ACUTE

LYMPHOBLASTIC LEUKEMIA • Anorexia, fatigue, malaise, and irritability often are

• Childhood ALL – first disseminated cancer shown to present, low grade fever
be curable • Bone and joint pain – severe and can wake patient at
night
EPIDEMIOLOGY • Pallor, fatigue, exercise tolerance, bruising or
• Diagnosed in approximately 2, 400 children younger epistaxis
than 15 yr of age in the US • On physical examination:
• Peak incidence: 2-3 yr of age o Pallor
• Occurs more in boys than girls at all ages o Listlessness
o Purpuric and petechial skin lesions
o Proliferative nature manifested as
ETIOLOGY
lymphadenopathy, splenomegaly,
• Most cases of ALL caused by post-conception
hepatomegaly
somatic mutations to lymphoid cells
• B lymphoblastic leukemia is the most common
• Exposure to medical diagnostic radiation both in
immunophenotype
utero and in childhood-associated with increased
o With onset at 1-10 yr of age
incidence of ALL
o Median leukocyte count at presentation:

33, 000/uL
o Thrombocytopenia seen in 75% of patients

DIAGNOSIS
• Strongly suggested by peripheral blood findings that
indicate bone marrow failure
• Anemia and thrombocytopenia – seen in most
patients
• Leukemic cells might not be reported in the
peripheral blood routine lab exam
• ALL is diagnosed by bone marrow evaluation that
demonstrates > 25% of bone marrow cells as
homogenous population of lymphoblasts
• CNS or meningeal leukemia – lymphoblasts found,
CSF leukocyte count is elevated

CELLULAR CLASSIFICATION DIFFERENTIAL DIAGNOSIS
• Morphology – usually adequate alone to establish a • When only pancytopenia is present – aplastic anemia
diagnosis and myelofibrosis should be considered
• Other studies are essential for disease classification, • High index of suspicion is required to differentiate
which can have a major influence on the prognosis ALL from infectious mononucleosis and juvenile
and choice of appropriate therapy idiopathic arthritis
• Phenotypically – surface markers show that 85% of • ALL must be differentiated from AML and other
cases of ALL are classified as B lymphoblastic malignant diseases including:
leukemia o Neuroblastoma
• Chromosomal abnormalities are used to subclassify o Rhabdomyosarcoma
ALL into prognostic groups o Ewing sarcoma
o Retinoblastoma

TREATMENT
• Single most important prognostic factor in ALL is the
treatment without effective therapy, the disease is
fatal
• Risk-directed therapy has become the standard of
current ALL treatment and takes into account age at

diagnosis, initial WBC immunophenotypic and
CLINICAL MANIFESTATIONS cytogenetic characteristics of blast populations,
rapidity, and early response
• Initial presentation is usually nonspecific and
relatively brief • INITIAL THERAPY-REMISSION INDUCTION

By: Tony Tagacay II

 o Designated to eradicate the leukemic cells ACUTE MYELOGENOUS LEUKEMIA
o Therapy given for 4 wk and consists of
vincristine weekly, corticosteroid, and single
dose of long-acting, pedylated asparaginase
EPIDEMIOLOGY
preparation • Accounts for 11% of the cases of childhood leukemia in
o 98% are in remission defined by <5% blast the US
in the marrow • Relative frequency of AML increases in adolescence,
o Intrathecal-given at start of treatment representing 36% of cases of leukemia in 15-19 y/o
• SECOND PHASE OF TREATMENT-CONSOLIDATION
o Focuses on intensive CNS therapy in CELLULAR CLASSIFICATION
combination with continued intensive • The characteristic feature of AML is that 20% of bone
systemic therapy in an effort to prevent marrow cells on bone marrow aspiration or biopsy
later CNS relapses constitutes fairly homogeneous population of blast
o Intrathecal chemotherapy given repeatedly cells
by lumbar puncture • With features similar to those characterize early
o Regimens provide 14-28 wk of therapy, differentiation states of the myeloid-monocyte-
often termed intensification megakaryocyte series of blood cells
§ Includes phases of aggressive • WHO has proposed new classification system that
treatment (delayed incorporates morphology, chromosome abnormalities,
intensification) as well as relatively specific gene mutations
nontoxic phases of treatment
(interim maintenance)
o Multiagent chemotherapy, including such
medications as cytarabine, methotrexate,
asparaginase, and vincristine, is used during
these phases to eradicate residual disease
• MAINTENANCE PHASE
o Last for 2-3 yr
o Patient given daily mercaptopurine, weekly
oral methotrexate, intermittent doses of
vincristine and corticosteroid
• TREATMENT OF RELAPSE
o Major impediment to a successful outcome
is relapse of the disease
o Outcomes remain poor among those that
relapse, with the most important prognostic
indicators being time from diagnosis and
the site of relapsed disease
o Relapse occurs in the bone marrow in 15-
20% of patients with ALL
o Carries the most serious complications
o Intensive chemotherapy with agents not
previously used followed by allogeneic stem
cell transplantation can result in long term

