Chapter (11) Hematology and Oncology Lectures for

Undergraduates

Intended learning outcomes: by the end of this chapter the student should be able to:
1- Identify etiology, clinical picture and treatment of anemias
2- Recognize bleeding disorders and indication of blood component transfusion
3- Define abnormalities of other blood cell components with differential diagnosis of splenomegally,
lymphadenopathy and abdominal masses
4- Understand the most common pediatric oncologic disorders mainly leukemias

Hemostasis and bleeding disorders

Physiology: As a result of injury to the blood vessel endothelium, three events take place
simultaneously:
1. Reactive vasoconstriction at the site of injury.
2. Platelet plug formation (1ry hemostatic mechanism).
3. F ibrin thrombus formation due to activation of clotting mechanism (2ry hemostatic
mechanism).
When to suspect bleeding or hemostatic disorder ( Symptoms ):
1- Repeated prolonged spontaneous heavy bleeding.
2- Bleeding from more than one orifice.
3- Easy bruising, ecchymosis and petechiae.
4- Prolonged bleeding after minor trauma or wounds.
5- Prolonged Bleeding after surgery and OR repeated hemarthrosis; (Hemophilia)

Bleeding Disorders
Abnormal bleeding includes either purpura (platelet defects and vascular disorders) OR
defective coagulation. OR both.
Etiologic classification:
1. Vascular disorders
2. Platelet disorders (Quantitative = thrombocytopenia or Qualitative = thrombasthenia)
3. Coagulation defects (Inherited = hemophilia Or Acquired)

1. Purpura
It is a clinical term (bleeding in skin and mucous membrane). It may be vascular OR
platelet defect either; thrombocytopenic or non-thrombocytopenic.
1. Vascular Bleeding Disorders
A heterogeneous group of conditions characterized by easy bruising and spontaneous
bleeding from the small vessels. It is a palpable purpura. Vascular defects may be
inherited or acquired.
a. Hereditary hemorrhagic telangiectasia; autosomal dominant.
b. Acquired:
1. Purpura associated with infections e.g. septcemia as a part of DIC or meningiococcal
septicemia.
2. Henoch-Schönlein purpura (revise your immunology chapter)
3. Collagen disorders e.g. SLE (more during adolescence specially females)
4. Scurvy: vitamin C deficiency (extremely rare).

Fig :1 coagulation
cascade
www.slideshare.net

Fig :2 Secondary
Hemostatic Mechanism.
www.eclinpath.com
2. Platelet Disorders
1. Quantitative:
- Decreased marrow production.
- Abnormal distribution in hemangiomas
- Increased platelet destruction.
- Combined decreased production and increased destruction (antenatal infection).
2. Qualitative:
Hereditary: as von Willebrand disease type 2B and thrombasthenia (as Glanzmann).
Both are not uncommon
Acquired: due to drugs like salicylates.
3. Quantitative and qualitative: as
Bernard Soulier syndrome, May-Hegglin Anomaly (mild thrombocytopenia
with giant platelets).
I) Quantitative platelet defects (Thrombocytopenic
Purpura)
Characterized by spontaneous skin purpura ecchymosis and hemorrhage.
Causes of thrombocytopenia:
1) Failure of platelet production:
1. Congenital defects: e.g.
- TAR syndrome (Thrombocytopenia with absent radius).
- Fanconi anemia (pancytopenia) + Features + chromosomal breakage; autosomal
recessive (AR).
2. Acquired defects:
- Infections: viral or protozoal e.g. malaria.
- Drugs: Cytotoxic, cotrimoxazole, and penicillamine.
- Myelodysplasia and bone marrow failure.
- Malignant infiltrations: as in leukemia, advanced lymphoma and metastases.
- Ionizing radiation and radiotherapy.
2) Abnormal distribution: (sequestration)
- Splenomegaly
- Giant hemangioma (Kasabach Merritt syndrome).
3) Increased destruction (Decreased platelet survival):
A-Immune-mediated:
- Idiopathic thrombocytopenia (ITP).
- Autoimmune diseases as SLE.
- Drug induced as heparin.
 - Infections (viral as varicella, Flue, CMV, EBV, (HIV in Africa and HCV in
Egyptians adults and after MMR vaccination).
- Post-transfusion (Antibodies against P antigen).
- Neonatal thrombocytopenia:
* Isoimmune (Platelet Ag1-ve mother, and +ve infant (incompatibility).
* Autoimmune (maternal antibodies as in ITP and SLE).
B- Non-immune destruction: as DIC, hemolytic uremic syndrome (HUS) in
children and thrombotic thrombocytopenic purpura (TTP) during adolescence.

II) Qualitative Platelet Defects

A. Congenital:
1- von Willebrand disease:
- Three types; I, II and III mostly Autosomal Recessive.

Fig (4): Inheritance of vW disease (http://www.hog.org/handbook/section/2/the-

inheritance)
- There is reduced vWF which promotes platelet adhesion and provides a carrier
molecule for FVIII, protecting it from premature destruction.
- Clinically presented with mucous membrane bleeding specially menorrhagia
There is defective platelet aggregation by vWAg while aggregation by ADP and
collagen is normal.
- Abnormal platelet adhesion with lower factor VIII activity.
- Prolonged both (BT, PTT) + low F VIII + vWF activity (decreased vW antigen).
- Treatment:
Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP), a synthetic vasopressin
analog, increases endogenous VWF by secretion from its natural site of synthesis and
storage, the vascular endothelial cell, following intravenous, subcutaneous, or intranasal
administration (which typically increase plasma VWF: FVIII levels two-fold to four-fold
above the baseline within 30 min, and in general high levels last in the plasma for 6–8 h).
It is effective in von Willebrand disease (VWD) type 1, not in VWD type 3, and of variable
efficacy in VWD type 2, with particular concern regarding transient thrombocytopenia in
type 2B VWD (gain of- function mutation). Limitations of this therapy include
tachyphylaxis, hyponatremic seizures, or arterial thrombosis in elderly patients with
atherosclerotic disease.
When desmopressin is not effective, VWF containing factor concentrates (some with
variable amounts of FVIII) are used. These products have been used for several years in
children and adults without major complications. There is current emphasis on secondary
long-term prophylaxis with VWF–CFCs for severe VWD patients with multiple
hemarthroses, recurrent gastrointestinal bleeding, or frequent severe epistaxis.

Recombinant VWF has recently been entered into clinical trials and has been shown to
have a higher level of high
molecular weight VWF multimers than normal plasma derived VWF

2- Glanzmann' s Thrombasthenia:
-Presented with mucous membrane bleeding especially petechial and epistaxis.
Defective platelet aggregation to ADP and collagen due to deficiency of platelet
glycoprotein IIb & IIIa.
B. Acquired:
1. Aspirin therapy. 2. Uremia. 3. Heparin.
III) Qualitative + Quantitative Purpura
Bernard Soulier syndrome
- Large platelets with deficiency of glycoproteins Ib.
- Platelets don't aggregate with ristocetin like in VW disease there is also
thrombocytopenia.

Laboratory tests for platelet disorders

Platelet count
Low (normal 150-400x109/L) Normal
Bleeding time (PFA 100)

Abnormal Normal
- Blood film: few platelets & size
blasts, red cell morphological changes, .
Coagulation profile
- Bone marrow aspiration for - Platelet aggregation
marrow infiltration or aplasia. - Platelet adhesion PT, PTT
- Platelet antibodies. - VWF assay Clotting factors assays
- Screening for DIC.
- Other tests: STORCH-EB(NW).
 Idiopathic (Immune) Thrombocytopenia (ITP)
Newly diagnosed (Acute) ITP: (platelet count < 100,000/mm3) in the 1st 3
months
- It is uncommon in children and usually follows viral infections as measles, varicella,
EBV or vaccinations specially MMR vaccination.
- occurs about 2 weeks post viral as purpura, ecchymosis all over the body with epistaxis
and or gum bleeding.
- No pallor, or lymphadenopathy or organomegaly. No bone aches
- Spontaneous remissions are usual in 60% within 3 months while 10-15 % may persists
from 3-12 months however in 25-30% of cases the disease runs a chronic course (lasts
for more than one year ).
- Short term steroids or intravenous immunoglobulin (IVIG) are sometimes used.
- No platelet transfusion is needed because of the immediate destruction except if IVIG is
given prior to platelet transfusion.
- Thrombocytopenia may persist beyond 3 months up to one year or more.

