2022 5.4a.

Childhood Malignancy (Part 1)

DR. MELANIE VICTORIA G. DAR | 04/28/2021
PEDIATRICS II

OUTLINE MULTIMODAL THERAPY

I. Introduction III. Common Childhood Tumors • Standard approach in treatment
II. Leukemia A. Hodgkin Lymphoma − Especially the solid tumors
A. Acute Lymphoblastic B. Renal Tumors − Surgery: control local disease
Leukemia C. Neuroblastoma − Chemotherapy: helps eradicate systemic spread
B. Acute Myelogenous D. Liver Tumors − Radiation therapy: control local disease
Leukemia E. Rhabdomyosarcoma • Newer treatment modalities
C. Chronic Myelogenous − Especially with leukemia, lymphoma, and solid tumors
Leukemia − Molecularly targeted therapy
− Biotherapeutics
− Cell and gene therapy
LEGEND
− HSCT
Remember Lecturer Book Previous Trans Presentation
HELLO
SURGERY
• Successful resection is vital in improving survival rates
I. INTRODUCTION − If it is completely excised, local control is increased
− Chances of relapse or tumor regrowth is lessened
CHILDHOOD MALIGNANCY
• Biopsy:
• Childhood cancer constitutes 1-3% of malignancies
− establish histopathologic diagnosis
• Most common malignancy in the Philippines –
− Confirm metastasis
− Leukemia (most common)
− Determine treatment response
− Brain tumors
○ Ex: For patients who underwent adjuvant chemotherapy, surgery
− Retinoblastoma
is included in the middle of the treatment
• Top 4 malignancies in the US
− Document complication
− Leukemia
• Role:
− CNS tumors
− Staging of the disease
− Lymphoma ○ Because some tumors are staged during surgery
− Neuroblastoma − Bypassing obstructions
− Insertion of central venous access
BIOLOGICAL BASIS OF CHILDHOOD CANCER ○ For patients who will need chemotherapy in the future
• Majority of childhood cancers DO NOT HAVE A CLEARLY − Insertion of feeding tubes
INHERITED PREDISPOSITION
− One of the most common questions of parents “Where did it come CHEMOTHERAPY
from? Wala naman sa lahi namin.”
• Principle:
• Current evidence:
− Use of multidrug combination regimens
− Cancer is a result of multiple changes in the DNA of the tumor ○ Rationale: Overcome resistance to individual agents
cell
○ Synergistic cytotoxic effects
• Common genomic or genetic alteration in cancer
− Administration of chemotherapy before the development of
− Germline (constitutional) mutation metastasis
○ Single nucleotide variation or polymorphism − Administration of drugs at maximally tolerated doses
○ Uniparenteral disomy gain or loss of function
• Adjuvant Chemotherapy
− Somatic (acquired)
− Given after local therapy with surgery or radiation
○ Activating or inactivating mutation
− Eliminate micrometastatic deposits in the lungs, bone, LN, and
○ Copy neutral loss of heterozygosity and epigenetics
other sites at the time of diagnosis
• Neoadjuvant chemotherapy
HEREDITARY DISORDERS THAT CAN PREDISPOSE A CHILD − Giving the drugs before the local procedures
TO DEVELOP CA − Goal is either to decrease the size of the mass for local control to
• Down syndrome: increased risk for leukemia (AML) be well-administered and completely done in the middle of
• Y chromosome in a phenotypically female child: increased risk for treatment
gonadoblastoma
• 47 XXY: increased risk for dysgerminoma and extragonadal germ cell II. LEUKEMIA
tumor (GCT)
A. ACUTE LYMPHOBLASTIC LEUKEMIA
• WAGR syndrome
• Normal marrow cells are replaced by undifferentiated immature
− Wilms tumor
cells called BLASTS
− Aniridia
− Normal: <5% of the nucleated cells in the BM
− Genital abnormalities
− Not seen in peripheral blood EXCEPT
− Mental Retardation (MR) ○ Infection or bleeding
• Beckwith Wiedemann Syndrome: increased risk for Wilms tumor and ○ BM replacement of granulomas, fibrosis or malignant cells
Hepatoblastoma (Leukoerythroblastosis)
• Retinoblastoma requiring loss of both copies of the RB1 gene for the − >5% blasts forms: suspicion of leukemia
tumor to develop − Methods to characterize
• Inherited p53 mutations occurring in the Li Fraumeni Syndrome ○ BM morphology
− A lot of cancers can arise from these mutations ○ Cytochemistry
• NF type 1: gliomas along the optic tract ○ Immunophenotyping
• Tuberous sclerosis associated with cardiac rhabdomyosarcomas and ○ Demonstration of chromosomal and molecular genetic
giant cell astrocytoma abnormalities
• VHL disease: cerebellar hemangioblastoma, retinal angioma, RCC,
pheochromocytoma
• Ataxia telangiectasia associated with high risk for leukemia and
lymphoma

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 2022 5.4a. Childhood Malignancy (Part 1)
DR. MELANIE VICTORIA G. DAR | 04/28/2021
PEDIATRICS II

Morphologic characteristics of lymphoblasts and myeloblasts

Characteristics Lymphoblasts Myeloblasts
Size 10-20um 14-20 um
Nucleus
Shape Round or oval Round or oval
Chromatin Smooth, homogenous Spongy, loose, finely develop meshwork
Nucleoli 0-2 and indistinct 2-5 and distinct” punched out”
Nuclear membrane Smooth and round Irregular
Nuclear-cytoplasmic ratio High (PBS: scanty to absent cytoplasm) Low

