrombocytopenia Auto-immune: Pregnant women with ITP/Hx of ITP –Passive transfer of antibodies (IgG) from mother. –Even when mother has a normal platelet count (Splenectomy) –Nadir-few days; Platelets < 50,00 have 1% risk of ICH. –IVIG to mother, Fetal platelet counts, C sec, US, IVGG to baby 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 –Mothers 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 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
ITP Usually acute onset; immune mediated; post viral Peak 2-5 years of age, males=females Spontaneous bruises, petechiae PE –no lymphadenopathy (LN), hepatosplenomegaly. CBC- other cell lines normal, large plts on smear Treat if plt< 10,000 or wet ITP, avoid NSAIDS, Aspirin Treat- IVIG best response, hours; Side effects. –Anti-D (WInRho) Rh+,hemolysis, quick response –Steroids good response, SE, inexpensive, need BM BM- Increased megakaryocytes, otherwise normal
Petechiae ITP- Thrombocytopenia Hemolytic 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 affected Drug induced- –Likely –By reducing production or increasing destruction DIC
Platelet Size 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, 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 1.Acrodermatitis enteropathica 2.Ataxia telangiectasia 3.Atopic dermatitis 4.Langerhans cell histiocytosis 5.Wiskott-Aldrich syndrome 6
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
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??
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 –Fanconis anemia-AR, s hromosomal –Fanconis 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, HIV Drug induced- Chloramphenicol Exposure to Toxins, Radiation Autoimmune disease such as lupus Idiopathic Treatment- BM/Stem cell transplant
Microcytic anemia is a characteristic laboratory abnormality of all listed diseases except 1. Iron deficiency 2. Lead poisoning 3. Sickle cell disease 4. Thalassemia trait
Iron deficiency Low MCV, low MCHC, low retic, RDW 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.
Beta 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 or Delta- Increased Hb F and A 2. Smear abnormalities significant even with MILD anemia. Anemia Low MCV, normal RDW, normal retic Smear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stippling Hb Electrophoresis: Increased Hb A 2 and/or F. Normal iron studies, no response to iron
Beta 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
Thalassemia- Alpha Reduced Alpha chains 4 types- carried on 4 allelles. (xx/xx) One absent- Silent carrier (x-/xx) 2 absent- Alpha Thal trait (xx/- - or x-/x-) 3 absent- Hb H disease (x-/- -) Has 4 excess Beta chains) 4 absent- Hydrops fetalis (- -/- -) NB period: Excess Gamma chains form Hb Barts- FAST moving Hb on Newborn screening
Megaloblastic anemias Vitamin B 12 or Folate deficiency (defective DNA synthesis) Defective maturation of other cell lines- leukopenia and/or Thrombocytopenia Hypersegmented neutrophils, large metamyelocytes and bands Causes hyperhomocysteinemia. Dietary deficiency of vitamin B12 due to vegetarianism. Can occur in breast-fed infants of vitamin B12–deficient mothers Severe vitamin B12 deficiency - a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression Underlying 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 deficiency Hemoglobinopathies –Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysis Loss –Blood loss
Question A 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 1.Hereditary spherocytosis 2.Sickle cell disease 3.Hepatitis 4.G6PD deficiency 6
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
Children with congenital spherocytosis have all of the listed conditions except: 1. positive Direct Coombs 2. splenomegaly, gallbladder stones 3. abnormalities in spectrin and /or ankyrin 4. increased MCHC 5. abnormal osmotic fragility test. 6
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 girls present illness is infection with –Coxsackie virus –Parvovirus B19 –Epstein-Barr virus –Hepatitis A virus –Influenza A virus
HS- with severe anemia 1.Coxsackie virus 2.Parvovirus B19 3.Epstein-Barr virus 4.Hepatitis A virus 5.Influenza A virus 6
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-B 0 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
Sickle cell Hemolysis- life span days. Abnormal cell shape, abnormal adherence to endothelium, decreased oxygenation, Increased polymerization. Symptoms start by 2-4 months of age. Hb electrophoresis, S >75 %. Start Penicillin daily and give until age 5. Prevention of pneumococcal infections. PPV (Pnu-23) age 2, 5 Meningococcal vaccine Folic 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: 1. High WBC 2. Associated alpha thalassemia trait 3. Low hemoglobin 4. Repeated episodes of dactylitis
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
Pulmonary Hypertension Prevalence of pulmonary HT in SCD from %. The presence of hemolysis, chronic anemia, and the need for frequent transfusions were directly associated with development of PHT. On follow-up, PHT was significantly associated with an increased risk of death. -Am J Hematol July N Engl J Med Feb 2004.
