Transcript Pediatric Board Review Course Pediatric Hematology/Oncology

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 +
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.
2.
3.
4.
5.
G 6 PD deficiency
Hereditary
spherocytosis
Physiologic anemia
ABO incompatibilty
Rh hemolytic
disease
0%
1
0%
0%
2
3
0%
0%
4
5
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 :
–
–
–
–
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-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
2.
3.
4.
5.
transfusion
IVIG
Steroids
Exchange
transfusion
Washed maternal
platelets
0%
1
0%
0%
2
3
0%
0%
4
5
Immune thrombocytopenia
Auto-immune: Pregnant women with ITP/Hx of ITP
–
–
–
–
Passive transfer of antibodies (IgG) from mother.
Even when mother has a normal platelet count (Splenectomy)
Nadir-few days; Platelets < 50,00 have 1% risk of ICH.
IVIG to mother, Fetal platelet counts, C sec, US, IVGG to baby
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
1.
2.
3.
4.
perform a bone marrow
aspirate to confirm the
diagnosis
Do a skeletal survey to
rule out bony fractures
Start treatment with either
IVIG or anti-D
Administer platelet
transfusion
0%
1
0%
2
0%
3
0%
4
ITP
Usually acute onset; immune mediated; post viral
Peak 2-5 years of age, males=females
Spontaneous bruises, petechiae
PE –no lymphadenopathy (LN), hepatosplenomegaly.
CBC- other cell lines normal, large plts on smear
Treat if plt< 10,000 or wet ITP, avoid NSAIDS, Aspirin
Treat- IVIG best response, 48-72 hours; Side effects.
– Anti-D (WInRho) Rh+ ,hemolysis, quick response
– Steroids good response, SE, inexpensive, need BM
BM- Increased megakaryocytes, otherwise normal
Petechiae, HSP
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
0%
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0%
0%
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3
0%
0%
4
5
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
Thrombocytosis
H- Hemorrhage, Hereditary Asplenia, Down myeloprol.
IPLATELES-
Infections, Kawasaki, Immune:GVH, Nephrotic syndrome
Polycythemia vera, Myeloproliferative, Essential
Leukemia (CML)
Anemia,- Iron, Vit E, Sideroblastic
Tumors
Epinephrine, Steroids
Lymphoma, Hodgkins
Exercise, T- Trauma, Fractures
Splenectomy
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, ShwachmanDiamond 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, HIV
Drug induced- Chloramphenicol
Exposure to Toxins, Radiation
Autoimmune disease such as lupus
Idiopathic
Treatment- BM/Stem cell transplant
Normal smear
Microcytic anemia is a characteristic laboratory
abnormality of all listed diseases except
1. Iron deficiency
2. Lead poisoning
3. Sickle cell
0%
disease
4. Thalassemia
trait
1
2
3
4
Microcytic anemia
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 DeltaIncreased Hb F and A2.
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 A2 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
– IntrinsicMembrane 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
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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.
2.
3.
4.
5.
positive Direct Coombs
splenomegaly,
gallbladder stones
abnormalities in spectrin
and /or ankyrin
increased MCHC
abnormal osmotic
fragility test.
0%
1
0%
0%
2
3
0%
0%
4
5
6
Spherocytes
Spherocytes
Nucleated rbc
Coombs-AIHA
Osmotic 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
1. Coxsackie virus
2. Parvovirus B19
3. Epstein-Barr
virus
4. Hepatitis A virus
5. Influenza A virus
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3
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6
Newborn Screening
You get a call from a frantic parent because she
received a letter from the State regarding her
baby’s test results on NBS.
FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH.
FSA- Sickle B+ thal, Sickle cell trait
FSC- SC disease
FAS- Sickle cell trait
FAC- Hb C trait
FAE- Hb E trait
FE - Hb EE disease, E-Thal
Sickle cell
Hemolysis- life span 20-50
days. Abnormal cell shape,
abnormal adherence to
endothelium, decreased
oxygenation, Increased
polymerization.
Symptoms start by 2-4 months
of age.
Hb electrophoresis, S >75 %.