Cytoplasm
Color Blue Blue-gray
Amount Thin rim More abundant
Granules Absent Present
Auer rods Absent Present

Cytologic features of the morphologic types of ALL according to FAB classification

Cytologic features L1 L2 L3
Cell size Small cells predominate Large, heterogeneous in size Large and heterogeneous
homogenous
Nuclear chromatin Smooth, homogenous Variable, heterogeneous Finely stippled and homogeneous

Nuclear shape Regular, occasional clefting, or Irregular, clefting and indentation Regular, oval to round
indentation common
Nucleoli Not visible, or small inconspicuous One or more present, often large Prominent, one or more vesicular

Amount of cytoplasm Scanty Variable, often moderately Moderately abundant

abundant
Basophilia cytoplasm Slight or moderate, rarely intense Variable, deep in some Very deep

cytoplasmic vacuolation Variable Variable Often prominent

Immunophenotype 4. Mixed lineage/ Biphenotypic expression

− Leukemic cells show both lymphoid and myeloid surface
• More precise and biologically-oriented categorization than antigens
morphologic approach − Arise from a transformed pluripotent stem cell capable of
− More objective differentiation in the lymphoid or myeloid pathway
• Based on the expression of lineage and maturation specific
antigens present on the cell surface and in the cytoplasm of
lymphoblasts
Cytogenetics and Molecular genetics
• Provides important insights into the differentiation and maturation of • Abnormalities in
normal B and T lymphocytes − Chromosome number (ploidy)
• 3 broad categories: − Structure (translocation)

1. B- precursor cell ALL Clinical Manifestations

− 80-85%
• May present as an incidental finding on a routine blood cell count
− Reactive with monoclonal antibodies specific for B-cell associated
antigens • Common presenting symptoms
○ CD9, CD19, CD20 − Fever
− Absence of surface immunoglobulin − Pallor
− Express CD10 (common ALL/ CALLA) − Bruising
− Express intacytoplasmic immunoglobulin (cIg) − Petechiae
− Bone pain
2. Mature B-cell ALL ○ Due to stretching of the periosteum or joint capsule by
− 1-2% leukemic infiltration
− Presence of surface immunoglobulin (IgM), monoclonal for − Limp
kappa or lambda light chains • 30-50%: enlargement of the spleen or liver
− Indistinguishable with disseminated Burkitt’s lymphoma − Palpable more than 4 cm below the costal margins
− Express CD19, CD20, and HLA-DR • Lymphadenopathy
− Morphologically blasts have the FAB L3 features • Degree of organ infiltration correlates with peripheral blood blasts
count
3. T-cell ALL − as your peripheral blood blast count increases the more
− 10-15% manifestations of organ infiltration is noted particularly
− More associated with older age at diagnosis, high wbc count, and lymphadenopathy and splenomegaly
bulky extramedullary disease
− Outcome is inferior

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PEDIATRICS II

Peripheral Blood • “Touch prep” biopsy

− Helpful in elucidating morphology when aspiration is not successful
• At diagnosis
• ALL vs NHL
− Anemia
− ALL: >25% lymphoblasts in the BM
− Abnormal leukocyte and differential counts
− NHL: <25% lymphoblasts in the BM
○ 20%: >50,000% wbc count
○ 10%: extremely high leukocytosis (>100,000)
○ Absolute granulocytopenia Extramedullary Leukemia
○ Hypereosinophilia: t(15:14) (q31;q32) translocation • CNS Leukemia: 20%
○ Blasts cells may or may not be present • Anterior Mediastinal Mass: 10%
− Thrombocytopenia • Genitourinary Tract Manifestation:
• RBC: − Testicular Enlargement: 1-2%
− Normocytic-normochromic − Others: Enlarged Kidneys, Priapism, Ovarian involvement
− Low reticulocyte count • Bone and Joint Manifestations: 40%
− Tear drop cells, nucleated rbc reflecting marrow invasion • GI Manifestation: bleeding
• Ocular Manifestation: Retinal hemorrhages, ocular motor palsies,
Bone Marrow papilledema, monocular blindness
• Hypercellular, homogenous population of cells • Pulmonary Manifestation: Pulmonary Leukostasis
• Leukemia is suspected in patients with >5% blasts • Dermatologic manifestation: Leukemia cutis
• Diagnosis is made if blasts cells is >25%

Clinical and laboratory features in ALL

Factor Favorable Intermediate Unfavorable
Age (years) 1-9 ≥10 < 1 and MLL +
WBC (X 10/ l) <50 ≥50
Immunophenotype Precursor B cell T cell t (9;22)/BCR-ABL1
t (4;11)/ML-AF4
Genetics Hyperdiploidy > 50 chromosomes Diploid t(1;19)/TCF3-PBX1 Hypodiploid <44 chromosomes
or DNA index > 1.16
Trisomies 4, 10, and 17
t(12;21)/ ETV6-CBFA2

