• childhood cancers originate from the deeper,

visceral, parenchyma rather than from the

epithelial layers that line the ducts and glands of
organs and compose the skin.
• Lymphohematopoietic cancers (i.e.,ALL,AML, Hodgkin and
NHL) 40%.
• central nervous system cancers for approximately 30%.
• embryonal tumors and sarcomas for approximately 10%

• In contrast, epithelial tumors of organs such as

lung, colon, breast, and prostate, seen in adults.
• Many adult cancer patients endure no more than a year of
treatment. while treatment in children is
prolonged ,average 3 years.
• Second Malignancies
• Chemotherapy and radiation therapy
• Development and CNS function
• Cardiac, Renal, and Pulmonary Toxicity
• Reproductive Function
• Several syndromes are associated with an increased risk
of developing
malignancies, which can be characterized by diffrent
mechanisms
• One mechanism involves the inactivation of
tumorsuppressor genes such as RB in familial
retinoblastoma.
 Age Association with Specific
Malignancies
• The embryonal tumors, including neuroblastoma, Wilms tumor,
retinoblastoma, hepatoblastoma, and rhabdomyosarcoma, usually
occur during the 1st 2 yr of life
• ALL peaks incidence is 1-4 yr of age.
• Brain tumors have a peak incidence in the 1st decade of life.
• Non-Hodgkin lymphomas are uncommon earlier than 5 yr of age but
steadily increase thereafter.
• During adolescence, bone tumors, Hodgkin disease, and the gonadal
and soft tissue sarcomas predominate.
 Childhood leukemia
• Uncontrolled proliferation of immature blood cells
with a different immunological subtypes which is lethal
within 1 –6 months without treatment
• The disorder starts in the bone marrow, where normal
blood cells are replaced by leukemic cells
• Morphological (FAB), immunological, cytogenetic,
biochemical, and molecular genetic factors characterize
the subtypes with various response to treatment
• A familial syndrome, Li-Fraumeni syndrome, in which 1 mutant
P53 allele is inherited, also has been described in patients who
develop sarcomas, leukemias, and cancers of the breast, bone,
lung, and brain.
• Neurofiromatosis is a condition characterized by the proliferation
of cells of neural crest origin, leading to neurofiromas.
• Thse patients are at a higher risk of developing malignant
schwannomas and pheochromocytomas.
• A second mechanism responsible for an inherited predisposition to develop
cancer involves defects in DNA repair.
• Syndromes associated with an excessive number of broken chromosomes due
to repair defects include Bloom syndrome (short stature, photosensitive
telangiectatic erythema), ataxia-telangiectasia (childhood ataxia with
progressive neuromotor degeneration), and Fanconi anemia (short stature,
skeletal and renal anomalies, pancytopenia).
• signifiantly increased rates of cancer, especially leukemia. Xeroderma
pigmentosum likewise increases the risk of skin cancer, owing to defects in
repair to DNA damaged by ultraviolet light.
• Th third category of inherited cancer predisposition is
characterized by defects in immune surveillance.
• Ths group includes patients with Wiskott-Aldrich syndrome,
severe combined immunodefiiency, common variable
immunodefiiency, and the X-linked lymphoproliferative
syndrome.
• Th most common types of malignancy in these patients are
lymphoma and leukemia.
 ALL CLL Lymphomas MM
naïve