Chronic ITP:
- Thrombocytopenia (Platelet count < 100,000/mm3) lasts for more than one year.
- May be idiopathic or as a part of other diseases as SLE, HIV, Hodgkin's disease or +
autoimmune hemolytic anemia (Evan's syndrome; it is more difficult to treat).
- The onset is insidious with less severe hemorrhages than in acute ITP.
- The spleen is usually not felt except with other associated diseases.
- The diagnosis is based on the clinical picture and presence of low platelet count with
increased juvenile megakaryocytes in BM with no other abnormality (figure 5).
Treatment:
- Supportive care: avoid both trauma and unnecessary medications. In severe bleeding
or platelet count < 10,000 /mm3 :- Give short course of Steroids , IVIG, OR anti-D
immunoglobulin and rarely splenectomy in chronic refractory ITP
- Platelet transfusion has no role except in life-threatening bleeding after giving IVIG.
-

Figure (5): Bone marrow picture in Figure (6): Hemoarthrosis with

ITP (http://imagebank.hematology.org) hemophilia (WWW.Dovepress.com)

SUMMARY OF ITP TREATMENT

 2. Coagulation Disorders
a) Hemophilia A
- Factor VIII deficiency
- Sex-linked recessive disorder; inheritance from maternal side.
- 33% have no family history with spontaneous mutations.
Clinical features:
- Early: cephalhematoma, profuse bleeding after circumcision or tooth extraction.
- Late: recurrent painful joint bleeding (hemo-arthrosis); if bleeding occurred in same
joint repeatedly ( target joint ) as knees, ankles or elbows(figure 6) and muscle
hematomas with progressive deformity and crippling.
- The clinical severity of the disease correlates with the degree or severity of the factor
deficiency.
Severe form: F VIII < 1 %
Moderate form: F VIII 1-5 %
Mild form: F VIII > 5 % - 30%
- Operative and post-traumatic hemorrhages are life-threatening both in severely and
mildly affected patients. Spontaneous intracerebral hemorrhage or induced by mild
trauma may occur and may be the leading cause of death.
Laboratory findings:
1. Prolonged activated partial thromboplastin time (APTT) .
2. Normal prothrombin time (PT)
3. Factor VIII assay: low F VIII activity.
4. F VIII genotype if possible
Antenatal diagnosis: is feasible
Treatment: Replacement therapy with cryoprecipitate or factor VIII plasma derived or
recombinant either episodic or as prophylactic. Screening for f-VIII inhibitors
KEY POINTS IN HEMOPHILIA TREATMENT

Products for Factor VIII Replacement

Approximate concentration
Product Factor content
of factor (μ/ml)
Fresh frozen plasma All factors 1
Cryoprecipitate F VIII, vWF, Fibrinogen 5 – 10
Factor VIII concentrates F VIII + Vwf 20 – 25
- Desmopressin (DDAVP): to raise factor VIII in mild cases. It stimulates vWF
release from stores. Dose: 0.3 -0.4 μg/kg/12 hs.
- Other pharmaceutical agents include:
a. Epsilon aminocaproic acid (EACA) and Tranexamic: antifibrinolytic agents
c. Analgesics to control pain in hemarthrosis as acetaminophen (not aspirin).
Complications of hemophilia:
- Serious life-threatening hemorrhage as intracranial hemorrhage.
- Joint deformity and limitation of movement.
- Viral or non viral transmission after plasma transfusion therapy ( very rare ).
- Formation of Factor VIII inhibitors.
 b) Hemophilia B
- Factor IX deficiency
- Sex-linked recessive disorder (as in hemophilia A).
- C/P like hemophilia A, but most of cases are mild with rarely serious bleeding.
- Treated with fresh OR fresh frozen plasma OR f IX replacement.

c) Acquired disorders of hemostasis

1) Vitamin K deficiency: due to
a- Inadequate supply and decreased gut flora (as in hemorrhagic disease of the
newborn) Early 2nd -6th days post conception or late 6-24 weeks.
b- Impaired absorption due to lack of bile salts (obstructive jaundice).
c- Liver diseases:
- Decreased vitamin K dependent factors (II, VII, IX, X).
- Decreased fibrinogen and factors V, XI, XII, and XIII.
- Other factors which act as antifibrinolytic.
d - Disseminated intravascular coagulopathy (DIC): complicating fulminant sepsis,
shock, hypoxia and acidosis resulting in widespread pathologic activation of
coagulation with trapping of platelets resulting in microthrombi and severe bleeding.
 ANEMIA
DEFINITION
Abnormally low hemoglobin (Hb), hematocrit (PCV) and red cell count
below the normal (cut-off) values for age and sex.
At birth, normal Hb is 19 +/- 2 gm/dl
The fall in Hb conc. during the first two to three months of life is physiological
Anemia is defined as Hb concentration
• <11 gm/dl till age of 5 yrs
• <11.5 gm/dl between 5 & 9 yrs
• <12gm/dl between 9 & 12 yrs
After adolescence lower values of normal Hb concentration are
• In girls >12 years: 12 gm/dl
• In boys
->12-14 years: 12.5gm/dl
-14-18 years: 13gm/dl
->18 years and later: 14gm/dl
CLASSIFICATION OF ANEMIAS
• Nutritional anemias mainly including iron deficiency anemia and megaloblastic
anemias (folate and B12 deficiency)
• Hypoplastic anemias including congenital and acquired aplastic anemias
• Hemolytic anemias including hereditary hemolytic anemias and acquired immune
and non-immune hemolytic anemias.
• Others as anemia of chronic disease, infection, malignancy, collagen disease, anemia
2ry to bone marrow infiltration and autoimmune hemolytic anemia.
IRON DEFICIENCY ANEMIA
Iron deficiency anemia
Iron deficiency is defined as decreased total iron body content. Iron deficiency anemia
occurs when iron deficiency is severe enough to diminish erythropoiesis and cause the
development of anemia. Iron deficiency is the most prevalent single deficiency state on a
worldwide basis
Daily Iron requirements: 1 - 2 mg / kg / Day (10% absorbed)
Food iron content:
▪ Breast milk and cow milk 0.5 - 1.5 mg / L
Iron absorption 49 % from breast milk & 10 % from cow milk
▪ Food Sources of Iron
➢ Easily Absorbed: contain iron as heme: Beef, Lamb, Chicken and Turkey
(especially dark meat), Liver, Oily Fish, Meat Products
➢ Less Easily Absorbed: non-heme iron: Fortified breakfast cereals, Pulses (peas,
beans, lentils), Bread, Dried fruit (apricots, figs), Dark green vegetables (spinach,
broccoli), Eggs
The iron in red meat is absorbed up to seven times more easily than the iron in vegetables,
cereals and fruits
Substances that diminish the absorption of ferrous and ferric iron include phytates,
oxalates, phosphates, carbonates, and tannates

Etiology of iron deficiency

1-Dietary factors
▪ In infants and young children, iron deficiency results from rapid growth and
inadequate intake
▪ Exclusively breast-fed FT infants for more than 6months and preterm infants for
more than 2 months will develop iron deficiency
2-Blood loss
Bleeding for any reason produces iron depletion, and if severe or persistent iron
deficiency anemia develops. Common causes in infancy and childhood are:
▪ Cow milk intolerance
▪ Parasitic infections
▪ Inflammatory Bowel Diseases
▪ Menorrhagia in adolescent girls
▪ Aspirin ingestion and non-steroidal anti-inflammatory drugs causing gastritis
3-Malabsorption of iron
▪ Prolonged achlorhydria may produce iron deficiency because gastric acid is
required to release ferric iron from food.
▪ Extensive surgical removal of the proximal small bowel or chronic diseases (eg,
untreated sprue or celiac syndrome)
▪ Chronic diarrhea and celiac disease
Tissue effects of iron deficiency
• GIT: Anorexia, Picca, Glossitis, Dysphagia
• CVS: Tachycardia, cardiomegaly and functional murmurs
• Musculoskeletal System: decreased muscle work capacity
• Immunologic System: mild lymphocyte and neutrophil dysfunction
• CNS: Impaired intellectual functions and behavioral disorders have been described
in severe cases
Iron deficiency anemia: Diagnostic tests
1-Blood Smear AND Blood Indices
• Hypochromic microcytic red cells
• MCV < Normal for age
• MCH < 27.0 pg
• MCHC < 30%
• Wide Red Cell Distribution Width( RDW )
2- Iron profile
• Serum Ferritin Decreased
• Serum IRON Decreased
 • Increased Iron Binding Capacity
• Decreased transferrin iron saturation (16% or less)
3-Free erythrocyte protoporphyrin FEPP elevated
4-Therapeutic response to iron therapy
5- Bone Marrow Examination: delayed cytoplasmic maturation, decreased or absent
stainable iron; but usually not indicated
6- Specific diagnostic workup to detect possible etiologies
Management
Treatment of iron deficiency anemia consists of correcting the underlying etiology and
replenishing iron stores. Iron therapy is as follows:
• Oral ferrous iron salts are the most economical and effective form
• The oral dose is 4-6 mg/kg/day of elemental iron, best on empty stomach, not taken
with milk product, given as 3/day
• Duration of oral therapy is 6-8 weeks after Hb returns normal to replete iron stores
• Ferrous sulfate is the most commonly used iron salt
• Better absorption and lower morbidity have been claimed for other iron salts
• Toxicity is generally proportional to the amount of iron available for absorption
• Reserve parenteral iron for patients who are either unable to absorb oral iron or who
have increasing anemia despite adequate doses of oral iron
• Reserve transfusion of packed RBCs for patients who are experiencing significant
acute bleeding or are in danger of hypoxia and/or coronary insufficiency
• Response assessment: reticulocytosis within few days after initiation of oral iron
therapy and Hb rise by at least 1gm /dl 4 weeks after starting therapy.
Causes of Failure to respond to oral iron therapy
1-Persistent or unrecognized blood loss
2-Defective administration, dose, preparation
3-Coexistent disease that interferes with iron absorption or utilization
• Infection (functional iron deficiency)
• Malignancy
• Chronic hepatic or renal disease
• Concomittant deficiencies of B12, folate as in nutritional anemia
• Concomittant deficiency of thyroid hormones
• Lead poisoning
• IRIDA: Iron refractory iron deficiency anemia, due to excess hepcidin

Megaloblastic anemias
Characteristics:
• Macrocytes in Peripheral Blood
• Megaloblasts in Bone Marrow
• Associating mild-to moderate thrombocytopenia and/or neutropenia
Etiology:
•
 > 95 % due to folate and B12 deficiency
• Congenital disorders of DNA synthesis
• Acquired defects in DNA synthesis as liver disease; S.A.; Leukemia; Aplastic
anemia
• Drug induced as antimetabolites
Folate deficiency
• relatively uncommon
• Boiling foods causes loss of 40% of folate
Folate deficiency can occur if the infant/child
▪ Infant on pure goat milk diet (6ugm/L)
▪ has chronic diarrhea
▪ on prolonged broad spectrum antibiotics
▪ has jejunal resection
▪ enhanced erythropoiesis
▪ has chronic hemolytic anemia
▪ severe malnutrition
▪ Drugs as methotrexate, pyremethamine, and trimethoprim
▪ Inborn errors of folate transport and metabolism