CNS status CNS1 CNS2a CNS3

Traumatic spinal tap with blast
MRD (end of induction) <0.01% 0.01%-0.99% ≥1%

Therapy − DIC: more common in patients with T cell ALL

• Current regimens: >95% complete remission; 80% long-term event
free survivors
• Factors of outcome
1. Development of complex chemotherapeutic regimens
designed to achieve clonal eradication
2. Improvement in supportive care
3. Recognition of CNS as sanctuary site
4. Application of risk-adapted therapy
• Phases of therapy
1. Remission induction
 Designed to destroy measurable leukemia cells rapidly and
minimize residual leukemia burden
2. CNS-directed therapy
 Used to address the issue of pharmacologic sanctuary,
especially the brain and spinal cord that are not well
penetrated by conventional doses of most antileukemic drugs
3. Intensification (or Consolidation)
 Reduce the total body leukemia cell burden further and
address issues of drug resistance
4. Continuation (or Maintenance)
 Eradicate the residual leukemia cell burden
Complications of Treatment
1. Metabolic Complications
− Hyperkalemia, hyperuricemia, hyperphosphatemia, and
hypocalcemia (Tumor Lysis Syndrome)
− Hyperuricemia may lead to acute renal failure secondary to uric
acid deposition in the kidney
− TXT: IV Hydration, Allopurinol or Recombinant urate oxidase
2. Anemia and Thrombocytopenia
− TXT: transfusion (PRBC or Platelet concentrate)
3. Coagulation abnormalities
− Txt: FFP and cryoprecipitate
− L Asparaginase induced coagulopathy by inhibition of AT III,
plasminogen and fibrinogen
4. Infection
− Most frequent complication
− Granulocytopenia: primary cause of treatment-related Mortality
− Any febrile episode must be considered potentially bacteremic
− Txt: Broad-spectrum IV antibiotics
○ Start with 3rd generation cephalosporins
○ Imipenem (meropenem)
○ Vancomycin
− Fungal disease: Candida and Aspergillus species
○ Fluconazole
○ Other azoles
− Pneumocystis carinii: fatal interstitial pneumonia
○ Prophylaxis with TMP-SMX
5. Typhlitis
− RLQ pain with rebound tenderness, abdominal distention,
vomiting, and sepsis
− Consequence of intensive chemotherapy
− Txt: bowel rest, IVF, broad spectrum antibiotics
6. Acute Neurologic Toxicity
− Seizures: associated with intrathecal chemotherapy, high dose
methotrexate, and cranial irradiation
− Transient episode of somnolence, anorexia, lethargy, and fever:
6-8 weeks after cranial radiation
○ Accompanied by EEG changes, CSF pleocytosis, and fever
− Vincristine: peripheral and autonomic neuropathy
○ Constipation, absent DTR, distal muscle weakness, gait
abnormalities, paresthesia, and CN palsies
○ Txt: Vitamin B complex and may resolve spontaneously

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 2022 5.4a. Childhood Malignancy (Part 1)
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PEDIATRICS II

7. Others Morphology and Cytogenetics

− L Asparaginase: Pancreatitis, HSR, transient hyperlipidemia
• Diagnosis is based on:
− Steroids: HPN, Hyperglycemia, Myopathy, mood and behavior
problems, bone fractures − Morphologic characteristic of blasts in BM smear
○ Auer rods: Thin needle-shaped cytoplasmic deposits that stain
pink with Wright-Giemsa stain and are strongly MPO positive
Late Effects of Treatment − Cytochemical stains
1.CNS Sequelae ○ Myeloperoxidase (MPO)
− Low and low average IQs ○ Sudan Black B (SBB)
− Leukoencephalopathy: ○ Peroxidase
○ Multifocal demyelination visible on CT or MRI ○ Chloroacetate esterase
○ Poor school performance, confusion, memory problems, ○ Non-specific esterases
personality changes, progressive dementia and coma ○ Periodic Acid Shift (PAS)
○ RF: large doses of cranial radiation (>24Gy), high cumulative
doses of chemotherapy Immunophenotype
2. Growth • HLA-DR, CD33
− Survivors are shorter than expected for their age − Expressed by blasts of myeloid origin
− Obesity: corticosteroids, high dose cranial radiation • HLA-DR: expressed by monocytic cells
• CD33, CD13: expressed on neutrophil and monocyte precursor
3. Bony Morbidity − CD33 is absent in mature neutrophils
− Osteopenia, fractures, osteonecrosis: Corticosteroids • CD14: specific for monocytic lineage
− Osteonecrosis or Avascular Necrosis • CD41, CD42, CD61: expressed by megakaryocytic cells and platelets

4. Cardiac Sequelae Cytogenetics

− Increased afterload and decreased contractility: Anthracycline • MLL gene (11q 23) translocation: most common in infants with AML
Therapy (Doxorubicin)
• AML M3: associated with RARA rearrangements
− That’s why you have to have a baseline 2D-Echo prior to starting
• AML M4eo: associated with inv(16) or t(16;16)
treatment to rule out any cardiac abnormalities