Start Penicillin daily and give
until age 5. Prevention of
pneumococcal infections.
PPV (Pnu-23) age 2, 5
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
0%
1
0%
2
0%
3
0%
4
Sickle cell crises
Vaso-occlusive crisisdactylitis, long bones,
back, chest. Trt. Pain
meds, hydration.
Aplastic crisis: low Hb,
low retic, Secondary to
Parvovirus infection.
Splenic sequestration
crisis: spleen palpation
Hyperhemolytic crisis
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
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)
Repeat TCD is
normal
2. Continue
indefinitely
3. the child reaches
18 years
4. MRA/MRI are
reported normal
1.
0%
1
0%
2
0%
3
0%
4
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
0%
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2
3
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5
6
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.
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 200X109/L, ANC 750. Most appropriate step is t
1.
2.
3.
4.
5.
Amoxicillin for 10
days
G- CSF for 10 days.
BM aspirate
Refer to a
hematologist
Repeat CBC in 1-2
weeks
0%
1
0%
0%
2
3
0%
0%
4
5
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)
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 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.
2.
3.
4.
5.
Disseminated intravascular
coagulation
Factor VIII deficiency
hemophilia
Immune thrombocytopenic
purpura
Neonatal alloimmune
thrombocytopenia
Von Willebrand disease
0%
1
0%
0%
2
3
0%
0%
4
5
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.
2.
3.
4.
There is a 50 % chance that
his sons will have the
disease.
There is a 50 % chance that
his daughters will be carriers
There is a 100 % chance that
his sons will have the
disease
There is a 100 % chance that
his daughters will be carriers
0%
1
0%
2
0%
3
0%
4
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 Willebrand’s Disease
1-2 % 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- 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
0%
1
2
3
4
5
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- 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 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 transfusionmediated 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.
2.
3.
4.
5.
all units are tested only for
hepatitis B and C
all units are tested only for
human immuno-deficiency virus
(HIV)
all units are tested for HIV,
hepatitis B, and hepatitis C
all units are tested for HIV,
hepatitis B, hepatitis C, sickle
cell trait, cytomegalovirus, and
Epstein-Barr virus
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
0%
1
0%
0%
2
3
0%
0%
4
5
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
Childhood Cancer Distribution
Distribution-All ages
Leukemia
Lymphoma
Brain Tumor
Soft tissue sarcoma
Germ call
Bone
Neuroblastoma
Renal
Retino
Hepato
Carcinoma
Other
Cancer in Children
Leukemias, Brain
tumors, Lymphomas
2nd leading cause of
death 1-14yrs
12,400 cases per
year
Proto-Oncogenes imp
for function-Activated
-Amplification --n-myc
-Point mutation-NRA’s
-Translocation- Ph
chromosome t (9:22);
BCR-ABL
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.
2.
3.
4.
5.
acute lymphoblastic
leukemia
Aplastic anemia
Gaucher disease
lead poisoning
Multifocal
osteomyelitis
0%
1
0%
0%
2
3
0%
0%
4
5
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); 2500-3500 cases per
year
Peak age 2-5 years
More likely in Trisomy 21, Ataxia-Telangiectasia,
Bloom syndrome, Fanconi anemia.
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 + Intensive systemic chemo
Testicular disease: RT
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
10-20 fold increase
ALL : AML= 4 :1
< 2 years: M7 AML
DS: 400 fold Increase in M7 AML
Superior response to Rx of AML
Transient Myeloproliferative disorder in 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 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
1.
2.
3.
4.
Has a better prognosis
than Non Hodgkins
Can progress to acute
leukemia
Fever, night sweats, wt
loss are used for
staging
Has a bimodal age
distribution
0%
1
2
3
4
6
Hodgkin’s Lymphoma
Bimodal age distribution: first peak 20-30, again after
age 50. Rare < 5 years.
5 % of all malignancies; 40 % of lymphomas,
Sx: Painless adenopathy, 1/3 have “B” symptoms( fever,
night sweats, wt loss)
Pathology: Reed-Sternberg cell (large cell with
multilobed nuclei); B-cell, 4 subtypes.