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Myeloproliferative disorders
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
 Etiology
The etiology is unknown. The following factors are important in the pathogenesis of
leukemia:
1. Ionizing radiation.
2. Chemicals (e.g., benzene in AML).
3. Drugs (e.g., use of alkylating agents or with radiation therapy increases the risk of
AML).
4. Higher risk in congenital disorders:
 trisomy 21 (14 times higher) and other trisomies
 Turner syndrome
 Klinefelter syndrome
Infection (viral –HTLV, EBV, HIV)
• Th leukemias are the most common malignant neoplasms in childhood, accounting
for approximately 31% of all malignancies that occur in children younger than 15 yr
of age.
• Acute lymphoblastic leukemia (ALL) accounts for approximately 77%
• acute myelogenous leukemia (AML) for approximately 11%,
• chronic myelogenous leukemia (CML) for 2-3%,
• juvenile myelomonocytic leukemia (JMML) for 1-2%..
• Th leukemias may be defied as a group of malignant diseases in which genetic
abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation
of cells.
• Th result is a disruption of normal marrow function and, ultimately, marrow failure
• ALL has a striking peak incidence at 2-3 yr of age and occurs more in boys
than in girls at all ages
• Phenotypically, surface markers show that approximately 85% of cases of ALL
are classifid as B lymphoblastic leukemia (previously termed precursor B-ALL
or pre–B-ALL), approximately 15% are T-lymphoblastic leukemia, and
approximately 1% are derived from mature B cells.
• Th rare leukemia of mature B cells is termed Burkitt leukemia and is one of the
most rapidly growing cancers in humans, requiring a diffrent therapeutic
approach than other subtypes of ALL.
• A small percentage of children with leukemia have a disease characterized by
surface markers of both lymphoid and myeloid derivation
• Th initial presentation of ALL usually is non specific and relatively brief. Anorexia,
fatigue, malaise, and irritability often are present, as is an intermittent, low-grade fever.
• Bone or joint pain, particularly in the lower extremities, may be present. Less
commonly, symptoms may be of several months’ duration, may be localized
predominantly to the bones or joints, and can include joint swelling.
• Bone pain is severe and can wake the patient at night. As the disease progresses, signs
and symptoms of bone marrow failure become more obvious with the occurrence of
pallor, fatigue, exercise intolerance, bruising, or epistaxis, as well as fever, which may
be caused by infection or the disease.
• Organ infitration can cause lymphadenopathy, hepatosplenomegaly, testicular
enlargement, or central nervous system (CNS) involvement (cranial neuropathies,
headache, seizures).
• distress usually is related to anemia but can occur in
patients with an
obstructive airway problem (wheezing) as the result of a
large anterior
mediastinal mass (e.g., in the thymus or nodes).
• This problem is most typically seen in adolescent boys
with T-cell ALL (T-ALL). T-ALL also usually has a higher
leukocyte count
 Clinical Manifestations of
Extramedullary Invasion
A .due to Central nervous system involvement
 occurs in less than 5% of children with ALL. may present :
 Signs and symptoms of raised ICP
 Signs and sxs of parenchymal involvement- focal neurologic signs
 Diabetes insipidus (posterior pituitary involvement).
 Chloromas of the spinal cord—(very infrequent in ALL) may present with back pain,
leg pain, numbness, weakness, Brown–Séquard syndrome, and bladder and bowel
sphincter problems
 CNS hemorrhage—AML > ALL.
 Is due to Leukostasis in cerebral blood vessels, leading to leukothrombi, infarcts, and hemorrhage
b.
 Thrombocytopenia and coagulopathy, contributing to CNS hemorrhage.
 B. Due to Genitourinary Tract
Involvement

• Testicular Involvement- presents with painless enlargement of the

testis.

• Priapism

• Renal Involvement- present with hematuria, hypertension, and renal

failure.
• Evaluated in many patients by ultrasonography;
• more common in T-cell ALL or mature B-cell ALL
 Gastrointestinal Involvement

 GI tract is frequently involved in ALL. The most

common manifestation is bleeding.

 Leukemic infiltrates in the GI tract are usually

clinically silent until terminal stages when
necrotizing enteropathy might occur.

 The most common site for this is the cecum, giving rise to a
syndrome known as typhlitis.
 Bone and Joint Involvement

 Bone pain is initial sxs in 25% of patients. results from:

• leukemic infiltration of the periosteum, bone infarction, or expansion of
marrow cavity by leukemic cells.