5. Sexual development and fertility French-American-British (FAB) Classification

− Ovarian and testicular functions are relatively unaffected • M0: Acute Myeloblastic Leukemia with Minimal Differentiation
− BM: Hypercellular, >90% are blasts
6. Second malignancies − Blasts: lack cytoplasmic granules, nucleoli, or Auer rods
− AML, brain tumors, NHL, CA of the parotid and thyroid glands − MPO, SBB (-)
− Immunophenotypic analysis: CD13, CD14, CD33 or CD34, some
7. Relapsed ALL tdT
− 20-25% − Associated with high incidence of cytogenic abnormalities:
− Factors: ○ Chromosome 5,7
○ Duration of initial remission ○ Trisomy8
 Most important prognostic factor ○ MLL rearrangements
 Early relapse: occurring while on, or within 6 months from
completion of initial therapy; Worse outcome • M1: Acute Myeloblastic Leukemia without maturation
○ Site of relapse − BM: Hypercellular and filled with myeloblasts (>90% blasts)
 Isolated extramedullary relapse: superior outcome − (+) MPO, SBB
 Most common sites: CNS & Bone Marrow, Testicular
− Blasts: shows minimal myeloid differentiation
relapse in males
○ Contain scanty gray-blue cytoplasm and few or no azurophilic
○ Immunophenotype
granules or Auer rods
○ Prominent nucleoli
B. ACUTE MYELOGENOUS LEUKEMIA − Flow cytometry: HLA-DR, CD13, CD3, CD34
• Bimodal distribution − Cytogenic abnormalities
− Higher incidence in children younger than 2 years, then again in ○ Monosomy 5 or 7
adolescence 15-20 years old ○ Trisomy 8
• Incidence is similar in all pediatric age group regardless of age
• Predisposing factors • M2: Acute Myeloblastic Leukemia with maturation
1.Exposure − Show some maturation beyond the myeloblast stage in the BM
 Environment and beyond the promyelocyte stage in 10% of the WBC marrow
 Toxin − Myeloblasts constitute >30% of BM cells, <90% of non-erythroid
 Prior treatment with chemotherapy and radiation cells
→ Alkylating agents: cyclophosphamide, ifosfamide,
nitrogen mustards • M3: Acute Promyelocytic Leukemia
→ Topoisomerase II inhibitors: epipodophyllotoxin, − 2 Types:
anthracycline 1. Hypergranular variant
2. Genetic → Most common
3. Other exposures → >30% of blasts are promyelocyte and myeloblasts
 Benzene exposure → Most promyelocytes have heavy granulation
 Alcohol consumption during pregnancy → Auer rods and Auer rod bundles are common
 Maternal tobacco and marijuana use 2. Microgranular variant
 Foods: Soya, green and black tea, cocoa, red wine, → Cells with fine cytoplasmic granules
products and vegetables that contain DNA topoisomerase
− (+) MPO, SBB, Chloroacetate esterase
II inhibitors
− Express CD13, CD33, CD11, and CD15, (-) HLA Dr, CD14
 Prolonged exposure to pesticides
− (+) RARA rearrangements (t(15;17)): PML:RARA

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PEDIATRICS II

• M4: Acute myelomonocytic leukemia Clinical Presentation

− Presence of blasts cells with both granulocytic and monocytic
• Presenting signs and symptoms result from the leukemic blasts cell
features
infiltration of the BM
− BM: >30% infiltration by immature myeloid precursors
• Leukemia cells overwhelm the process of normal hematopoiesis
− (+) extramedullary involvement (leukemia cutis, lymphadenopathy,
− Anemia, Thrombocytopenia, Neutropenia
hepatosplenomegaly) (+) peripheral blood monocytosis
• Fatigue, fever, pallor, skin or mucosal bleeding, bone pain,
− (+) MPO, SBB, NSE
infections not responding to appropriate antibiotic therapy
− May be associated with t(6;9), abnormalities of chromosome 3,
• WBC: <1000/ul - >500,000/ul
and MLL gene rearrangements (t(9;11))
• DIC has been observed in patients with all FAB subtypes
− M4eo
○ AML-M4 with moderate eosinophilia − More common in Acute Promyelocytic Leukemia (APL)
○ (+) chloroacetate and PAS ○ Express abnormally high levels of Annexin II
○ Exhibits an inv(16) or t(16;16)  Increases the production of plasmin (fibrinolytic protein)
− CD13, CD15, CD33, CD4, CD11c, CD14, CD64, HLA-DR • Hyperleukocytosis
− WBC of >100,000
• M5: Acute Monocytic Leukemia − Increased risk of mortality from leukostasis
− >80% are monocytic cells • Extramedullary leukemia (20-25%)
− 2 subtypes: − Chloromas (tumor nodules)
1.M5a (undifferentiated) ○ Solid tumors of myeloblasts that may occur in any area of the
→ >80% of the cells are monoblasts body
→ Patients tend to be younger, have higher presenting ○ Most common in the orbit and epidural area
WBC counts, have poorer prognosis − CNS disease
2. M5b (differentiated) − Gingival infiltration
→ <80% of the monocytic cells are monoblasts ○ Present as hyperplasia, often accompanied by bleeding
→ Most cells are monoblasts or promonocytes ○ More common with M4 and M5 leukemia
→ PBS: Profound monocytosis − Hepatosplenomegaly
− Strongly (+) NSE activity, (-) MPO, SBB − Testicular involvement
− CD13, CD15, CD33, CD4, CD11c, CD14, CD64, HLA-DR − Leukemia cutis
− Exhibits: MLL rearrangement ○ Presents as slightly purple lesions (ie blueberry muffin spots)
○ M5a: t(9;11) or t (11:17) ○ More common in infants with monocytic leukemia
○ M5b: t(10;11)
Treatment
• M6: Acute Erythrocytic Leukemia • Chemotherapy
− Uncommon form • Phases:
− Rare in children
− >50% erythroblasts infiltration in the BM 1. Remission Induction
− Exhibit monosomy 5 or 7, or trisomy 8 − Consists of 2-4 cycles of intensive chemotherapy
− Goal: to induce remission
• M7: Acute Megakaryoblastic Leukemia ○ Presence of fewer than 5% blasts visible on BMA obtained
− BM: infiltration with pleomorphic megakaryoblasts that often after the recovery of counts
display cytoplasmic budding and most appear in clusters ○ Absence of minimal residual disease in the marrow
− (+) Periodic Acid Shift (PAS) − Combination therapy:
− Non Down syndrome AML M7: exhibit t(1;22) ○ Cytarabine + Daunorubicin (Doxorubicin here in the
○ Poor prognosis Philippines)
− Down Syndrome AML M7: good prognosis ○ Additional: Etoposide, Thioguanine, dexamethasone