Vitamin B12 deficiency

Causes
Inadequate intake :< 2mg/day
• Malnutrition
• Severe maternal deficiency in breast-fed infants
Defective absorption
• Failure to secrete IF (congenital, autoimmune, acquired as corrosives)
• Specific B12 malabsorption: absent IF, congenital ileal transport defect “Imerslund
Grasbeck S.”, congenital deficiency of TCII, chelating agents as EDTA and
phytates)
• Generalized malabsorption
• Competition for B12 : small bowel bacterial overgrowth , Diphyllobothrium latum
infestation
Clinical features of megaloblastic anemias
1. Insiduous:Pallor, lethargy,anorexia,sore red tongue, glossitis,± diarrhea
2. Suggestive history
3. Vit.B12 deficiency is also associated with neurological manifestations
• Infants: neurodevelopmental delay, hypotonia, athetoid movements
• Older Children: subacute dorsolumbar degeneration of the cord
4. Easy bruising from associating thrombocytopenia
Megaloblastic anemia: diagnosis
 • RBCs: Hb reduced; MCV increased; MCHC Normal; RDW increased; Blood Film
Macrocytes ; Anisocytosis ; Poikilocytosis
• WBCs: Leucopenia and hypersegmented neutrophils
• PLTs: Moderately decreased
• BONE MARROW : Cells are large( megaloblastic ) , open stippled nucleus ;
nuclear - cytoplasmic dissociation ; frequent mitosis ; Hypersegmented nutrophils
; Megakaryocytes: increased lobulation
• Serum B12 ( N: 200 - 800 pg )
• Serum folate ( < 3 ng/ml is low ) and red cell folate ( N : 74 - 640 ng / ml )
Therapy of folate deficiency
1. Oral folate 5-15 mg/ day for at least 2 weeks up to several months in a dose of
1mg/day
2. Vitamin B12 deficiency should be ruled out
3. Response assessment
➢ Retics reach peak at 4 - 7 days
➢ Hb returns to normal in 2 - 6 weeks
3. Treatment of the cause
4. Chronic hemolytic disease should receive oral folate as routine in dose of 1-5mg
/ day
THERAPY OF VITAMIN B12 DEFICIENCY
1. Prophylactic in at risk patients
2. Active therapy :
Monthly IM 50 - 100 ug Vit. B 12
3. Response assessment
➢ Retics peak after 6 -8 days
➢ BM megaloblastic changes are completely reversed in 72 hours after therapy
onset

Anemia in bone marrow failure syndromes

A- Isolated red cell bone marrow failure
Congenital
➢ Pure red cell aplasia ( Diamond Blackfan )

➢ Congenital dyserythropoietic anemia ( CDA )

Acquired
Transient erythroblastopenia
➢ Idiopathic ( TEC: transient erythroblastopenia of childhood )
➢ Secondary : Drugs, infection, malnutrition , chronic hemolytic anemia
(parvovirus B19 )
➢ Acquired pure red cell aplasia

Pure red cell aplasia ( Diamond-Blackfan anemia )

 Inheritance AR , AD , X-linked. Erythroid progenitor cell is abnormally absent or
scanty in the bone marrow
Clinical Picture
• Anemia and pallor develop in the first 3 months of age
• No hepatosplenomegaly
• In 25% associated congenital anomalies (short stature , skeletal ,heart , urinary
tract, craniofacial )
Investigations
• Macrocytic anemia with reticulocytopenia
• Platelet and white cell count normal
• BM : virtual absence of erythroid precursors
• Chromosomal studies are normal
• Potentially malignant : ALL,AML,Hepatocellular carcinoma
Treatment Options
• Transfusion therapy
• Steroids
• Bone marrow transplantation

Transient erythroblastopenia of childhood (TEC)

Transient humoral suppression of erythropoiesis
Onset of anemia: between 6 months and 4 years
Equal sex
Laboratory investigations
• Normocytic anemia ( Hb 3-8 gm/dl ); Retics 0% ; Normal WBCs and PLT
• BM absence of red cell precursors
Therapy supportive red cell transfusion (if needed) and folic acid
Prognosis: Spontaneous recovery in weeks to months

B- Aplastic anemia

Aplastic anemia definition

Presence of pancytopenia with reticulocytopenia and bone marrow hypoplasia
Pancytopenia definition
Describes decrease in all blood cell lines
• Anemia (Hb less than 10 gm/dl)
• Neutropenia ( less than 1,500/cmm)
• Thrombocytopenia (PLT less than 100,000/cmm)
Bicytopenia definition
Bicytopenia means decrease in two of three cell lines, and may suggest pancytopenia in
development

1- Hereditary aplastic anemia :Fanconi anemia

➢ Autosomal recessive(AR) disease characterized by
• Pancytopenia ; onset at 4-12 years
• Macrocytic anemia with reticulocytopenia ,
• BM hypocellularity and fatty replacement
• Congenital anomalies : pachy skin pigmentation, short stature , skeletal anomalies
(thumb, radius, long bones ) , hypogonadism , microcephaly , deafness , MR ,
renal and cardiac anomalies
• Chromosomal studies show chromosomal breakages and structural anomalies
➢ Associated with higher incidence of leukemia mainly AML
➢ Treatment : supportive treatment and bone marrow transplantation

2- Acquired aplastic anemia

Aplastic anemia (AA) is a rare disorder characterized by pancytopenia and a hypocellular
bone marrow. Injury to or loss of pluripotent hematopoietic stem cells, in the absence of
infiltrative disease of the bone marrow, is the major pathophysiologic characteristic of the
disease.
Etiology of Acquired Aplastic Anemia
1. Viral Infection
Well-documented association of viruses with aplastic anemia
• Parvovirus B19
• HIV
• EBV
• Type C hepatitis (HCV) , HAV and HBV .The onset of AA may be either during
the acute or recovery phase of hepatitis .
2. Drugs & Chemicals
• The most frequently known precursor of AA
• Some agents, such as chloramphenicol, benzene, ionizing radiation and
antineoplastic agents, cause an aplasia that is dose related, vary in severity from
person to person and usually allow marrow recovery after withdrawal of the agent.
• Other agents, including pesticides and some anticonvulsants and antimicrobials like
chloramphenicol and sulphonamides cause a reaction which is not dose related and
therefore cannot be predicted with hematological monitoring during administration
as the aplasia may occur even after cessation of drug therapy.
3- Idiopathic Aplastic Anemia
• No specific cause can be named in > 70% of AA cases: IDIOPATHIC APLASTIC
ANEMIA
• An immune pathogenesis, without recognizable association of virus- or drug-
associated disease, may be the underlying factor in the majority of AA cases
• The successful treatment of both mild and severe AA with immunosuppressive
agents supports this theory
Diagnostic evaluation
• Detailed history of drug , toxin , radiation, family history
 • Blood count ; absolute retics and neutrophil count . Low plat.count
• ANA and Anti DNA ; Rhd factor ; liver function tests ; tuberculin test
• BM aspirate and biopsy : hypoplastic marrow ( decreased cellularity and
replacement of normal marrow elements by fibrofatty tissues )
• Cytogenetic studies on blood lymphocytes using mitogen stimulation to
diagnose Fanconi anemia
• Cytogenetic studies on BM to diagnose myelodysplasia (MDS)
• Viral serology : mainly hepatitis A , B and C , EBV , HIV
• Skeletal x-rays , IVP , chest x-ray : for associating anomalies in Fanconi anemia

Treatment outlines
Regardless of the cause, AA is a disease which requires intensive treatment
1. Avoidance of precipitating factor
2. Supportive care: for Infection ,bleeding ,anemia
3. Bone marrow transplant: from HLA -matched donor
4. Immunosuppressive therapy
5. Others as high-dose steroids
Immunosuppressive Therapy in Acquired Aplastic Anemia using:
▪ Animal antisera to human leukocytes (ALG) or thymocytes (ATG):
Possible main mechanism of action include: immunosuppression with
destruction of cytotoxic T cells. Hematologic response is usually evident within
several months; transfusion independence may be evident by 2 to 3 months after
initiating therapy. Relapse rates are 5-10%. Response rate 30-70%
▪ Corticosteroids are usually administered in conjunction with ALG or ATG to
decrease side effects.
▪ Other immunosuppressive agents, such as androgens or cyclosporine A (CSA),
tested alone, have achieved low or variable results.
▪ The combination of ATG, high dose methylprednisone and androgens show a 74%
response rate

Hemolytic anemias in pediatrics

I. Hemolytic anemias due to corpuscular defects
A. Membrane defects
 Primary : Hereditary spherocytosis , Hereditary elliptocytosis ,Hereditary
stomatocytosis
 Secondary : Abetalipoproteinemia
B. Enzyme defects
 Energy potential defects : hexokinase, phosphofructokinase , pyruvate kinase
 Reduction potential defects : G6PD , 6PGD ,Glutathione enzymes
C. Hemoglobin defects
 Heme : Congenital erythrpoietic porphyria
  Globin :
➢ Quantitative : alpha and beta thalassemia
➢ Qualitative:Hemoglobinopathies (Hb S, C, H, M )
D. Congenital dyserythropoietic anemia