 Radiologic changes seen most frequently include:

• Osteolytic lesions involving medullary cavity and cortex
• Transverse metaphyseal radiolucent bands
• Transverse metaphyseal lines of increased density (growth arrest lines)
• Subperiosteal new bone formation.
• Skin Involvement
 Skin involvement occurs most commonly in neonatal leukemia or AML.
• Cardiac Involvement
 1/2-2/3 of patients demonstrated cardiac involvement at
autopsy, although symptomatic heart disease occurs in< 5%.
 Pathologic findings include leukemic infiltrates and hemorrhage of the
myocardium or the pericardium.
• Lung Involvement
 This may be due to leukemic infiltrates or hemorrhage
• Th diagnosis of ALL is strongly suggested by peripheral blood fidings that
indicate bone marrow failure. Anemia and thrombocytopenia are seen in most
patients
• ALL is diagnosed by a bone marrow evaluation that demonstrates >25% of the
bone marrow cells as a homogeneous population of lymphoblasts.
• Initial evaluation also includes CSF examination. If lymphoblasts are found and
the CSF leukocyte count is elevated, overt CNS or meningeal leukemia is
present.
• Ths fiding reflcts a worse stage and indicates the need for additional CNS and
systemic therapies.
• Elevation of the lactate dehydrogenase is oftn a clue to the diagnosis of ALL. When
only pancytopenia is present, aplastic anemia (congenital or acquired) and
myelofirosis should be considered.
• Failure of a single cell line, as seen in transient erythroblastopenia of childhood,
immune thrombocytopenia, and congenital or acquired neutropenia, is rarely the
presenting
feature of ALL.
• A high index of suspicion is required to differentiate ALL from infectious
mononucleosis in patients with acute onset of fever and lymphadenopathy and from
juvenile idiopathic arthritis in
patients with fever, bone pain but often no tenderness, and joint swelling.
The hallmark of the diagnosis of acute leukemia is the blast cell:
 a relatively undifferentiated cell with diffusely distributed nuclear chromatin
 one or more nucleoli
 and basophilic cytoplasm
ALL must be diffrentiated from AML and other malignant diseases
that invade the bone marrow and can have clinical and laboratory
fidings similar to ALL, including neuroblastoma,
rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma
3. Chest radiograph: Mediastinal mass in T-cell leukemia.
4. Blood chemistry: Electrolytes, blood urea, uric acid, liver function tests,
immunoglobulin levels.
5. Cerebrospinal fluid: Chemistry and cells.
 CSF findings for the diagnosis of CNS leukemia require:
• Presence of more than 5 WBCs/mm3
• Identification of blast cells on cytocentrifuge examination.
 CNS involvement in leukemia is classified as follows:
• CNS 1 <5 WBCs/mm3, no blasts on cytocentrifuge slide
• CNS 2 <5 WBCs/mm3, blasts on cytocentrifuge slide
• CNS 3 >5 WBCs/mm3, blasts on cytocentrifuge slide
6. Coagulation profile:
Decreased coagulation factors more common in AML are
hypofibrinogenemia, factors V, IX, and X.
7. Cardiac function: Electrocardiogram (ECG) and echocardiogram.
8. Infectious disease profile: Varicella antibody titer,
cytomegalovirus (CMV) antibody titer, herpes simplex antibody,
hepatitis antibody screening.
9. Immunologic screening: Serum for immunoglobulin levels, C3 and
C4.
 Classification
Acute leukemia can be classified based on:
• morphologic characteristics:
• cytochemical features
• immunologic characteristics
• and cytogenetic and molecular characteristics
Morphology: FAB classification
FAB classification of lymphoblasts(L1-3)
 L1 85% of children with ALL
• Cell size: small cells predominate, similar sizes
• Nuclear chromatin: usually homogeneous
• Nuclear shape: oval, almost fills cell
• Nucleoli: Normal; occasionally clefted or indented
• Cytoplasm: Scanty
• Basophilia of cytoplasm: very few
• Cytoplasmic vacuolation: variable
L2 14% of children with ALL
• Variable in size
• Nuclear chromatin: variable, heterogeneous
• Nuclear shape: irregular clefting,
indentation common
• Nucleoli: one or more present, often large
• Cytoplasm: variable, often moderately
abundant
• Basophilia of cytoplasm: variable,
sometimes deep
• Cytoplasmic vacuolation: variable
• L3 1% of children with ALL
• Large homogeneous cells
• Nuclear chromatin: finely stippled and homogeneous
• Nuclear shape: normal, i.e. oval to round
• Nucleoli: prominent, one or more
• Cytoplasm: moderately abundant
• Basophilia of cytoplasm: very deep
• Cytoplasmic vacuolation: often prominent
 Prognostic factors
Prognostic Average risk High risk
factors (Favorable) (Unfavorable)
WBC <50,000 >50,000
Age 1-10 yrs <1yr, >10yr
Gender Female Male
Response to rx <4 weeks >4 weeks
Relapse after >6 months <6 months
treatment
Surface Pre B cells T/B cells
markers
Cytogenetics Hyperploidy Hypoploidy
 Cont’d