2. Postremission Therapy
− Includes autologous HSCT, allogeneic HSCT, or continued
courses of chemotherapy
− CNS leukemia in AML
○ Highly sensitive with chemotherapy
○ Cranial radiation: does not decrease CNS relapse

Prognostic Factors
Factor Remark
Age Older worse prognosis

Race Caucasian better than Hispanic, African American

WHO Classification Asian?

• Includes additional entities such as immunophenotype, molecular BMI Obesity negative prognostic factor
genetic, and clinical characteristics
• Divides myeloid disease into 4 major subtypes WBC High WBC worse prognosis
1) Myeloproliferative diseases
2) Myelodysplastic-myeloproliferative diseases CNS involvement Higher risk of isolated CNS relapse, no significant
3) MDS effect on OS (overall survival)
4) AML
1. AML with recurrent cytogenetic translocations
2. AML with myelodysplasia-related features
3. Therapy-related AML and MDS
4. AML not otherwise specified

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Cytogenetics Basis for risk classification: • Myeloid blasts crisis is more common and carries a poorer prognosis
(most important Complex karyotype, abnormalities of 5 or 7,
independent trisomy 8: poor prognosis Treatment
prognostic AML M7 associated with monosomy 7: poor
factor) prognosis • Tyrosine Kinase Inhibitors
AML M3 with t(15;17): favorable subtype − Imatinib mesylate
AML M2 with t(8;21) and AML M4eo with inv (16): ○ First line therapy for adults with chronic phase CML
favorable subtype ○ Blocks enzymatic activity of several tyrosine kinases, mainly
ABL, by attaching to ATP binding site
Response to Early MRD (minimal residual disease) post ○ Higher rates of hematologic and cytogenic remission
therapy induction associated with good prognosis (should ○ Side effects
have a result of <0.01%)  Myelosuppression
 Peripheral and periorbital edema
 Muscle cramps
C. CHRONIC MYELOGENOUS LEUKEMIA  GI intolerance
• 1-3% of childhood leukemia  Skin rash
− May present as adult type CML or as Juvenile CML/Juvenile  CHF
myelomonocytic leukemia − Nilotinib
• Median age of diagnosis: 67 years old (rarely seen in children) ○ Structure derivative of Imatinib
• Male predominance ○ Effective at lower concentrations
• Only identified risk factor: Ionizing Radiation − Dasatinib
○ For the treatment of Imatinib resistant chronic phase CML
Pathobiology • Hematopoietic Stem Cell Transplant
• Diagnosis is associated with t(9;22)(q34;q11) chromosomal − Provide prolonged DFS (disease-free survival) in CML
translocation − Only proven curative therapy
• Presence is not pathognomonic for CML
− Because we could also see this in patients with: ***we did not discuss Chronic Lymphocytic Leukemia because it is not
○ 25-50% of adult patients: (+) Ph chromosome is present at same in children
diagnosis
○ 3-5% with ALL III. COMMON CHILDHOOD SOLID TUMORS
○ 2% with AML A. HODGKIN LYMPHOMA
• Involves reciprocal translocation of the ABL gene at the end of the q • Malignancy involving B cell Lymphocytes
arm of chromosome 9 to a site on the q arm of chromosome 22 • Criteria for diagnosis: “abnormal giant cells”
within the bcr region • Sternberg (1898) and Reed (1902)
− Credited for the first definitive and thorough description of
Clinical Presentation histopathology
• 3 Phases: − Multinucleated giant cells (Reed–Sternberg cells)