II. Hemolytic anemias due to extracorpuscular defects

1. Isoimmune
 Hemolytic disease of the newborn
 Incompatible blood transfusion
2. Autoimmune
 Idiopathic
 Secondary : Infection ; Drugs ; Hematological disorders ; Immunological disorders
; Tumours
3. Non-immune extracorpuscular hemolytic anemias
 Idiopathic
 Infection: EBV , VH , septicemia , malaria
 Drugs : phenacetin , lead , benzene , vitamin K , phenylhydrazine
 Microangiopathic hemolytic anemia : Thrombotic thrombocytopenic purpura ,
hemolytic uremic syndrome , burns , post-cardiac surgery
 Miscellaneous : Wilson disease , erythropoietic porphyria , hypersplenism

Laboratory tests used to demonstrate hemolytic process

i - Related to accelerated hemoglobin catabolism
▪ Increased indirect serum bilirubin level
▪ Increased Urine urobilinogen excretion
▪ Increased Fecal urobilinogen excretion
▪ Decreased serum Haptoglobin level
▪ Increased Serum lactate dehydrogenase ( LDH )
▪ In Urine : hemoglobinuria and hemosiderinuria
▪ Blood smear : red cell fragments (schistocytes ) , spherocytes
II- RELATED TO INCREASED ERYTHROPOIESIS
▪ Increased Reticulocyte count
▪ Macrocytosis
▪ Normoblastemia
▪ Spherocytosis
▪ BM : erythroid hyperplasia
▪ Radiography : hair on end appearance

G6PD deficiency
• G6PD catalyses the first step in the hexose monophosphate(HMP) shunt which is necessary
• for producing NADPH. NADPH is required for the maintenance of reduced glutathione (GSH)
that protects the RBC from oxidative damage
• G6PD deficiency is the most common red cell enzymopathy that affect 400 million people
worldwide.
• G6PD deficiency is X-linked disorder caused by different mutations in the G6PD gene,
resulting in protein variants with different levels of enzyme activity that are associated with a
wide range of biochemical and clinical phenotypes.
• It is X-linked recessive disorder that affects males; with variable expression in carrier females.
Clinical Manifestations
• Major clinical manifestations are acute hemolytic anemia after infection or ingestion of
drug or fava Beans and/or neonatal jaundice. A very small proportion of G6PD-
deficient individuals have a chronic hemolytic anemia variant
• Favism presents as an acute hemolytic crisis, usually after 24 to 72 h of ingestion of
fava beans with severe intravascular hemolytic anemia (sometimes requiring blood
transfusion) and hemoglobinuria (dark urine) and indirect hyperbilirubinemia(jaundice)
• Drugs capable of producing an acute haemolytic crisis in G6PD deficiency can be
classified into two main groups:
1- Drugs that have been shown to be capable of producing clinically significant
haemolytic anaemia in doses that are normally used including:
2- Drugs that have been shown to have a minor effect on red cell survival when
given in large doses, such as aspirin, but which can be given safely to most
patients with G6PD deficiency (Table ).
• Infection is the most common cause of acute hemolysis in G6PD-deficient persons,
although the exact mechanism by which this occurs is unknown. The most common
infectious agents causing hemolysis include Salmonella, Escherichia coli, beta-hemolytic
streptococci, rickettsial infections, viral hepatitis, and influenza A
• Patients with the rare chronic hemolytic anemia variant of G6PD deficiency have, in
general, a history of severe neonatal jaundice, chronic anaemia exacerbated by
oxidative stress, blood transfusion requirement, splenomegaly and gallstones at early
age.
Figure 2: MGG stained blood smear from a patient with G6PD deficiency and
Table : Drugs and G6PD Deficiency
WHO Classification of G6PD variants
Classified according to the severity of the clinical phenotype
• Class I: severe enzyme deficiency with chronic nonspherocytic haemolytic
anaemia
• Class II: severe enzyme deficiency (less than 10% of normal)
• Class III: moderate-to-mild enzyme deficiency (10%-60% of normal)
• Class IV: mild or no enzyme deficiency (60%-100% of normal)
• Class V: increased enzyme activity more than twice normal
➢ There appeared to be 2 types of mutations among Africans: G6PD A, a normally active
enzyme with rapid electrophoretic mobility, and G6PD A–, an enzyme with the same
mobility as G6PD A, but with diminished activity [mostly Class III WHO phenotype]
➢ The enzyme variant found in Mediterranean subjects was designated as G6PD B– but
Now known as G6PD Mediterranean [mostly Class II WHO phenotype]

Diagnosis of G6PD Deficiency

1. G6PD deficiency can be diagnosed by red cell enzyme activity assay
2. CBC and blood film
• During hemolytic attacks CBC and blood film show shows Fragmented red cells
(shistocytes) ,spherocytes ,reticulocytosis, Heinz bodies in red cells
• Normal CBC and red cell morphology between attacks

Treatment and Prevention

➢ Nonspecific supportive measures such as red cell transfusions in severe hemolytic
anemia provide the only currently accepted approach
➢ Phototherapy is recommended in case of neonatal hyperbilirubinemia, but exchange
transfusion may become necessary in severe cases.
➢ G6PD-deficient patients should be advised to avoid fava beans and potentially
hemolytic drugs or, in case of necessary drugs, to ensure they are used in subhemolytic
doses.

Beta thalassemia
• Beta-thalassemia is one of most common autosomal recessive disorders worldwide and
the second most common hereditary anemia in Egypt after G6PD deficiency. High
prevalence is present in populations in the Mediterranean, Middle-East, Transcaucasus,
Central Asia, Indian subcontinent, and Far East.
• Beta-thalassemia is caused by the reduced (beta) or absent (beta0) synthesis of the beta
globin chains of the hemoglobin (Hb) tetramer (alpha2beta2), depending on the type of
gene mutation in the beta globin gene at chromosome 11.
• Within the red blood cell precursors, when the beta globin chains are reduced or absent,
the in excess alpha chains precipitate and lead to oxidative damage of the cell
membrane, thereby resulting in apoptosis (ineffective erythropoiesis). The clinical
severity of beta-thalassemia is related to the extent of imbalance between the alpha
globin and nonalpha globin chains. The nonalpha globin chains include, in addition to
the beta globin chains, also the gamma chains, which are a specific component of fetal
Hb (HbF; alpha2gamma2) and are present in a small amount in normal adult individuals
and in increased but variable amount in the beta-thalassemia syndromes.
• Three clinical and hematological conditions of increasing severity are recognized
➢ The beta-thalassemia carrier state, which results from heterozygosity for beta-
thalassemia, is clinically asymptomatic and is defined by specific hematological
features
➢ Thalassemia major is a severe transfusion-dependent anemia
➢ Thalassemia intermedia comprehend a clinically and genotypically very
heterogeneous group of thalassemia-like disorders, ranging in severity from the
asymptomatic state to the severe transfusion-dependent type.

Beta thalassemia major [Cooley’s anemia]

• Patients are homozygous for thalassemia gene [β0/ β0 or β0/ β+ ]
• Clinically: disease onset before 1 year with anemia, failure to thrive, jaundice, and
hepatosplenomegaly. If neglected : Mongoloid facies and Hair on end appearance in
skull x-ray
• Laboratory
1. Hypochromic microcytic anemia
2. Hemoglobin electrophoresis reveals
 ▪ Hb A is zero-30%
▪ Hb F 70-98%
▪ Hb A2 2-5%
3. Serum ferritin is normal or elevated in the presence of iron overload
Complications in untreated thalassemia major

http://www.thalassaemia.org.cy/about-haemoglobin-disorders/beta-
thalassaemia/management.shtml
Management of beta thalassemia major
Over the last three decades, clinical observations, studies and research have established
that thalassaemia major is a treatable condition.
The major components of life long treatment are
• Regular red cell transfusions to keep pre-transfusion hemoglobin at 9-10 gm/dl
• Iron chelation therapy to prevent and treat iron overload.Available iron chelators
include
➢ Desferroxamine [Desferral] given subcutaneous by special pump over 8-12
hours/day for 5-7 days/week. Can be given by continuous intravenous
infusion in severe iron overload and cardiac toxicity.
➢ Oral deferiprone [Ferroprox]
➢ Oral deferasirox [ Exjade]
• Management of complications related to excess iron deposition and toxicity in body
organs, mainly the Heart, Endocrine system , Liver and bone
 • Vitamin D and calcium for osteoporosis
• Prevention and management of transfusion-associated infections, hepatitis C virus
being most important.
• Bone marrow transplantation from HLA matched donor offers cure, but limited by
availability of donors
• Genetic counselling and antenatal diagnosis are available preventive measures

PREVENTION OF THALASSEMIA BY PREMARITAL SCREENING IS BEST

MEASURE OF MANAGEMENT

BETA THALASSEMIA MINOR

• Heterozygote for β or β+ gene mutation
0

• No organomegaly
• Hypochromic microcytic anemia
• Hb electrophoresis
Hb A2 > 4 % - F > 1 %
• DD: Iron deficiency anemia
ALPHA THALASSEMIAS
➢ There are 4 alpha genes on chromosome 16
➢ Absence of 1 or 2 genes (α α / α ; α +/ α +) : α Thalassemia trait : microcytosis
without anemia
➢ Absence of 3 out of 4 genes : Hemoglobin H disease , β4 (HbH) that usually
presents with picture of thalassemia intermedia
➢ Absence of 4 genes : Hydrops foetalis due to :Hb Bart (gamma4) : strong O2
affinity , so not delivered to tissues

SICKLE CELL DISEASE

➢ Sickle cell disease [SCD] is an autosomal recessive chronic hemolytic anemia that
results from mutation in the β globin gene on chromosome 11 resulting in the
presence of predominantly hemoglobin S (Hb S)
➢ Hb S results from a single nucleotide variant in Beta globin chain of hemoglobin,
changing the sixth amino acid in the β-hemoglobin chain from glutamic acid to valine
(Glu6Val).
➢ When red blood cells (RBCs) containing homozygous HbS are exposed to low
oxygen tension, the deoxygenation of Hb S induces formation of hemoglobin
polymers that disrupt the RBCs cytoskeleton and give rise to the characteristic rigid
sickle appearance [figure ] .Sickled red cells have short life span, are destroyed when
they pass by the spleen resulting in hemolytic anemia and they
➢ may cause obliteration of blood vessels causing vaso-occlusive crisis .
➢ Homozygosity for the sickle mutation (HbSS disease) is responsible for the most
common and most severe variant of SCD: sickle cell anemia.Other variants of SCD
 result from the interaction of different mutations of the human β-globin genes
including coinherited β-thalassemia gene ( sickle thalassemia) .