Rx: based on stage; Staging depends upon one side or
both sides of the diaphragm. Stage !-2, EFS 85-90 %,
Stage 3-4; 75 % EFS.
Second malignancy in patients who have recd
combination chemo and RT-- Leukemia, NHL, Breast
cancer.
Non Hodgkins Lymphoma
Most common lymphoma in childhood
10-15 % of all cancers (after leukemia, Brain tumor)
50 % of all cancers in Africa (Burkitt’s)
More in males, Caucasians
Common in immunodeficiencies (SCID, Wiskott-Aldrich syndrome,
HIV, following stem cell transplant.
Types:
– small, non-cleaved 40 % (B cell)
– Lymphoblastic lymphoma 30 % (T cells)
– Large cell 20 % (B, T, indeterminate)
Sites: Abdomen, mediastinum, head and neck
Majority are high grade
Chromosomal translocations involve c-myc oncogene (chr 8)
Burkitt’s Lymphoma
Endemic Burkitt’s
– African type, head and neck,
jaw
– 95 % chance of EBV
Sporadic Burkitt’s
– Abdomen
– 15-20 % chance of EBV
Treatment- Early diagnosis,
surgery, chemotherapy, Tumor
lysis, Treatment based on
stage and histology.
Immunotherapy: Anti-CD 20
monoclonal antibody;
(Rituximab)
Prognosis: Stage Overall 70 %
cure rate, early 85 %.
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 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, IVmetastases, V -bilateral
Treatment: Nephrectomy, Chemo-all, St III-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
0%
1
0%
0%
2
3
0%
0%
4
5
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
0%
1
0%
0%
2
3
0%
0%
4
5
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-monthold 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.
2.
3.
4.
5.
Most common extra-cranial
solid tumor
Prognosis better with N-myc
oncogene amplification and
tumor diploidy (DNA index 1)
Most common cancer in the
first year of life
Frequent in <4 years, 97 %
cases by 10 years
Most commonly diagnosed
as Stage III or IV
0%
1
0%
0%
2
3
0%
0%
4
5
6
Neuroblastoma
Low risk:
– Surgery alone; >95 % 5 year survival
Intermediate risk:
– Surgery and Chemo; 80-90 % 5 year survival
High risk:
– Induction chemo, surgery, Chemo with autologous
transplant, RT, Biologic therapy
– 30 % 5 year survival
Stage IVs- Localized 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 SarcomaX ray and MRI
Osteogenic Sarcoma
MRI, Bone scan, Biopsy, CT Chest.
Peak incidence- 2nd decade
Predisposition: Hereditary retinoblastomas, LiFraumeni, 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, Neoadjuvant 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 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,
Ewing’s Sarcoma
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.
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.
K high, P high,
LDH normal, Na high
K high, P normal,
LDH high,
Na nl
K normal, P high,
LDH high, Na high
K normal, P normal,
LDH high, Na normal
K high, P high,
LDH high, Na normal.
0%
1
0%
0%
2
3
0%
0%
4
5
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
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)
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
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.
acute myeloid leukemia
as a second malignancy
disseminated varicella
drug-induced ITP
late-onset aplastic
anemia due to
chemotherapy
viral-induced ITP
0%
1
0%
0%
2
3
0%
0%
4
5
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 < 5th percentile and she is Tanner stage I.
Most likely to have an abnormal test of
1.
2.
3.
4.
5.
Growth hormone
Estradiol
Follicle stimulating
hormone
Gonadotropin
releasing hormone
Thyroid stimulating
hormone
0%
1
0%
0%
2
3
0%
0%
4
5
6
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. Growth hormone
deficiency
2. Hypothyroidism
3. Impotence
4. Infertility
5. Osteoporosis
0%
1
0%
0%
2
3
0%
0%
4
5
6
Chemotherapy effects
Chemotherapy with alkylating agents
Females:
less effects than males
normal puberty
early menopause
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
0%
1
0%
0%
2
3
0%
0%
4
5
6
GVHD ( Graft vs Host disease): All are true
except
1.
2.
3.
4.
5.
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
0%
1
0%
0%
2
3
0%
0%
4
5
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
GOOD LUCK