survival


PROGNOSIS CLINICAL MANIFESTATIONS
• Improvements in therapy and risk stratification have • Signs and Symptoms of AML is a result of replacement
resulted in significant increases in survival rates with of bone marrow by malignant cells and caused by
current data showing overall 5 yr survival around secondary bone marrow failure
90% • AML present with signs and symptoms that are
uncommon in ALL

o Subcutaneous nodules (blueberry muffin
lesion)
o Infiltration of gingiva
o Signs and laboratory findings of Disseminated
Intravascular Coagulation (DIC)

By: Tony Tagacay II

 rd
o Discrete masses (chloromas or granulocytic • 3 most common CA in children younger than 15
sarcomas) • Infectious agents may be involved such as
o Human herpesvirus 6
DIAGNOSIS o Cytomegalovirus
• BMA and biopsy reveals features of hypercellular o Epstein Barr virus
marrow consisting of a monotonous pattern of cells
• Flow cytometry and special stains assist in identifying PATHOGENESIS
myeloperoxidase-containing cells • Reed-Sternberg (RS) cell: pathognomonic feature of
HL
PROGNOSIS AND TREATMENT o Considered hallmark of HL
• Aggressive multiagent chemotherapy is successful in
inducing remission in approximately 85-90% of
patients
• Current survival rate – 60-70% with modern therapy

CHRONIC MYELOGENOUS LEUKEMIA
• Clonal disorder of the hematopoietic tissue that
accounts for 2-3% of all cases of childhood leukemia
• 99% are characterized by a specific translocation,
known as Philadelphia chromosome resulting in a BCR-
ABL fusion protein
• Diagnosis is suggested by a high white blood cell count
with myeloid cells at all stage of differentiation in

peripheral blood and bone marrow CLINICAL MANIFESTATIONS
• Confirmed by cytogenic and molecular studies that • Patients commonly present with painless, nontender,
demonstrate Philadelphia chromosome and the BCR- firm, rubbery, cervical or supraclavicular
ABL gene rearrangement lymphadenopathy and some mediastinal involvement
• Characterized by initial chronic phase, which the • Depending on extent and location, it may present with
malignant clone produces an elevated leukocyte count airway obstruction
o Predominance of mature forms, with o Pleural or pericardial effusion
increased numbers of immature granulocytes • Hepatocellular dysfunction
• Chronic phase terminates 3-4 yr after onset • Bone marrow infiltration
• CML moves into the accelerated or blast crisis phase • Systemic symptoms – B symptoms important in
• IMATINIB (Gleevec) staging
o Designed specifically to inhibit the BCR-ABL o Unexplained fever >38
tyrosine kinase o Weight loss >10% tbw over 6 mo
• Second generation tyrosine kinase inhibitors, o Drenching night sweats
DASATINIB, improved remission in adults
o Currently being studied in children


LYMPHOMA
rd
• 3 most common cancer among US children
• Annual incidence of 15 cases/million
• Most common cancer in adolescents
• >25% of newly diagnosed cancers in persons 15-19 y/o

HODGKIN LYMPHOMA (HL)
• Malignant process involving the lymphoreticular
system of that accounts for 6% childhood cancers

EPIDEMIOLOGY
• Worldwide incidence: 2-4 new cases/100,000
• Peak at 15-35 yr and after 50 yr (bimodal age
distribution)

By: Tony Tagacay II
 o Extralymphatic disease
DIAGNOSIS o Presence of B symtoms
• Persistent unexplained lymphadenopathy
unassociated with obvious underlying inflammatory or PROGNOSIS
infectious process should undergo chest radiography • Patients with favorable prognostic factors and early
to identify presence of large mediastinal mass before stage disease have
lymph node biopsy o Event free survival (EFS) 85-90%
o Overall survival (OS) at 5 yr of >95%
TREATMENT
• Chemotherapy and Radiation therapy are both NON-HODGKIN LYMPHOMA (NHL)
effective in the treatment of HL • Accounts for approximately 60% of lymphomas in
• Treatment determined by: children
o Disease stage • Second most common malignancy in patients age 15-
o Presence or absence of B symtoms 35
o Presence of bulky nodal disease • Annual incidence – 750-800 cases/yr
• TABLE 496-3 CHEMOTHERAPY REGIMENS COMMONLY • Pediatric NHL: usually high grade and aggressive
USED IN CHILDREN, ADOLESCENTS AND YOUNG
ADULTS WITH HODGKIN LYMPHOMA PATHOGENESIS
• 4 Major Pathologic Subtypes:
o Lymphoblastic lymphoma
o Burkitt lymphoma
o Diffuse large B-cell lymphoma
o Anaplastic large cell lymphoma