Difference between normal red cells and sickle red cells

Normal red cells Sickle red cells
Disc shaped Sickle shaped
Soft Hard
Easily flow through small blood vessels Often Stuck in small blood vessels
Lives for 120 days Often lives for 20 days or less

Clinical manifestations sickle cell anemia [homozygous state]

I. Vaso-occlusive Sickle Cell Crisis
The sites most often affected by the vaso-occlusive action of sickled cells are found in the
lungs, liver, bone, muscles, brain, spleen, penis, eyes, and kidneys.
Severe pain is the most common emergency in sickle cell disease (acute sickle cell crises
Painful sickle crisis may be precipitated by:
• Dehydration
• Infection
• Fever
• Hypoxia (decrease in oxygen to body tissue)
• Cold exposure
• Pregnancy and stress
Acute vaso-occlusive sickle cell crisis can manifest as
• Bone crisis: acute or sudden pain in a bone can occur, usually in an arm or leg: bone
ischemia can be complicated by infarction and secondary infection causing
osteomyelitis. Acute dactylitis in infants and young children can result in painful
swelling of hands and feet
• Acute chest syndrome: Sudden acute chest pain with dyspnea and coughing up to
hemoptysis. Low-grade fevers can be present. It should be differentiated from
pneumonia
• Abdominal crisis: Constant and sudden abdominal pain. The pain may or may not
be localized to any one area of the abdomen. Nausea, vomiting may or may not
occur.
• Joint crisis: Acute and painful joint crisis may develop without significant
traumatic history. Its focus is either in a single joint or in multiple joints. Avascular
necrosis of the hips can occur, causing permanent damage
 • Genitals: Priapism (a constant erection of the penis) is less common in children
than adults
II- Central Nervous System: STROKE
Stroke is serious complication in SCD due to occlusion of large cerebral vessels .Two thirds
of stroke in SCD start in childhood.
III- Defective immune system in SCD and patients are highly susceptible to infections
from certain forms of bacteria, especially streptococcus pneumonia , hemophilus influenza
, meningococcal infection, and salmonella
IV- Chronic hemolytic anemia with hyperhemolytic crises
V-Auto-splenectomy: repeated crises damage the spleen, resulting in decrease splenic
functions and functional autosplenectomy with increased liability for infections
VI- Kidneys: Some amount of kidney damage occurs in nearly every person with sickle
cell disease
VII-Sequestration crisis : intrasplenic or intrahepatic sickling prevents blood from leaving
the spleen or liver and acute engorgement occurs in the spleen ( only in young children) or
the liver .It manifests as acute onset of exagerated anemia , hypotension and shock with
enlargement of the involved organ .It is very serious life threatening condition
VIII-Hypoplastic crisis: bone marrow hypoplasia secondary to parvovirus infection results
in pancytopenia

Laboratory diagnosis of sickle cell anemia

• Normochromic normocytic anemia
• Sickling test : adding reducing agent as (Na
metabisulphite) causes sickling of red cells in
blood film
• Hemoglobin electrophoresis : reveals presence of
hemogloglobin S

Treatment of sickle cell disease

• Prevention of Vaso-occluve crisis: Good hydration, avoidance of precipitating
factors, hydroxyurea therapy
• Treatment of Vaso-occluve crisis: Good hydration, simple red cell transfusion or
exchange transfusion to decrease sickled red cells, analgesics for pain
• Infection: bacterial infection treated with antibiotics
• Anemia: may require red blood cell transfusion
• Hydroxyurea may be used to increase the amount of Hgb F and decrease the
amount of Hgb S, which can decrease the long-term risks of sickle cell crises

Congenital red cell membrane defects

▪ Molecular lesions of the red cell membrane proteins at the cell membrane skeleton level
including Spectrin ,Actin ,and Protein 4.1
▪ This results in regidity of the red cells and sequestration in the splenic capillaries
 They include the following diseases based on red cell shape in peripheral blood film:
• Hereditary spherocytosis : predominance of microspherocytes
• Hereditary ovalocytosis : predominance of ovalocytes : oval shaped red cells
• Hereditary stomatocytosis : predominance of stoma-shaped red cells

Hereditary spherocytosis (HS)

➢ In 75 percent of cases, hereditary spherocytosis is inherited in an autosomal dominant
pattern.
➢ Mutations in at least five genes cause hereditary spherocytosis
➢ Most newborns with hereditary spherocytosis have severe anemia, although it improves
after the first year of life.

Four phenotypes: according to the severity of signs and symptoms.

• Mild form [20 to 30 % of HS patients] : may have very mild anemia or sometimes
have no symptoms
• Moderate form [60 to 70 % of HS patients]: typically have anemia, jaundice, and
splenomegaly. Many also develop gallstones. The signs and symptoms of moderate
hereditary spherocytosis usually appear in childhood
• Moderate/severe form [10 % of HS patients]: have all the features of the moderate
form but also have severe anemia.
• Severe form [3 to 5 % of HS patients]: have life-threatening anemia that requires
frequent blood transfusions. They also have severe splenomegaly, jaundice, and a
high risk for developing gallstones.

Diagnosis of HS
• Presence of microspherocytes in peripheral blood film
• Increased osmotic fragility

Acquired autoimmune hemolytic anemia (aiha)

Classification and causes
• Warm antibody type: The most common antibody involved is IgG, sometimes
IgA.Hemolysis occur at body temperature (37oC)
➢ Causes :idiopathic, systemic lupus erythematosus (SLE), lymphoma, , Evans'
syndrome (thrombocytopenia associated with AIHA)
 • Cold antibody type: The most common antibody involved is IgM . Antibodies only
bind red blood cells at low body temperatures, typically 28-31°C and cause
hemolytic anemia
➢ Causes : cold haemagglutinin disease, paroxysmal cold haemoglobinuria,
Mycoplasma pneumoniae, lymphoma, infectious mononucleosis or other viral
infections
• Drug-related: drug absorbed on to red cell surface, eg penicillins, cephalosporins,
or immune complex mediated, eg sulphonamides, sulfasalazine

Warm Autoimmune Hemolytic Anemia (WAIHA)

➢ WAIHA is the most common of the autoimmune hemolytic diseases.
➢ About half of the cases are idiopathic, with the other half attributable to a predisposing
condition or medications being taken.
Pathophysiology
➢ The IgG antibodies attach to red blood cells, leaving their FC portion exposed
➢ The FC region is recognized and grabbed onto by FC receptors found on monocytes and
macrophages in the spleen
➢ These cells will pick off portions of the red cell membrane, almost like they are taking
a bite.
➢ The loss of membrane causes the red blood cells to become spherocytes. Spherocytes
are rigid and destroyed when they cross the red pulp of the spleen as well as other
portions of the reticuloendothelial system causing extravascular hemolytic anemia
➢ The red blood cells trapped in the spleen cause the spleen to enlarge, leading to the
splenomegaly
Clinical findings
• Pallor
• Jaundice
• Splenomegaly
• Features of the 1ry disease in non idiopathic WAIHA
Laboratory findings
• Severe anemia with increased mean corpuscular volume (MCV)
• Indirect hyperbilirubinemia
• Diagnosis is made by a positive direct Coombs test, that detects antibodies
attached to the surface of red blood cells.
Treatment
• Corticosteroid therapy is primary treatment for warm antibody AIHA.
• If refractory to steroids, other options include intravenous immunoglobulins ,
danazol, and immunosuppressive therapy including rituximab (antiCD20) ,
cyclosphosphamide, azathioprine, or cyclosporine.
• If refractory to medical therapy, splenectomy should be considered.
• Approach to diagnosis of a child with anemia

Full history taking :

Family history of consanguinity and/or similar conditions as in chronic

hemolytic anemia
Age of onset and course of anemia
Detailed nutritional history
History suggestive of chronic blood loss in iron deficiency anemia
History of preceding viral infection , drug intake , or certain types of
food as in favism
History of splenectomy , repeated transfusion , and chelation therapy
chronic hemolytic anemia
History of easy bruising and/or mucosal bleeding due to associating
thrombocytopenia as in aplastic anemia
History of jaundice and dark urine ( hemoglobinuria )
History of gall stones and/or cholecystectomy ( chronic hemolytic
anemia )

Complete clinical examination :

- Assessment of growth : stunted growth in chronic hemolytic anemia

- Signs of nutritional deficiencies as in iron deficiency anemia
- Examine for jaundice and hepatosplenomegaly ( chronic hemolysis)
- Skeletal anomalies as in Fanconi and Diamond Blackfan anemia
- Signs of pancytopenia as purpura , bruising , fulminant infections as
in aplastic anemia and leukemia
-Examine for lymphadenopathy and hepatosplenomegaly as in
hematological malgnancies
-Pubertal assessment : delayed in poorly chelated adolescents with
 chronic hemolytic anemia as in thalassemic patients
-Examine for associating congenital anomalies as cardiac and renal
anomalies in Fanconi anemia