FAB L1 L2/L3

Mediastinal -VE +VE

enlargement
Visceromegall -VE +VE
y
LDH Moderate High

Ethinic group White Black

 Differential diagnosis

• Leukemic reaction in bacterial infection, acute

hemolysis,tuberculosis, sarcoidosis,
histoplasmosis
• Lymphocytosis: pertussis
• Infectious mononucleosis
• Aplastic anemia
• Idiopathic thrombocytopenia
• Bone marrow infiltration by a solid tumor
(NBL,NHL, RMS)
• Rheumatoid arthritis, rheumatoid fever
 Aims of Therapy

• 1. To induce a clinical and hematologic remission

• 2. To maintain remission by systemic chemotherapy and
prophylactic CNS therapy
• 3. To treat the complications of therapy and of the disease
• AML can present with any or all of the fidings associated with marrow failure
in ALL. In addition, patients with AML present with signs and symptoms that
are uncommon in ALL, including
• subcutaneous nodules or “blueberry muffi lesions (especially in infants),
• infitration of the gingiva (especially in monocytic subtypes),
• signs and laboratory fidings of disseminated intravascular coagulation (especially
indicative of APL),
• discrete masses, known as chloromas or granulocytic sarcomas.
• Thse masses can occur in the absence of apparent bone marrow involvement
and typically are associated with a t(8;21) translocation. Chloromas also may
be seen in the orbit and epidural space
• CML is a clonal disorder of the hematopoietic tissue that accounts for 2-3% of all cases of
childhood leukemia.
• Approximately 99% of the cases are characterized by a specifi translocation, t(9;22)(q34;q11),
known as the Philadelphia chromosome, resulting in a BCR-ABL fusion protein.
• Th presenting symptoms of CML are nonspecifi and can include fever, fatigue, weight loss, and
anorexia. Splenomegaly also may be present, resulting in pain in the lef upper quadrant of the
abdomen.
• Th diagnosis is suggested by a high white blood cell count with myeloid cells at all stages of
diffrentiation in the peripheral blood and bone marrow and is confimed by cytogenetic and
molecular studies that demonstrate the presence of the characteristic Philadelphia chromosome
and the BCR-ABL gene rearrangement.
• Ths translocation, although characteristic of CML, is also found in a small percentage of patients
with ALL
• JMML, formerly termed juvenile CML, is a clonal proliferation of hematopoietic stem
cells that typically affcts children younger than 2 yr of age.
• Patients with this disease do not have the Philadelphia chromosome that is characteristic
of CML. Patients with JMML present with rashes, lymphadenopathy, splenomegaly, and
hemorrhagic manifestations.
• Analysis of the peripheral blood oftn shows an elevated leukocyte count with increased
monocytes, thrombocytopenia, and anemia with the presence of erythroblasts.
• Th bone marrow shows a myelodysplastic pattern, with blasts accounting for <20% of
cells.
• Patients with neurofiromatosis type 1 and Noonan syndrome have a predilection for this
type of leukemia, since they have germline mutations involved in RAS signaling.
Thrapeutic reports are largely anecdotal.
 Infant Leukemia
• Approximately 2% of cases of leukemia during childhood occur before the age of 1 year. In
contrast to older children, the ratio of ALL to AML is 2 : 1.
• Leukemic clones have been noted in cord blood at birth before symptoms appear, and in 1 case
the same clone was noted in maternal
cells (maternal to fetal transmission).
• Chromosome translocations can also occur in utero during fetal hematopoiesis, thus leading to
malignant clone formation.
• Thse patients oftn present with hyperleukocytosis and extensive tissue infitration producing
organomegaly, including CNS disease.
• Subcutaneous nodules, known as leukemia cutis, and tachypnea caused by diffse pulmonary
infitration by leukemic cells are observed more oftn in infants than in older children.
 complete remission is defined
as:
1. No symptoms attributable to the disease (e.g., fever and bone pain)