CLINICAL MANIFESTATIONS
• Depends primarily on pathologic subtype and sites of
involvement
• Staging System used for NHL is ST. JUDE/MURPHY
classification

LABORATORY FINDINGS
RELAPSE • CBC
st
• Most relapses occur within the 1 3 yr after diagnosis • BUN
• Poor prognostic features include: • ELECTROLYTES
o Tumor bulk • CREATININE
o Stage at diagnosis
By: Tony Tagacay II
 • LDH
• BILIRUBIN DIAGNOSIS
• URIC ACID • Complete history
• ALANINE AMINOTRANSFERASE • Physical examination
• CALCIUM • Neurologic assessment with neuroimaging
• ASPARTATE AMINOTRANSFERASE • MRI with or without gadolinium: neuroimaging
• PHOSPHORUS standard
• BMA & BIOPSY
• LP with CSF ANALYSIS SPECIFIC TUMORS
• CHEST X-RAY • ASTROCYTOMAS
• CT SCAN • EPENDYMAL TUMORS
• PET SCAN • CHOROID PLEXUS TUMORS
• EMBRYONAL TUMORS
TREATMENT • PINEAL PARENCHYMAL TUMORS
• Primary modality of treatment is multiagent systemic • CRANIOPHARYNGIOMA
chemotherapy with intrathecal chemotherapy • GERM CELL TUMOR
• READ TABLE 296-4 • TUMORS OF THE BRAINSTEM
• Surgery: mainly for diagnosis
• Radiation therapy: in special circumstances NEUROBLASTOMA

EPIDEMIOLOGY
PEDIATRIC BRAIN TUMORS • Most common extracranial solid tumor in children
• Most commonly diagnosed malignancy in infants
ETIOLOGY • Median age at diagnosis is 22 mos
• Not well defined • 90% of cases are diagnosed by 5 yr of age
• Male predominance in medulloblastoma and
ependymoma PATHOGENESIS
• Cranial exposure to ionizing radiation: associated with • Etiology in most cases remain unknown
higher incidence of brain tumors • Familial neuroblastoma accounts for 1-2% of all cases
• Linked to mutations in PHOX2B and ALK genes
EPIDEMIOLOGY • BARD1 gene: identified as a major genetic contributor
• Overall annual incidence – 47 cases/million younger
than 20 yr of age CLINICAL MANIFESTATIONS
• Highest in infants and children 5 yr of age or younger • May develop any site of sympathetic nervous system
tissue
PATHOGENESIS • Half arise in the adrenal gland
• In children 0 – 14 yr • Most common sites of metastasis:
o Most common tumors are: o Regional lymph nodes
§ Pilocytic astrocytoma (PA) o Long bones and skull
§ Medulloblastoma/ primitive o Bone marrow
neuroectodermal tumors (PNET) o Liver
• In adolescents o Skin
o Pituitary tumors and PA • Signs and symptoms reflect the tumor site and extent
of disease
CLINICAL MANIFESTATIONS • Can mimic other disorders – can result to delayed
• Depends on: diagnosis
o Tumor location
o Tumor type DIAGNOSIS
o Age of the child • Discovered as a mass or multiple masses on plain
• Classic triad of headache, nausea/vomiting, radiography, CT or MRI
papilledema-associated with midline or infratentorial • Tumor markers including catecholamine markers,
tumor HOMOVANILLIC ACID & VANILLYLMANDELIC ACID:
• Supratentorial tumors: associated with lateralized elevated in urine
deficits • The INTERNATIONAL NEUROBLASTOMA STAGING
• Parinaud syndrome: seen with pineal region tumors SYSTEM (INSS): used to stage patients after surgical
resection
By: Tony Tagacay II