1. Chronic Phase
− Most patients may be asymptomatic
− S/Sx are caused by the accumulation of mature and immature
granulocytic cells
− Generalized malaise, weakness, weight loss, fever, pallor,
organomegaly (splenomegaly)
− Abdominal pain from massive splenomegaly
− CNS, retinal and pulmonary dysfunction, arthritis, priapism
− WBC count usually exceed 100,00/ul
− (+) Basophilia and eosinophilia
− Platelet counts: >400,000/ul; thrombocytopenia may occur
− Anemia; Leukostasis
− BM: demonstrates normal myeloid maturation, with granulocytic
hyperplasia, increased M:E ratio; Megakaryocytic hyperplasia Epidemiology
− Low Leukocyte alkaline phosphatase (LAP score) to differentiate • Bimodal age distribution
with infection; increased vitamin B12 levels − Industrialized countries:
○ Early peak: middle to late 20s
2. Accelerated Phase
○ Second peak: after the age of 50 years
− Increased marrow or blood blast cell values of 10-19%
− Developing countries:
− Peripheral basophilia ○ Early peak: before adolescence
− >20% persistent thrombocytopenia unrelated to therapy or • 3 distinct forms:
thrombocytosis unresponsive to therapy
− Childhood form (14 years or younger)
− Increasing spleen size, or WBC count ○ Male predominance
○ Increase with increasing family size and decreasing
3. Blasts Crisis socioeconomic status
− Marrow or peripheral blasts exceeds 19% − Young adult form (15-34 years)
− May be myeloid or lymphoid or mixed ○ Equal gender distribution
− Presentation can mimic leukemia ○ Associated with higher socioeconomic status
○ Risk decreases significantly with increase sibship size and birth
Clinical Course order
• 90% of patients are in the chronic phase at diagnosis − Older adult form (55-74 years)
• Untreated: progressive disease in 3-8 years after diagnosis

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EBV and Hodgkin Lymphoma Diagnostic work-up

• Young adult form: delayed exposure to an infectious agent, risk factor • Excisional LN Biopsy - preferred procedure to establish the diagnosis
for development • PE: node bearing areas and measurement so change can be
• Childhood form: early, intense exposure to an infectious agent quantified
• Enhanced activation of EBV may precede the development of HL • CT of the neck is always recommended
• Virus is localized in the R-S cells, expression of EBV latent products, • CXR - primary information about mediastinal involvement and
EBV infection (clonal) intrathoracic structure
• CT and MRI scan - splenic and hepatic involvement
Clinical manifestation − Splenic involvement in 30-40%
• UTZ useful but only histologic assessment can provide definitive
• LAD (lymphadenopathy) in HL
evaluation of the spleen
− Painless supraclavicular or cervical adenopathy
• PET - preferred functional imaging for lymphoma staging and follow-
− Affected LN are firm, rubbery, sensitive to palpation
up
− 2/3 presents with some degree of mediastinal involvement
− Correlate with proliferative activity in tumors undergoing anaerobic
− Cause non-productive cough glycolysis
− Symptoms of tracheal or bronchial compression − Correlate whether residual mass like opacities in CT represent an
• Systemic Symptoms active disease or areas of fibrosis
− Nonspecific symptoms • Primary bone involvement - RARE (5-20%)
○ Fatigue − (+) bone pain, elevated ALP for age, extranodal disease
○ Anorexia − prompt evaluation of bony sites
○ Slight weight loss
− Technetium-99 Bone scan with plain radiograph of the abnormal
− Constitutional (B) Symptoms areas
○ Unexplained fever (T°>38°C orally)
− FDG PET - more sensitive and specific
○ Unexplained weight loss of 10% within 6 months preceding
• BMA involvement at initial presentation
diagnosis
− UNCOMMON and RARELY occurs as isolated site of extranodal
○ Drenching night sweats
disorder
• Pruritus
− Mild or severe
− Has a similar prognostic significance and confers poor prognosis Ann Arbor Staging Classification for HL
− Occurs in patients with advanced-staged disease STAGE DEFINITION
− More common in women I Single LN region (I) OR of a single extra lymphatic organ or
− Generalized site (Ie)
− Mechanism: II 2 or more LN region on the SAME SIDE of the diaphragm (II)
○ Cholestatic liver disease OR localized involvement of an extra lymphatic organ or site
○ Peripheral sensory neuropathy and 1 or more LN regions in the SAME SIDE of diaphragm (Ile)
− Resolves when HL is treated III LN region on BOTH SIDE of diaphragm (III) which may be
• Alcohol-induced pain accompanied by involvement of the spleen (Ills) OR by localized
− Usually in areas of nodal enlargement involvement of an extra lymphatic organ or site (Ille) or both
− Begins within minutes of drinking alcohol (Illse)
− Pain may develop in the chest and radiate to the extremities or IV DIFFUSE or DISSEMINATED involvement of one or more extra
back lymphatic organs or tissues with or without associated LN
− Resolves when HL is treated involvement
− Unknown mechanism
Treatment
Laboratory Profile • Radiation sensitive
• Peripheral blood: neutrophilic leukocytosis, lymphopenia, • Chemotherapy sensitive
eosinophilia and monocytosis
• Absolute lymphocytic count is usually normal in children at the onset B. RENAL TUMORS
• Anemia indicate advanced disease and usually results from impaired • Wilms Tumor or Nephroblastoma
mobilization of iron stores − Most common primary renal tumor in children
• HL + Hemolytic anemia: • Others:
− Coombs +, reticulocytosis, normoblastic hyperplasia − Clear Cell Sarcoma of the Kidney
• Autoimmune disorders associated with HL − Rhabdoid Tumor
− NS (Nephrotic syndrome) − Renal Cell Carcinoma
− AIHA (Autoimmune Hemolytic Anemia) • Peak age incidence: between 3 and 4 years old
− ITP (Immune Thrombocytopenic Purpura) • Usually sporadic, 1-2% familial
○ Occurs in patients in remission after completion of therapy for
HL
Etiology
• ESR, serum copper and ferritin: elevated
• C-reactive protein: diagnostic and prognostic index • Congenital anomalies (10-15%)
• Immunologic Status • Aniridia, genitourinary malformations, hemihypertrophy, WAGR
− NK cell activity - reduced in untreated patient syndrome, Denys-Drash syndrome, Beckwith Wiedmann
− Abnormal cellular immunity secondary to presence of suppressor Syndrome
T lymphocytes • Associated genes
− Depressed humoral immunity after treatment − WT1 on chromosome 11p
− Secondary to cytokine interactions − WT2
− Loss of heterozygosity of 16q
− Loss of short arm of chromosome 1
− Deletions and translocations in 7p
− p53 mutations