Laboratory Investigations :
- CBC and blood film examination : including total and differential LC
, red cell morphology , plat. number and morphology , and presence of
abnormal or immature cells . Red cell indicies , Retics count, and RDW
should be also included
- Total and direct S.bilirubin for indirect hyperbilirubinemia in
hemolytic anemias
- Serum LDH and haptoglobin level for suspected hemolysis
- Specific laboratory workup for certain types of anemia as :
- HB Electrophoresis for hemoglobinopathies and thalassemias
- Osmotic fragility testing and EMA for hereditary spherocytosis
- Enzymatic assay for G6PD deficiency and other enzymopathies
- Coombs testing for autoimmune hemolytic anemia
- Serum iron profile for suspected cases of iron deficiency anemia
- Bone marrow aspiration and trephine marrow biopsy for suspected
cases of aplastic anemia and leukemias
- Chromosomal breakage study for suspected Fanconi anemia
- Molecular genetic testing as in thalassemia and siderobalstic anemia
 Lymphadenopathy and splenomegaly.
Lymphadenopathy and splenomegaly are common in pediatric age group. They can be
caused by benign and malignant conditions.
Lymphadenopathy
Lymph nodes are considered enlarged if their diameter exceeds 1 cm for cervical and
axillary nodes and 1.5 cm for inguinal nodes.
Causes of lymphadenopathy:
1. Localized lymphadenopathy: enlargement of one node region.
• Acute non-specific infection (staph., strept., cat scratch disease… etc.).
• Chronic non-specific infection (following repeated acute infections).
• Chronic specific infection (following BCG vaccination, TB).
• Kawasaki disease (mucocutaneous lymph node syndrome)
• Hodgkin lymphoma.
• Metastasis.
2. Generalized lymphadenopathy: enlargement of more than two non-
contiguous node regions.
• Bacterial infections: as TB, salmonella, brucellosis, syphilis… etc.
• Viral infections: as CMV, EBV, rubella, rubeola, varicella…. etc.
• Fungal infections: histoplasmosis, coccidiomycosis.
• Protozoal infestation e.g. toxoplasmosis.
• Neoplastic diseases as Hodgkin and Non Hodgkin lymphoma, leukemia,
metastasis, and histiocytosis.
• Connective tissue disorders as juvenile rheumatoid arthritis and systemic lupus
erythematosus.
• Hypersensitivity states as serum sickness and drug reactions (e.g. antithyroid
drugs).
• Granulomatous disease: as sarcoidosis and chronic granulomatous disease.
• Storage disease: as Gaucher disease and Niemann-Pick disease.
• Lymphoproliferative disorders
• Miscellaneous: Hyperthyroidism.
Clinical and diagnostic approach to lymphadenopathy
1. History:
Duration of lymphadenopathy, history of persistent or recurrent fever, sore throat,
cough, easy bruising, limb pain, weight loss, night sweats, history of contact with
animals as cats or rodents, note all recent medications given.
2. Physical examination:
• General examination for hepatosplenomegaly, petichiae, thyroid enlargement,
arthritis, conjunctivitis, rash.
• Local lymph node examination:
a) Site:
• enlarged tonsillar and inguinal LN is likely to be due to localized infection.
• enlarged supraclavicular and axillary LN is most likely due to serious
disease.
b) Size: nodes bigger than 2.5 cm and nodes progressively increasing in size are
pathologic.
c) Consistency: lymph nodes due to infection or inflammation are warm, tender
and fluctuant, lymph nodes due to malignancy are firm, rubbery, not tender and
matted.
3. Investigations:
• Complete blood count, ESR.
• Bacteriologic culture of regional lesion (e.g throat).
• Skin test for TB and cat scratch disease.
• Serological test for EBV, CMV and toxoplasmosis.
• Chest X-ray and CT scan ( if indicated).
• Abdominal ultrasound and CT (if indicated).
• Bone marrow examination ( if hematologic abnormality is suspected).
• Lymph node aspiration and culture; helpful in isolating the causative organism and
deciding on an appropriate antibiotic when infection is the cause of the
lymphadenopathy
Lymph node biopsy:
Indications:
▪ If malignancy is suspected by history and physical examination.
▪ Size of lymph nodes is greater than 2.5 cm.
▪ Increase in size over base line in 2 weeks.
▪ No decrease in size in 4-6 weeks.
▪ Failure of shrinkage of LN after appropriate antibiotic therapy within 1 month.
 Figure 1 Diagnostic Approach of cervical Lymphadenopathy
Splenomegaly
The tip of the spleen is frequently palpable in otherwise normal infants and young children.
It is usually palpable in premature infants and in about 30% of full-term infants. It may
normally be felt in children up to 3 or 4 years of age. At an older age, the spleen tip is
generally not palpable below the costal margin and a palpable spleen usually indicates
splenic enlargement two to three times its normal size.
Causes of splenomegaly:
1- Hematologic disorders:
A) Hemoglobinopathies (sickle cell disease in infancy, sickle variants, thalassemia
major).
B) Spherocytosis.
C) Osteopetrosis and myelofibrosis.
2- Infections:
 A) Viral as CMV, EBV.
B) Bacterial as septicemia, typhoid fever, subacute bacterial endocarditis,
brucellosis, miliary TB.
C) Spirochetal: syphilis, leptospirosis.
D) Fungal: coccidioidomycosis.
3- Parasitic infestation: malaria, toxoplasmosis, schistosomiasis, visceral larva
migrans.
4- Immunologic and inflammatory disorders:
SLE, rheumatoid arthritis, serum sickness, amyloidosis, sarcoidosis, Histiocytosis.
5- Neoplastic disease: leukemia, lymphoma, Hodgkin’s disease, metastasis.
6- Storage disease:
▪ Lipidosis (Gaucher disease, Nieman pick).
▪ Mucopolysaccharidosis (Hurler, Hunter).
7- Congestive splenomegaly:
A. Intrahepatic (portal hypertension): cirrhosis of the liver (e.g., neonatal hepatitis,
α1-antitrypsin deficiency, Wilson’s disease, cystic fibrosis)
B. Prehepatosplenic or portal vein obstruction (e.g., thrombosis, vascular
malformations)
8- Anatomic splenic lesions:
▪ Cysts, pseudocysts.
▪ Hemangiomas, and lymphangiomas.
▪ Hematoma or rupture (traumatic).
Diagnostic approach to splenomegaly.
I. History
1. Fever or rigors ( EBV, subacute bacterial endocarditis, malaria).
2. Jaundice (liver disease).
3. Neonatal umbilical sepsis (portal vein thrombosis).
4. Family history of hemolytic anemia.
5. Trauma (splenic hematoma).
6. Bleeding (hematological malignancy).
II. Physical examination
1. Size, consistency of spleen.
2. Hepatomegaly.
3. Lymphadenopathy.
4. Ecchymosis, petechiae.
5. Fever.
6. Manifestations of liver disease.
 7. Splinter hemorrhages.
8. Cardiac murmurs.
9. Manifestations of collagen diseases.
III. Laboratory investigations
1- CBC.
2- Blood culture, viral studies (CMV, EBV), tuberculin test, smear for malaria for
evaluation for infection.
3- Evaluation for hemolytic anemia.
4- Liver function tests, α-1 antitrypsin, serum copper for evidence of liver disease.
5- Evaluation for portal hypertension: Ultrasound and Doppler of portal venous
system and endoscopy (if indicated to exclude esophageal varices)
6- ESR, C3, C4, ANA for evaluation for CT disease.
7- Evaluation for infiltrative disease by:
a- Bone marrow aspiration.
b- Enzyme assay for Gaucher’s disease.
8- Lymph node biopsy ( if significant lymphadenopathy).
9- Imaging studies: liver, spleen scan, CT scan, MRI.
Splenectomy: for biopsy (if diagnosis is not reached).
 Oncology
Childhood leukemias
Definition of acute leukemia
Acute leukemia occurs when a progenitor cell undergoes malignant transformation within
the bone marrow. Immature white blood cells called blast cells multiply and replace
normal bone marrow with eventual invasion into the bloodstream.
The first step of hematopoiesis involves differentiation into either lymphoid stem cells or
myeloid stem cells.
Acute lymphoblastic leukemia (ALL) occurs when there is proliferation of lymphoid
stem cells and acute myelogenous leukemia (AML) occurs when there is malignant
proliferation of myeloid stem cells.
There are acute and chronic forms of both lymphoblastic and myelogenous leukemia.
Epidemiology
Leukemia is the most commonly diagnosed cancer in children, accounting for about 30%
of all pediatric cancer cases.
Types of childhood leukaemia
• Acute lymphoblastic leukaemia (ALL) accounts for about 78% of all leukaemia
diagnosed in children. ALL is the most common cancer in children
• Acute myeloid leukaemia (AML) is the next most common and accounts for 15%
of childhood leukaemia. The incidence rates are highest in infants (under 1 year
old) and show little variation from age 3 years onwards.
• Chronic myeloid leukaemia (CML) accounts for 3-5% of childhood leukemias
Risk factors and pathogenesis of acute leukemia
Most acute leukemias arise de novo. However, there are some known predisposing
factors:
• Family history of AML
• Down syndrome
• Fanconi’s anemia
• Ataxia telangiectasia
• Previous chemotherapy and/or radiation
• Significant exposure to ionizing radiation and some chemicals like Benzene,
petroleum, smoking, paint, pesticides is known to increase the risk of childhood
leukemia
• Maternal abdominal X-ray during pregnancy increases the risk of childhood
leukemia by about 50%.
Prenatal genetic alterations such as translocations, additions, or deletions can result in
leukemia via the inappropriate expression of specific oncogenes , that are thought to be
important but insufficient disease initiators. A 'second hit' causing postnatal genetic
alterations that could result from environmental factors must be acquired to allow
leukemia to develop.
Clinical Presentation of acute leukemias
Presentation is highly variable as outlined in this table depending on the child's age and
the extent of leukemic infiltration of the bone marrow and other sites
Investigations
• The most useful initial investigations in primary care are complete blood picture
CBC and blood film. Typically, this shows pancytopenia due to bone marrow
infiltration. Blasts may elevate the white cell count (despite neutropenia) and their
presence on a peripheral smear is highly indicative of leukemia.
• However, the CBC will not always be abnormal in all cases of leukemia, as some
patients may not have marrow suppression. Similarly, peripheral blood films may
be normal if blast cells are confined to the bone marrow.
Any abnormal blood count or film in combination with suspicious clinical features
should be referred urgently to a specialist center
Further investigations conducted in secondary care are likely to include:
o Bone marrow aspiration and biopsy - for definitive diagnosis
o Immunophenotyping and cytogenetic analysis to enable risk stratification
o Imaging to determine the extent of the disease
o Lumbar puncture where there is suspected CNS infiltration
Diagnosis
Bone marrow with more than 20% replacement by blast cells (normal <5%) is diagnostic
of leukemia. Pancytopenia and blasts in the peripheral blood smear support the
diagnosis.