TREATMENT TREATMENT
• Patient age and tumor stage, combined with • 2 major schools of thought
cytogenetic and molecular features of tumor • Children’s Oncology Group: advocates surgery prior to
determine the treatment risk group and prognosis initiating treatment
• Stage 1 & 2: low-risk-surgery • International Society of Pediatric Oncology:
• Stage 4: surgery and observation recommends preoperative chemotherapy
o >90% cure rates with no further therapy • Surgery entails radical nephrectomy
• Intermediate-risk neuroblastoma: surgery, • Prognostic factors for risk-adapted therapy include:
chemotherapy and radiation therapy o Age
o Excellent prognosis and 90% survival with o Stage
moderate treatment o Tumor weight
• High-risk neuroblastoma: intensive chemotherapy, o Loss of heterozygosity at chrom 1p and 16p
chemotherapy with autologous stem cell rescue,
surgery, radiation and 13-cis-retinoic acid OTHER PEDIATRIC RENAL TUMOR
o 25-35% long term survival rate • MESOBLASTIC NEPHROMA
• CLEAR CELL SARCOMA OF THE KIDNEY
WILMS TUMOR • RHABDOID TUMOR OF THE KIDNEY
• Also known as NEPHROBLASTOMA • RENAL CELL CARCINOMA
• Most common primary malignant renal tumor of
childhood
nd

• 2 most common malignant abdominal tumor in
childhood
SOFT TISSUE SARCOMAS
• Most common sites of metastases:
o Lungs RHABDOMYOSARCOMA
o Regional lymph nodes
o Liver EPIDEMIOLOGY
• Most common pediatric soft tissue sarcoma
EPIDEMIOLOGY • Accounts for approximately 3.5% of childhood cancers
• Accounts for 6% of pediatric malignancies • Arise at any anatomic sites:
• >95% of kidney tumors in children o Head and neck (25%)
• 8 cases/million younger than 15 yr of age o Orbit (9%)
• 75% of cases occur in children younger than 5 yr with o Genitourinary tract (24%)
peak incidence 2-3 yr o Extremities (19%)
• Most cases are sporadic o Retroperitoneal and other sites (remainder)

ETIOLOGY, GENETICS & MOLECULAR BIOLOGY PATHOGENESIS
• Genetic mutations have been detected • Thought to arise from same embryonic mesenchyme
• Mutations in WT1 gene, located at 11p13: observed in as striated skeletal muscle
15-20% of cases • Large percentage arise in areas lacking skeletal muscle
• Mutations in CTNNB1, encoding B-catenin: observed in • 3 recognized histiologic subtypes:
15% of WT o Embryonal type
• In 70% of tumors, loss of heterozygosity or loss of o Botryoid type
imprinting is observed o Alveolar type
o Pleomorphic type (adult form)
CLINICAL PRESENTATION
• Most common initial clinical presentation: incidental CLINICAL MANIFESTATIONS
discovery of asymptomatic abdominal mass • Most common presenting feature is a mass that may
• Hypertension is present in 25% of tumors or may not be painful
• Abdominal pain, gross painless hematuria and fever – • Symptoms are caused by displacement or obstruction
frequent findings of normal structures

DIAGNOSIS DIAGNOSIS
• Abdominal radiography • Early diagnosis requires high index of suspicion
• Abdominal ultrasonography • Microscopic appearance: small round blue cell tumor
• CT of abdomen • Differential diagnosis:
By: Tony Tagacay II
 o Neuroblastoma
o Lymphoma TREATMENT
o Ewing sarcoma • 5 yr survival rate with nonmetastatic extremity: 65-
75% with chemotherapy and surgery
TREATMENT • Complete surgical resection is important for cure
• Treatment is multidisciplinary and includes: • Current approach: preoperative chemotherapy
o Pediatric oncologist • Most important prognostic factor: histologic response
o Pediatric surgeon to chemotherapy
o Radiation oncologist • For patients who require amputation: early prosthetic
• Treatment based on risk classification of tumor, fitting and gait training
which is determined by:
o Stage of tumor PROGNOSIS
o Tumor histology • Surgical resection alone is curative for patients with
o The amount of tumor resected prior to parosteal osteosarcoma
chemotherapy • Conventional osteosarcoma requires multiagent
chemotherapy
• 75% with nonmetastatic extremity osteosarcoma are
cured with current multiagent treatment protocols
NEOPLASMS OF BONE
EWING SARCOMA
OSTEOSARCOMA
EPIDEMIOLOGY
EPIDEMIOLOGY • In the US, 2.1/million children

• Annual incidence in US is 5.6 cases/million younger
than 15 yr of age PATHOGENESIS
• Highest risk period: during adolescent growth spurt • Immunohistochemical staining assist in diagnosis
• Small, round blue cell tumor
PATHOGENESIS • MIC-2 (CD99) staining: usually positive