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) 1. Repeat TCD is normal 2. Continue indefinitely 3. the child reaches 18 years 4. MRA/MRI are reported normal 6
Sickle cell and Stroke Affects 10 % of patients Infarctive stroke (younger patients) and Hemorrhagic stroke (older) STOP I study established the role of yearly TCD (transcranial doppler) to measure cerebral blood flow velocity as a tool for determining stroke risk. Transfusion therapy as current therapy for high risk patients (CBF> 200cm/sec) Reversal of CBF velocity is not sufficient to stop transfusion therapy. (STOP II)
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 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 1. Sickle retinopathy 2. Ischemic stroke 3. Acute Chest syndrome 4. Pulmonary Hypertension 5. Leg ulcers 6
Iron overload One unit -200mg Iron No physiologic way of removal transfusions transfusions Desferioxamine available. Can be given IV or subq infusion or subq shots. Compliance an issue. December Oral chelator available (Deferasirox)- FDA approved.
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.
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
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 200X10 9 /L, ANC 750. Most appropriate step is t 1. Amoxicillin for 10 days 2. G- CSF for 10 days. 3. BM aspirate 4. Refer to a hematologist 5. Repeat CBC in 1-2 weeks 6
Neutropenia Severe neutropenia ANC < 500/mm3 Viral infection(hepatitis, Influenza, Measles, Rubella, RSV, EBV)- No Rx. Cyclic neutropenia –Sporadic Autosomal dominant disorder –21 day intervals, nadir < 200/uL –G CSF treatment Severe Congenital Neutropenia (Kostmann) –AR, ANC< 200, BM arrest, high dose G CSF, risk of malignancy (MDS/AML) and sepsis. BMT cure.
Neutropenia Auto-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, Antibodies Ethnic neutropenia- (Benign familial)-AA Drug Induced- Procainamide, Anti-thyroid, Sulfasalazine.
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
All of the following are true in CGD (Chronic granulomatous disease) except Neurophils cannot destroy catalase positive organisms Unable to secrete Hydrogen peroxide Pneumonia, Underweight, recurrent infections Nitroblue Tetrazolium test is for diagnosis Have 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 ) 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)
Lab studies (What do they measure?) CBC and Peripheral smear PT, INR and PTT –PT - Factor VII, common pathway –PTT- Factor VIII, IX, XI, XII, common pathway Mixing studies (Inhibitors and deficiency) Specific coagulation factor assays Fibrinogen
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.
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
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. 1. Disseminated intravascular coagulation 2. Factor VIII deficiency hemophilia 3. Immune thrombocytopenic purpura 4. Neonatal alloimmune thrombocytopenia 5. Von Willebrand disease 6
Bleeding disorders Tests for bleeding Hemophilia A Hemophilia B Hemophilia C VW 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. 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 6
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 Willebrands Disease 1-2 % of population Type I - 80 % of cases; Quantitative defect, Autosomal dominant (AD) Type %, 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- 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
The most common cause of familial predisposition to thrombosis is 1.Hemophilia antibodies 2.Protein C deficiency 3.Protein S deficiency 4.Factor V Leiden mutation 5.Antithrombin III deficiency 6
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
Hypercoagulable states Factor V Leiden % 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 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.
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 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 6
Transfusion- Notes CMV negative- give leukocyte reduced. Irradiated products- To prevent GVHD Washed cells- To reduce febrile reactions Phenotype matched –To prevent allo-immunization Sickle negative- In sickle cell patients, neonates
CANCER IN CHILDREN Distribution-All ages
Cancer in Children Leukemias, Brain tumors, Lymphomas 2 nd 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 (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. 1. acute lymphoblastic leukemia 2. Aplastic anemia 3. Gaucher disease 4. lead poisoning 5. Multifocal osteomyelitis 6
ALL (Acute Lymphoblastic leukemia) Can present with generalized bone pain Bruising, nose bleeds Unusual fevers, infection Lymphadenopathy, hepatosplenomegaly
ALL (Acute Lymphoblastic leukemia) Abnormal to see blasts in the peripheral smear Diagnosis: >25 % blasts in the BM. Normal marrow has < 5 % blasts Single most common childhood cancer (29% of all childhood cancers); cases per year Peak age 2-5 years More likely in Trisomy 21, Ataxia-Telangiectasia, Bloom syndrome, Fanconi anemia.
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
Down Syndrome and Leukemia fold increase ALL : AML= 4 :1 < 2 years: M7 AML DS: 400 fold Increase in M7 AML Superior response to Rx of AML Transient Myeloproliferative disorder in 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 leukemias Increased incidence in < 1 year of age Higher incidence: –Downs, Fanconi, Bloom, DBA, Kostmann, Neurofibromatosis I, Schwachman-Diamond Sx: Fever, bleeding, pallor, anorexia, fatigue, Bone/Jt pain, LN, GI Sx. Chloromas (green) – solid collection in bone/soft tissues Types: M0-M7, commonest M2 M7- Downs syndrome
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 % 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 Hodgkins disease are true except 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 6
Hodgkins Lymphoma Bimodal age distribution: first peak 20-30, again after age 50. Rare < 5 years. 5 % of all malignancies; 40 % of lymphomas, Sx: Painless adenopathy, 1/3 have B symptoms( fever, night sweats, wt loss) Pathology: Reed-Sternberg cell (large cell with multilobed nuclei); B-cell, 4 subtypes. Rx: based on stage; Staging depends upon one side or both sides of the diaphragm. Stage !-2, EFS %, Stage 3-4; 75 % EFS. Second malignancy in patients who have recd combination chemo and RT-- Leukemia, NHL, Breast cancer.