DIAGNOSTIC CLASSIFICATION AND PROGNOSIS OF CHILDHOOD ALL

VERSUS AML
ALL AML
Morphologic • L1: blast cells small, uniform, • M0 undifferentiated
Classification typical of childhood ALL, • M1 without maturation
[FAB high nuclear to cytplasmic • M2 with granulocytic
Classification] ratio maturation
 • L2: blast cells larger,
heterogenous, lower nuclear to
cytoplasmic ratio
• L3: vacuolated blasts,
basophilic cytoplasm
Classification B-Lineage ALL
according to • Mature B ALL [ Burkitt
immunophenotyping leukemia]: 1-3% bad
prognosis
• Pre B ALL : 80%
T-cell ALL :10-15% high risk
Epidemiology • Peak age 2-5 years old
• 80% of childhood acute
leukemia
Prognostic factors Favorable (low risk):
• B-cell precursor
• Age 1-9 years old
• WBC < 50,000
• Absence of CNS disease
• Trisomies 4, 10, 17
• TEL/AML translocations
Unfavorable (high risk):
• T-cell precursor
• Age >10 years old
• WBC >50,000
• CNS disease
• MLL rearrangements
• t(9:22) translocation
• Induction failure
Prognosis Cure rate:
• 85% cure in low risk
• M3 acute promyelocytic
• M4 granulocytic and
monocytic maturation
• M5 monoblastic or monocytic
• M6 erythroleukemia
• M7 megakaryoblastic
• In children peaks below 2
years
• 20% of childhood acute
leukemia
Favorable:
• Younger age
• Hyperdiploidy
• Favorable cytogenetics
• t(8:21), inversion 16
• Moderate leukocytosis
• De novo
• <4 wks to complete
remission
Unfavorable:
• Older age
• WBC >100,000
• Secondary AML
• Monosomy 7
• Unfavorable cytogenetics
(eg. t(9,22))
• Severe leukocytosis
• >4wks to complete
remission
Cure rate:
• 70% low risk
 • 70% cure in high risk • 40% high risk
Differential diagnosis of childhood acute leukemia
The overall differential diagnosis is very wide, depending on the mode of presentation
and age of the child and includes the following conditions
• Infective:
o Epstein-Barr virus
o Parvovirus B19
o Other viral infections such cytomegalovirus, HIV
o Osteomyelitis
• Malignant:
o Non-Hodgkin's lymphoma
o A range of other childhood malignancies - eg, CNS tumors, lymphoma,
neuroblastoma, renal tumors, bone tumors and others
• Autoimmune:
o Systemic lupus erythematosus
o Juvenile idiopathic arthritis
• Hematological:
o Aplastic anemia
o Fanconi's anemia
o Megaloblastic anemia
o Lymphoproliferative disorders
o
Management of childhood leukemias
General
• Good supportive care and prevention and control of infection
• No routine immunizations during therapy and for six months afterwards
Acute lymphoblastic leukemia
Treatment for ALL typically consists of the following phases:
• Remission-induction phase (eg, dexamethasone or prednisone, vincristine,
asparaginase, daunorubicin)
• Intensification/consolidation phase: It includes administration of cytarabine,
cyclophosphamide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, 6-
thiouguanine, and vincristine.
• CNS-directed therapy consists of systemic chemotherapy that enters the CSF, as
well as intrathecal chemotherapy administered throughout the entire course of
treatment, which is primarily MTX but sometimes includes hydrocortisone and
cytarabine (“triple-intrathecal therapy”).
 • Continuation therapy targeted at eliminating residual disease (eg, MTX, 6-MP,
vincristine and glucocorticoid pulses)
Allogeneic HSCT (hematopoietic stem cell transplant): Usually following second
complete remission after relapse (if early) or first remission in high risk patients;
potentially prevents relapse and/or mortality versus chemotherapy alone.
Acute Myeloid leukemia
• AML is treated with intensive chemotherapy to destroy the leukemic cell
population as quickly as possible. Chemotherapy includes mainly cytarabine and
daunorubicin. It results in 75-90% remission after induction/consolidation
• Bone marrow transplantation is indicated in high risk patients
Complications of Childhood Leukemias
Early
These may cause a life-threatening presentation of leukemia:
• Neutropenia - overwhelming sepsis (usually Gram-negative) +/- disseminated
intravascular coagulation
• Thrombocytopenia - bleeding, pulmonary or gastrointestinal (GI) hemorrhage,
stroke
• Electrolyte imbalance: hyperkalemia and hyperphosphatemia (due to blast cell
lysis)
• Acute kidney injury (secondary to hyperuricemia)
• Acute airway obstruction (secondary to mediastinal thymic mass)
• Leukostasis - stroke, acute pulmonary oedema, and heart failure
• CNS involvement - stroke, seizures
During treatment
• Tumor lysis syndrome
• Renal or hepatic impairment
• Profound immunosuppression leading to sepsis (febrile neutropenia)
• Thromboembolism
• Alopecia
• Mucositis causing severe mouth pain
• Hyperemesis
• GI erosion/bleeding
• Peripheral neuropathy and constipation (due to vincristine)
Tumor Lysis Syndrome:
• Tumor lysis syndrome is an oncologic emergency caused by massive tumor cell
lysis that occurs most often after the initiation of cytotoxic therapy
 • Characterized by hyperkalemia, hyperphosphatemia, hyperuricemia and
hypocalcemia
• Risk factors for tumor lysis include large tumor burden and high tumor cell
proliferation rate such as high grade lymphomas (e.g. Burkitt) and T cell
leukemias.
• Principles of therapy involved monitoring these metabolic values extremely
closely and trying to minimize the effects.
• Treatment and prevention of tumor lysis syndrome includes intravenous hyper-
hydration, allopurinol and rasburicase to decrease uric acid production and urinary
alkanization to decrease the likelihood of uric acid precipitation in the renal
tubules.
Prognosis of childhood acute leukemia
• Prognosis has improved dramatically over the last few decades.
• ALL has an overall cure rate of 85%.
• Prognosis has improved in AML with cure rate 70%. patients with adverse
cytogenetic features or poor treatment response do badly even with allogenic bone
marrow transplants and have a less than 50% cure rate

ABDOMINAL MASS
• A palpable abdominal mass is the most common sign that should suggest a malignant
solid tumor
• Abdominal mass is defined as an unusually enlarged abdominal or retroperitoneal organ
(i.e., hepatomegaly, splenomegaly, or enlarged kidney) or a defined fullness in the
abdominal cavity not directly associated with an abdominal organ
• 60% of abdominal masses in children are due to organomegaly and 40% are due
to anomalies of development, neoplasms, or inflammatory conditions
• An approach to abdominal masses includes thinking about possible etiologies based on
the location of the mass with regards to the underlining abdominal anatomy as in the
figure and associated symptoms or signs. For example, if mass was found in the upper
right quadrant think about hepatoblastoma, Wilms’ tumor of the right kidney,
neuroblastoma of the right adrenal gland, or enlarged gall bladder
 http://www.raems.com/abdopelvicart.htm

Etiology of an abdominal mass in neonates, infants and children

Neonates
Renal
Hydronephrosis
Multicystic dysplastic kidney
Mesoblastic nephroma
Renal vein thrombosis
Polycystic kidney disease
Wilms’ tumor
Neuroblastoma
Pelvic
Gastrointestinal duplication
Ovarian cyst
Hydrocolpos
Hydrometrocolpos

Infants and children

Neuroblastoma
Wilms’ tumor
Lymphoma
Hepatoblastoma
Embryonal sarcoma
Teratomas
Gastrointestinal Duplication
Meckel’s diverticulum
Fecal mass
Ovarian cysts
Omental or mesenteric cyst

How to assess an abdominal mass?

Important history components include
• The patient’s age is one of the most important factors that narrow the potential
etiologies of an abdominal mass. The etiologies differ between neonates and
infants/children.
• The length of time since the mass was found, and the rapidity of growth of the mass,
Masses that have been found for a long time (several months to years) are more
likely to be benign. Masses that grow faster are more likely to be malignant.
• Symptoms and signs of gastrointestinal or genitourinary obstruction like cramping,
abdominal pain and vomiting, decreases in bowel movements or decrease volume
of urine. These symptoms can point to intussusception or volvulus. As well as
obstructive anomalies of urinary system
• The presence of constitutional symptoms includes pallor, anorexia, weight loss, and
Fever may point to a malignant or inflammatory pathology.
• History of pre-natal interventions as well as review prenatal ultrasounds (US) for
the presence of oligohydramnios or polyhydramnios may suggest a congenital renal
etiology especially in neonates and young infants.
• The presence or absence of watery diarrhea. A positive finding can indicate a
vasoactive intestinal peptide secreting neuroblastoma.
• The presence of blood in the urine can be a clue to a pathology that damage the
genitourinary tract such as Wilms tumor.