• Cause is unknown, certain genetic or acquired
condition predispose patients to develop CLINICAL MANIFESTATIONS
osteosarcoma • Pain, swelling, limitation of motion and tenderness
• Hereditary retinoblastoma: increased risk for over involved bone or tissue
development of osteosarcoma • Often associated with systemic manifestations
• Li-Fraumeni syndrome
• Pathologic diagnosis: made by demonstration of highly DIAGNOSIS
malignant, pleomorphic, spindle cell neoplasm with • Radiographic appearance: characteristic onion-
formation of malignant osteoid and bone skinning
• 4 pathologic subtypes: • Large, soft tissue mass often is visualized on MRI or CT
o Osteoblastic • Metastatic work-up: CT of the chest, radionuclide bone
o Fibroblastic scan, BMA, biopsy specimens from 2 sites
o Chrondroblastic
o Telangiectatic TREATMENT
• Best managed with comprehensive multidisciplinary
CLINICAL MANIFESTATIONS approach
• Pain, limp and swelling: most common presenting o Surgeon
symptoms o Oncologist
• Initial complaints may be attributed to sports injury or o Oncologist-plan therapy
sprain • Multiagent chemotherapy: important because can
shrink tumor rapidly
DIAGNOSIS
• Sunburst pattern: classic radiographic appearance
• Before biopsy, MRI of the primary lesion and entire
bone PROGNOSIS
• Metastatic work-up: CT of the chest and radionuclide • Small, nonmetastatic, distally located extremity
bone scanning tumors have the best prognosis
• Cure rate up to 75%
By: Tony Tagacay II
 • Patients with metastatic disease at diagnosis: poor NEOPLASMS OF THE LIVER
prognosis

• <30% surviving long term
HEPATOBLASTOMA
RETINOBLASTOMA
EPIDEMIOLOGY
• Occurs predominantly in children younger than 3 yr of
EPIDEMIOLOGY
age
• Approximately 250-350 new cases diagnosed each
• Median age of diagnosis – 1 yr
year
• Etiology is unknown
• Median age is approximately 2 yr
• Associated with familial adenomatous polyposis
• >90% cases are diagnosed in children younger than 5
yr of age • Alterations in antigen-presenting cell/B-catenin
pathway: found in most tumors
• Can be either hereditary or sporadic

• Hereditary form associated with loss of function of
RB1 gene
PATHOGENESIS
• Arises from precursors of hepatocytes
PATHOGENESIS • Histologically classified as whole epithelial cell type
containing fecal or embryonal malignant cells
• Appear as small round blue cell tumor with rosette

formation
CLINICAL MANIFESTATIONS
• Endophytic tumors: arise from inner surface of retina
• Presents as large, asymptomatic abdominal mass
• Exophytic tumors: from the outer retinal layer and can
• Arises from right lobe 3x more often than the left
cause retinal detachment
• Usually unifocal

CLINICAL MANIFESTATIONS
DIAGNOSIS
• Retinoblastoma: classically presents with leucoria –
white pupillary reflex • Biopsy of liver tumors: necessary to establish diagnosis
• Strabismus: initial presenting complaint • AFP – diagnosis and monitoring of tumor, elevated in
almost all hepatoblastomas serologic testing for

hepatitis B and C
DIAGNOSIS
• Plain radiographs and ultrasonography of abdomen
• Established by characteristic ophthalmologic findings

of chalky, white-gray retinal mass with a soft friable
consistency
TREATMENT
• Imaging studies are not diagnostic • Cure of malignant hepatic tumors depends on
complete resection of primary tumor
• Biopsies are contraindicated
• Chemotherapy using Cisplatin, Vincristine, Doxorubicin
• Indirect ophthalmoscopy with slit lamp evaluation

• Orbital UTZ, CT, or MRI: used to evaluate extent of
disease BENIGN VASCULAR TUMORS

TREATMENT HEMANGIOMAS
• Determined by size and location of the tumor • The most common benign tumors of infancy
• Enucleation: performed in unilateral disease • Risk is 3-5 times higher in girls than boys
• Bilateral disease: chemoreduction in combination with • Can be present at birth
focal therapy (laser photocoagulation or cryotherapy) • More than 50% located in the head and neck
has replaced the traditional approach of enucleation • Most are solitary lesions
of the more severely affected eye and irradiation of • Most hemangioma require no therapy
the remaining eye

PROGNOSIS
RARE TUMORS
• THYROID TUMORS
• Approximately 95% of children are cured with modern
• MELANOMA
treatment
• NASOPHARYNGEAL CARCINOMA
• Chemotherapy in combination with focal therapy are
intended to preserve useful vision • ADENOCARCINOMA OF THE COLON AND RECTUM
• Avoid external-beam radiation or enucleation • ADRENAL TUMORS
• DESMOPLASTIC SMALL ROUND CELL TUMOR


By: Tony Tagacay II