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PEDIATRICS II

Clinical Manifestations Pathology

• Initial S/Sx: • 2 kinds of histology
− Abdominal mass (60%) − Favorable
− Hypertension (25%) ○ May be classic or triphasic (composed of epithelial, blastemal,
− Hematuria (15%) and stromal elements); biphasic, or monomorphous
− Obstipation (4%) ○ Better prognosis
− Weight loss (4%) ○ That’s why we really need to check for the histopathology results
− Urinary Tract Infection (3%) to see any of these features for us to classify if it is favorable or
unfavorable because the treatment protocol would differ
Diagnosis − Unfavorable
○ Presence of anaplasia
• Complete blood count to evaluate for polycythemia or anemia ○ Cells have nuclear enlargement, nuclear atypia, irregular
• Urinalysis to check for hematuria and UTI mitotic features
• Blood chemistry: BUN, Creatinine, Uric Acid, SGOT, SGPT, LDH, ○ 2 types:
ALP  Focal; better prognosis
• Coagulation factors  Diffuse
• Imaging modalities
− Abdominal x-ray Treatment
− Renal UTZ including Doppler imaging of renal veins and IVC:
• 3 modalities of treatment
show heterogeneous solid nature of the tumor and the presence or
− Surgery
absence of thrombosis
− Chemotherapy
− CT scan or MRI of the abdomen
− Radiotherapy
− Contrast enhanced chest CT: for lung metastases

Staging
Stage Description Other Criteria
Stage 1 Completely resected tumor limited to kidney with intact capsule No biopsy or rupture of tumor prior to removal
No involvement of vessels or renal sinuses
No tumor at or beyond margins of resection Regional LN negative for
tumor
Stage II Completely resected tumor No tumor at or beyond margins of resection
Regional LN negative for tumor
One or more of the following:
Penetration of renal capsule
Invasion of vasculature extending beyond the renal parenchyma
Stage III Residual tumor present after surgery, confined to the abdomen One or more of the following present
One or more regional LN positive for tumor
Tumor implanted on or penetrating through peritoneum
Presence of gross unresected tumor or tumor at margin of resection
Any tumor spillage occurring before or during surgery, including
biopsy
Tumor removed in more than one piece
Stage IV Presence of hematogenous metastasis (lung, liver, bone, brain) Presence of LN metastasis outside the abdomen or pelvis

Stage V Wilms tumor in both kidneys

C. NEUROBLASTOMA Clinical Presentation

• 3rd most common malignancy in childhood
• Originates from neural crest cells that normally give rise to the
adrenal medulla and the sympathetic ganglia
• Most common solid tumor in children younger than 1 year
• More common in boys
• Majority are diagnosed within the 1st 5 years of life
Pathogenesis
• NB cell is one of the small round blue cell neoplasms of childhood
• Neurophil
− Characteristic feature of all except the most primitive
neuroblastomas
• Homer- Wright Pseudorosette
− Ring of neuroblasts surrounding areas of eosinophilic neutrophil
• MYCN Oncogene
− Tumors with MYCN amplification are usually highly aggressive
and are associated with poorer prognosis
• Anorexia, vomiting, abdominal pain, palpable mass, massive
involvement of the liver with metastatic disease
• Can occur anywhere in sympathetic NS
• Majority occurs in the abdomen (65%), followed by the thorax, pelvis,
rarely head and neck (Horner’s syndrome)
• Tumors along the spinal column can extend into the infra-foraminal
spaces and cause spinal cord compression
• Metastatic to lymph nodes, bone, BM, liver
Diagnostic Workup
• Hx: catecholamine related symptoms
− Hypertension, flushing, sweating, irritability, weight loss, pain,
limp
• PE: preorbital ecchymosis, cutaneous nodules; abdominal mass;
weakness/paralysis
• CT/MRI to locate tumor
• Bone scan; MIBG; PET
• Urinary catecholamines: Homovanillic acid (HVA) & vanillylmandelic
acid (VMA) because only neuroblastoma would express these
• Bilateral BMA and biopsy; chromosome studies

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PEDIATRICS II

D. LIVER TUMORS
• Malignant liver tumors
− 1% of pediatric malignancies
− Hepatoblastoma accounts 2/3
− Others: Hepatocellular CA, Sarcoma, Germ Cell Tumors,
Rhabdoid tumors
• Benign tumors
− 1/3 of liver masses
− Vascular tumors, hamartomas, adenomas, focal nodular
hyperplasia