Examination
• A complete general physical exam with vitals (including BP) and the temperature, .
A fever may indicate an infection that cause abdominal mass like hepatitis or
mononucleosis
• Height and weight and plot findings on a growth chart
• Examine the eye and the area around the eye. Bruising around the eye (periorbital
ecchymosis) and bulging eyeballs (proptosis) may indicate metastatic
neuroblastoma.
• Patients that lack an iris (aniridia) with abdominal masses most likely have a Wilms
tumor.
• Examine for the presence of generalized adenopathy, pallor, bruising, petechiae,
cachexia, jaundice, shoulder pain. All may point to malignancy
• Abdominal Examination for evidence of protrusion, bulging, or asymmetry
 • Listen for bowel sounds to assess for intestinal obstruction
• Palpation of 4 quadrants and flank area. Palpate mass for tenderness, and texture.
Look for guarding.
• Percussion for determining if the mass is a fluid filled cyst with dull percussion or
an air-filled structure with tympanic sound.
• Examine for ascites

Investigations
Radiologic imaging
• Plain abdominal x-ray: This would be the first imaging study to be ordered. to
determine the location and density of the abdominal mass. and to look for the
presence of multiple air and fluid levels or absence of air in the rectum in case of
intestinal obstruction. Calcification may indicate the presence neuroblastoma,
teratomas, kidney stones, or biliary stones.
• Ultrasound: Inexpensive and safe modality. Useful for discriminating solid and
cystic mass
• Computed tomography (CT) scan and Magnetic resonance imaging (MRI): Used
to attain more specific anatomic information of the abdominal mass.

Laboratory studies
• Complete blood count with differential. Anemia, neutropenia, or
thrombocytopenia can indicate bone marrow infiltration.
• Bone marrow biopsy and/or aspiration is indicated if one or more bone marrow
cell lines are compromised
• Chemistry panel, including electrolytes, uric acid, and lactate dehydrogenase
levels. An elevated uric acid or lactate dehydrogenase can suggest that a
malignancy may be present. Electrolyte abnormality indicates pathology with the
kidney or tumor lysis syndrome.
• Urinalysis: Hematuria or proteinuria suggests renal involvement.
• Test homovanillic acid and vanillylmandelic when you suspect neuroblastoma or
pheochromocytoma respectively
• Serum B chorionic gonadotropin and alpha-feto protein can be used to find
teratomas, liver, and germ cell tumors

Neuroblastoma.
• Neuroblastoma is the most common malignancy in infants.
• Neuroblastomas arise from neural crest cells within the sympathetic chain or adrenal
medulla, with 60% to 70% of cases originating within the abdomen
• Presenting symptoms include a palpable mass, pain, weakness, and failure to thrive.
• Other associated signs include periorbital ecchymoses, exophthalmos, and Horner’s
syndrome (miosis, ptosis and anhidrosis).
• Urinary catecholamines are elevated in 90% to95% of cases.
• CT scanning or MR imaging is needed to delineate the tumor size, extent of invasion
of adjacent structures, and presence of metastatic disease.
• Bone scan and skeletal radiographs are helpful in defining bony involvement.
• Bone marrow invasion should be evaluated by bilateral bone marrow biopsies.
• The outcome depends on the tumor stage and the patient’s age at diagnosis,
• Chemotherapy and surgical resection followed by radiation therapy are the treatment.
• Prognosis is poor

Wilms’ tumor.
• Wilms’ tumor is the second most common abdominal tumor in childhood.
• It is an embryonal renal neoplasm,
• Presentations include a flank or abdominal mass, left-sided varicocele, hematuria, and
hypertension.
• Such masses can be quite large at diagnosis because they can go unnoticed due to their
retroperitoneal location and are usually painless unless hemorrhage or rupture occurs.
• Wilms’ tumor may occur in association with other congenital anomalies or syndromes
including sporadic aniridia, isolated hemihypertrophy, cryptorchidism, it can be
bilateral
• Approximately 15% of patients will have metastatic disease at diagnosis, most
commonly affecting the lungs followed by the liver and regional lymph nodes.
• Sonography is the best initial imaging technique to confirm the kidney as the organ of
origin and to estimate the tumor size.
• Treatment includes surgery, if possible, radiation, and chemotherapy.
• Four-year survival rates range 70-80%

Malignant lymphoma
• Lymphoma is the third most common childhood malignancy
• It is divided into Hodgkin's disease and Non-Hodgkin's lymphomas.
• In both, there is replacement of normal lymphoid structure by collections of abnormal
cells (Reed-Sternberg cells in Hodgkin and diffuse or nodular collections of abnormal
lymphocytes or histeocytes in non-Hodgkin's lymphoma).

Etiology:
• Environmental factors (irradiation, chemicals and drugs as well as infection particularly
Epstein-Barr virus and HIV).
• Genetic predisposition as in primary immunodeficiency

Clinical features
• Lymphadenopathy
• Weight loss
• Bone pain
• Pancytopenia or selective blood cell depression secondary to bone marrow involvement
• Headaches and vomiting secondary to CNS involvement
• Cough, dyspnea, pneumonia, dysphagia secondary to anterior mediastinal involvement
• Superior vena cava syndrome (common in T-cell or lymphoblastic lymphoma)
• Abdominal mass, signs of intestinal obstruction (typical of Burkitt or B-cell
lymphoma),
• Patients with advanced-stage lymphoma at presentation, (Burkitt lymphoma and T-cell
lymphoma), may have signs and symptoms of renal failure because of tumor lysis
syndrome (high potassium, phosphorus, and uric acid, low calcium).

Diagnosis
• Lymphnode biopsy.
• chest X-ray
• Abdominal sonar
• bone scan.
• CT scan or MRI.

Treatment
1. Supportive care.
2. Chemotherapy
3. Local nodal irradiation.
4. Hematopoietic stem cell transplantation
prognosis : cure >90%

When to suspect childhood cancer

Although cancer in children is rare, it is the second most common cause of childhood mortality in
developed countries. It often presents with nonspecific symptoms similar to those of benign
conditions, leading to delays in the diagnosis and initiation of appropriate treatment. The
The presenting symptoms and signs can be described using an acronym "CHILD CANCER."
provided by The Pediatric Oncology Resource Center;
Continued, unexplained weight loss
Headaches, often with early morning vomiting
Increased swelling or persistent pain in the bones, joints, back, or legs
Lump or mass, especially in the abdomen, neck, chest, pelvis.
Development of excessive bruising, bleeding, or rash
Constant, frequent, or persistent infections
A whitish color behind the pupil
Constant tiredness or noticeable paleness
Eye or vision changes that occur suddenly and persist
Recurring or persistent fevers of unknown origin
If the patient presents repeatedly with the same symptom or if the symptom persists, you should
suspect cancer and follow in this table

When to suspect pediatric cancer and what to investigate initially

Sign or Type of Common When to evaluate Test
symptom cancer conditions in
differential
diagnosis
Fever Leukemia, Infection Fever lasts longer than CBC with
lymphoma 14 days with no differential
identifiable cause. white cell
count
Headache Brain tumor Tension Headache occurs during Head CT
headache, sleep, is associated with scan
migraine, neurologic signs and
infection vomiting.
Lymphadeno- Leukemia, Lymphadenitis, LN > 2 cm or with Evaluate if
pathy, lymphoma, systemic hematological finding LA does not
metastatic infection,collage or organomegaly respond to a
disease n vascular 7-day
disease antibiotic.
Vomiting Abdominal Infection, Vomiting lasts longer Abdominal
mass, brain gastroesophagea than 7 days with no and head CT
tumor l reflux identifiable cause. & scans
headache during sleep. Head CT
scan
Constipation Abdominal Poor diet Constipation is Abdominal
mass prolonged (> 1 month) and pelvic
and does not respond to CT scans
conventional ttt*.
Cough Mediastinal URIs*, reactive Cough is prolonged > 2 Chest
mass airway disease, weeks with no radiograph
pneumonia identifiable cause.
Bone or Leukemia, Musculoskeletal Pain is prolonged (> 2 Plain-film
muscle pain bone tumor, injury, viral weeks) and has no radiograph,
neuroblastoma infection identifiable cause. bone and
CT scans,
CBC
Hematuria Wilms' tumor Urinary tract Hematuria Hematuria
infection, has no
glomerulonephriti identifiable
s cause
*URI: upper respiratory infections ttt: treatment
 MCQs
1- A 5-year-old presents with a 1-month history of bone pain, increased bruising, swollen lymph glands, and
recurrent fever. Laboratory studies reveal a hemoglobin value of 6.8 g/dL, platelet count 60,000/mm3, and
leukocyte count 3500/mm3 with 2% neutrophils and atypical cells described. The most likely diagnosis is
A) Acute leukemia
B) Wilms' tumor
C) Hodgkin disease
D) Aplastic anemia
2- A 15-year-old female reports that she has had fever, weight loss, and night sweats for 3 months. On physical
examination, she has large painless swelling of the left cervical and supraclavicular lymph nodes. Her liver and
spleen are not enlarged. The initial evaluation of the patient should include
A) Bone marrow aspiration
B) Abdominal US
C) Chest radiograph
D) All of the above