2. No HSM, LAP, or other clinical evidence of residual leukemic tissue infiltration; normal
CSF examination (including cytocentrifugation)

3. A normal blood picture, with minimal levels of 500/mm3 granulocytes, 75,000/mm3

platelets, and 12 g/dL hemoglobin with no blast cells seen on the blood smear

4. A moderately cellular bone marrow with a moderate number of normal granulocytic and
erythroid precursors, together with adequate megakaryocytes and less than 5% blast
cells, none possessing frankly leukemic features.
What is minimal residual disease
• By morphology -can only detect blasts if over 5% ie 5 blasts in 100
normal cells

• Complete remission = <5% blasts in bone marrow --could have 4%

or 0.01%

• Flow cytometry --can detect 1 blast in 10,000 normal cells 0.01%

• PCR --1 blast in 100,000 normal cells 0.001%

 Then treatment is divided into phases
 Remission induction
 Consolidation with CNS prophylaxis
 interim maintenance.
 delayed Intensification and
 Maintenance phase
 Overall cure 80%
 Supportive measure
I. Treatment of infections
II. Transfusion of blood products
III. Cotrimoxazole preventive therapy
IV. Prophylactic treatment of tumor lysis syndrome, hyperleukocytosis and uric acid nephropathy
• The initial therapy is designed to eradicate the leukemic cells from
the bone marrow; this is known as remission induction
• Weekly Vincristine,
• corticosteroids,
• inthratecal methotrexate
• Weekly long-acting, pegylated asparaginase preparation.
• Daunomycin at weekly intervals(for high risk pts.)

• Remission is 98% (What is remission?)

• It is <5% blasts in the marrow and a return of neutrophil and platelet
counts to near-normal levels after 4-5 wk of treatment.
• The second phase of treatment, consolidation
• focuses on intensive CNS therapy with continued intensive systemic
therapy in an effort to prevent later CNS relapses.
• This period of treatment is often termed intensification and includes phases
of aggressive treatment (delayed intensification) as well as relatively
nontoxic phases of treatment (interim maintenance).
• Intrathecal chemotherapy is given repeatedly by lumbar puncture
• Medications
• intrime meintenance(3 months)
• Oral 6-mercaptopurine
• IV vincristine ,
• oral methotrexate
• intrathecal methotrexate
• Dexamethasone 6
• Delayed intensification(2months)
• Oral dexamethasone ,
• IV vincristine
• intramuscular L-asparaginase
• doxorubicin
• IV cyclophosphamide
• oral 6-thioguanine
• Cytarabine
• intrathecal methotrexate
• But if high risk
• systemic medications will be intensified from the out set
• CNS irradiation will be given together with Intrathecal
chemotherapy
 maintenance phase
• Finally, patients enter the maintenance phase of
therapy, which lasts for 2-3 yr, depending on the
protocol used.
• Patients are given
• daily mercaptopurine
• weekly oral methotrexate,
• intermittent doses of vincristine and a corticosteroid.
• Relapse occurs in the bone marrow in 15-20% of
patients with ALL and carries the most serious
implications
• The incidence of CNS relapse has decreased to
<5% since introduction of preventive CNS
therapy
• Testicular relapse occurs in about 2% of boys with
ALL.
 Complications of leukemia and its therapy
include the following

• Tumor lysis syndrome

• Renal failure
• Sepsis
• Bleeding
• Thrombosis
• Typhlitis
• Neuropathy
• Encephalopathy
• Seizures
• Secondary malignancy
• Short stature (if craniospinal radiation)
• Growth hormone deficiency
• Cognitive defects