HEPATOBLASTOMA
• More commonly diagnosed in patients with a history of prematurity
• Diagnosed in children younger than 5 years
• Slightly more common in males
Example of a periorbital hematoma (Racoon eyes) present in
neuroblastoma
HEPATOCELLULAR CA
• Primarily occurs in adolescents
Staging
• Most cases are diagnosed after 10 years
Stage 1 Localized tumor with complete gross excision, with or • More common in South East Asia
without microscopic residual disease
Pathogenesis
Stage 2A Localized tumor with incomplete gross excision, Ipsilateral
nonadherent LN negative for tumor • Environmental Factors
− Associated factors for Hepatoblastoma
Stage 2B Localized tumor with or without complete gross excision, ○ Occupational exposures in fathers (welding and soldering
with ipsilateral nonadherent LN positive for tumor. fumes, petroleum products, paints)
Contralateral nodes negative for tumor ○ Prenatal exposure to acetaminophen in combination with
petroleum products
Stage 3 Unresectable unilateral tumor infiltrating across the midline. ○ Prematurity and low birthweight
Or localized unilateral tumor with contralateral LN − Hepatocellular CA in childhood
involvement; or midline tumor with bilateral extension by ○ Associated with cirrhosis following perinatal infection with
infiltration. Hepatitis B during infancy
• Genetic Syndromes
*Neuroblastoma, to differentiate it with other malignancy, it Genetic syndromes associated with hepatoblastoma and
has the propensity to cross the midline hepatocellular carcinomas
Stage 4 Any primary tumor with dissemination to distant LN, bone, Hepatoblastoma Hepatocellular
BM, liver, skin, and or other organs (except as defined by • Beckwith-Wiedemann • Glycogen storage diseases
stage 4S) with metastasis syndrome (BWS) • Hereditary tyrosinemia (very high
• Hemihypertrophy incidence of HCC)
Stage 5 Localized primary tumor (as defined for Stage 1, 2A, 2B) • Familial adenomatous • Alagille syndrome
with dissemination limited to the skin, liver and /or BM polyposis • Neurofibromatosis
(limited to infants <1yr of age) • Li-Fraumeni syndrome • Ataxia telangiectasia
• Trisomy 18 • Fanconi anemia (coupled with
• Glycogen storage disease increased use of anabolic
Treatment types I-IV steroids)
• Surgery: debulk or total removal; curative in low-stage disease; 2nd- • Tuberous sclerosis
look after other Rx
• Chemotherapy: predominant modality of management in • Cytogenic alterations
neuroblastoma patients who have intermediate or high-risk disease − Trisomy of chromosome 2 and 20
• Radiotherapy (RT): to primary tumor site
• NB cells very radiosensitive Clinical Manifestation
− Before or after surgery • Asymptomatic abdominal mass
− Emergency relief for cord compression • Abdominal pain, nausea and vomiting, weight loss, anorexia
− Respiratory compromise • Liver function is normal
− Proptosis • Jaundice is not common
• Bone Marrow Transplant (BMT): − May be seen in
− children with poor prognosis initially may be treated with high dose ○ Liver tumors developing in the context of viral hepatitis and
chemotherapy with autologous stem cell rescue(s) HCC
− BMT may be used with relapse ○ Extensive disease with compression of the major bile duct
• Precocious puberty
Prognosis: − Associated with tumors producing BHCG or testosterone
• <1 year of age: best (75+% survival) • Thrombocytosis
• worst for children >2 with stage IV disease (10-20%)

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PEDIATRICS II

Diagnosis Treatment
• Plain film X-ray or Ultrasound of the abdomen • Surgery
• CT or MRI: needed for definitive characterization of the mass − most important modality for treatment
• Chest CT • Chemotherapy
− Lung: most common distant site of metastasis • Radiation therapy: no major role
• CBC • Hepatoblastoma
− Mild normocytic and normochromic anemia with − Chemosensitive tumor
thrombocytosis − Surgery remains the predominant mode of cure
• Serum AFP and BHCG − Unresectable despite neoadjuvant chemotherapy
− AFP: elevated >90% ○ Total hepatectomy with a liver transplant
○ Good marker, returns to normal with effective therapy and • Hepatocellular CA
increases with recurrence − Complete surgical resection
• Biopsy: for accurate diagnosis − Chemoresistant

Staging
Stage European, SIOPEL/PRETEXT North American Staging
Considers only pretreatment extent of the disease Based on surgical resectability and presence of metastases

1 Tumor involves only 1 quadrant; 3 adjoining liver quadrants are
free of tumor
2 Tumor involves 2 adjoining quadrants; 2 adjoining quadrants are
free of tumor
No metastases; tumor completely resected
No metastases; tumor grossly resected with microscopic residual
disease (i.e. positive margins, tumor rupture, or tumor spill at the time
of surgery

3 Tumor involves 3 adjoining quadrants or 2 adjoining quadrants; 1 No distant metastases; tumor unresectable or resected with gross
quadrant or 2 nonadjoining quadrants are free of tumor residual tumor, or positive nodes

4 Tumor involves all 4 quadrants; there is no quadrant free of Distant metastases regardless of the extent of liver involvement
tumor
***There’s a total difference between the two especially in large or huge liver tumors that are unresectable

E. RHABDOMYOSARCOMA
• Most common soft tissue sarcoma
• 75% occur in children below 10 years old
• Peak incidence: between 3-5 years old
• 2nd peak: adolescence
• Tumor site
− Head and neck (40%): most common in younger than 8 years
○ Orbital tumors: almost always of the embryonal subtype
− Genitourinary tract (20%)
− Extremities (20%): more common in adolescents, usually alveolar
subtype

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