Non Hodgkins Lymphoma Most common lymphoma in childhood % 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)
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 %.
Case 5 yr old boy with progressive vomiting, headache, unsteady gait and diplopia for 4 weeks. MRI shows a contrast enhancing tumor in the 4 th 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 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 Associations with Inherited Genetic disorders: –Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau disease, Li-Fraumeni (glioma), Turcot syndrome
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.
Wilms Tumor Histology: favorable(FH) vs unfavorable (UH) Staging: I-local, II-excised, III-residual, IV- metastases, V -bilateral Treatment: Nephrectomy, Chemo-all, St I- II-2 drugs-18 weeks, St III-IV- 3 drugs+ RT Prognosis: –FH: > 90% at 2 years –UH: < 60% at 2 years
Congenital anomalies associated with Wilms tumor include all of the following except 1.Polydactyly 2.Aniridia 3.Hemihypertrophy 4.Cryptorchidism 5.Denys-Drash syndrome 6
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 months Chest 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.Pseudotumor of the orbit 2.Trichinosis 3.Retinoblastoma 4.Rhabdomyosarco ma 5.Orbital cellulitis 6
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
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
All statements are true about Neuroblastoma except: 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 6
Neuroblastoma Low risk: –Surgery alone; >95 % 5 year survival Intermediate risk: –Surgery and Chemo; % 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 Sarcoma MRI, Bone scan, Biopsy, CT Chest. Peak incidence- 2 nd decade Predisposition: Hereditary retinoblastomas, Li- Fraumeni, Pagets, RT, Alkylating agents 60 % 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
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,
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.
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. 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 normal 5. K high, P high, LDH high, Na normal. 6
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 compression Local tumor extension or metastasis Lymphomas, neuroblastoma, soft tissue sarcomas Presentation: back pain worse with movement, neck flexion, straight leg raising, valsalva –Weakness; partial/complete paralysis, Incontinence Diagnosis: Clinical / Spinal MRI Therapy: Urgent treatment to relieve pressure and prevent permanent neurologic damage. –Neurology/Neurosurgery consult –High dose dexamethasone –Emergency radiation therapy –Laminectomy
Superior Vena Cava Syndrome Mass lesion obstructs flow through the SVC Sx 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, wheezing NHL, Tcell ALL, Lymphoma, Teratoma Secondary cause: occluded central venous catheter Try to get a diagnosis before therapy
Fever, Neutropenia Single most important risk factor: ANC Organisms: Gram negative, Staph epi in catheter patients Medication: Broad spectrum 3 rd generation antibiotics Anti-fungal after 4 days Examine 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. acute myeloid leukemia as a second malignancy 2. disseminated varicella 3. drug-induced ITP 4. late-onset aplastic anemia due to chemotherapy 5. viral-induced ITP 6
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 < 5 th percentile and she is Tanner stage I. Most likely to have an abnormal test of Growth hormone 2. Estradiol 3. Follicle stimulating hormone 4. Gonadotropin releasing hormone 5. Thyroid stimulating hormone 6
Late effects of cancer therapy RT: Hypothalamic pituitary axis is impaired; central hypothyroid and Adrenal insuff. Hypothalamic pituitary axis is impaired; central hypothyroid and Adrenal insuff. RT doses higher in brain tumor RT doses higher in brain tumor GH is dose sensitive to the effects of RT GH is dose sensitive to the effects of RT Age related: < 5 years susceptible Age related: < 5 years susceptible Panhypopituitarism with higher doses Panhypopituitarism with higher doses ovarian failure with RT 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.Growth hormone deficiency 2.Hypothyroidism 3.Impotence 4.Infertility 5.Osteoporosis 6
Chemotherapy effects Chemotherapy with alkylating agents Females: Females: less effects than males less effects than males normal puberty normal puberty early menopause early menopause Males: Males: irreversible gonadal toxicity sterility with azospermia Puberty usually not affected (leydig cells)
The most common reason for the failure of hematopoietic stem cell transplantation is 1.Veno-occlusive disease of the liver 2.Disease recurrence 3.Infection 4.Graft vs. host disease 5.Graft rejection 6
GVHD ( Graft vs Host disease): All are true except 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 6
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
Other topics- do read Histiocytosis Storage disorders