Pediatric Oncology

I. Cancer in Children
1) Many scientific findings started in pediatric oncology and then spilled out into the adult world
2) General statistics
a) 2% of new cases of cancer in US occur in children.
b) Major cause of death from disease for ages 1-15 years
Number one cause of death from disease in children (more than congenital heart disease,
CF)
c) 6,500 new cases annually in children
d) Incidence rate 14:100,000 population
e) Overall, there is an increase in incidence but a decrease in death rate
f) Acute lymphocytic leukemia has highest incidence
-1/3 of all pediatric cancer
Major incidence in early school years
Produces majority of deaths from cancer in children
g) Brain tumors are the most common solid tumor seen in children
Often are benign cellularly but are malignant due to their location
h) Many tumors (like Wilms tumor) occur early in childhood
i) Non-hodgkins occurs at any age; Hodgkins occurs in young adulthood
j) Retinoblastoma is an inherited malignancyOne of the first to show genetics of cancer
k) Lung cancer, breast cancer, prostate cancer etc are common in adults but are not seen in
children
3) Environmental factors
a) Ionizing radiation (generally to fetus) give risk ratio of 1.5.
b) Ultraviolet radiation leads to skin cancer in later life or with genetic predisposition.
c) Drugs, eg, diethylstilbestrol, immunosuppressive agents, anabolic androgenic steroids
d) Diet/modifications, no support yet
e) Viruses, eg, human T-cell leukemia virus, EBV, papilloma viruses
EBV: Hodgkins, nasopharyngeal CA
f) Really, we do not know what causes cancer we do know what increases the risk for it though


II. Molecular Pathogenesis
1) Oncogenes
a) Endogenous human, DNA sequences
b) Arise from normal cellular genes called proto-oncogenes
c) Alterations occur in either regulatory or structural region by variety of mechanisms (point
mutation, deletions, fusing chromosomal translocation, amplification).
Unsure why these things happen
d) Thought to act in a dominant fashion
e) Oncogene alterations important as cause of some pediatric tumors
rhabdomyosarcoma
Burkitts lymphoma - 8:14 translocation places c-myc next to Ig gene enhancer
2) Tumor-suppression genes
a) Down regulate cell growth
Decrease chances of developing malignancy
b) Inactivation allows malignant growth.
c) Knudsen proposed two-hit model to explain familial retinoblastoma.
You inherit one gene, and loss of the second gene due to mutation etc. cause malignancy
3) Other mechanisms
a) Disorders of DNA repair, eg, Fanconi anemia, xeroderma pigmentosum, Bloom syndrome
4) All of these etiologies began with pediatrics
a) Can now be applied to adult cancers as well





III. Principles of Diagnosis
1) The earlier the better
a) Be aware of presenting signs and symptoms of pediatric malignancy
b) Usually these are fairly nonspecific
c) Listen to the parents and take what they have to say seriously
2) Good history and physical examination
3) Persistent problems
4) Look at the parents
IV. Chemotherapy: complications that pediatrician might see
1) Fever/neutropenia
a) Culture and begin parenteral antibiotics if ANC < 500 or < 1000 and dropping in the presence
of fever > 38.3C
b) Know their neutrophil counts and whether they drop
c) Get this taken care of quickly if it occurs
2) Opportunistic infections include fungus, Pneumocystis carinii, viruses
a) Varicella used to be the number one cause of death in children with ALL
b) Must know how immunosuppressed your pediatric patients are
3) Metabolic problems - uric acid, K, Ca, etc.
a) This usually occurs in the induction period
b) These are stabilized once patient is stabilized
4) Hematologic issues - platelets, anemia
a) As chemotherapy continues this can be a problem until marrow regenerates
5) Immunizations are generally held until 6 months after completion of therapy



V. Leukemias (33% of pediatric malignancies)
Acute lymphoblastic leukemia (ALL)
a) Etiology
Most common childhood malignancy
(i) Used to be uniformly fatal
(ii) Now, survival rate is up to 90-95%
75% of leukemias
Peak age 4 years
Incidence: 42.1 per million white and 24.3 per million black children
b) Clinical/lab findings (pretty nonspecific)
Bone marrow failure/disruption is source of all signs/symptoms.
66% have signs/symptoms < 4 weeks at diagnosis
Pallor, bleeding (50%), fever (25%)
(i) Many have received antibiotic
(ii) Nosebleeds etc. due to thrombocytopenia
Bone pain (25%)
Examination can be normal, or hemorrhage, lymphadenopathy and organomegaly present.
c) 3 morphologic subtypes (seen in blood smear)
L1, small blasts, little cytoplasm (early B lineage)
L2, larger blasts, irregular nuclear shape, prominent nucleoli (T cell)
L3, larger blasts, homogenous nuclear chromatin, prominent nucleoli, deep blue cytoplasm,
prominent vacuolization (Burkitts association - mature B)
d) Subtyping will define treatment later on
e) Classification based upon cytologic, immunologic and karyotypic features of marrow analysis
f) Clinical/lab findings
80-85% B-progenitor cell derived, 15% T-progenitor cells, 1% mature B-cell
(i) Early B lineage cells are very chemosensitive
(ii) T lineage cells usually present in older patients
No staging system because most already disseminated throughout the body


Cytopenias most common presentation
g) The more chromosomes seen in type of leukemia, the better the prognosis
h) BCR-ABL has a particularly bad prognosis
i) Treatment
Based on type and clinical risk features - Chemotherapy is mainstay
(i) 2-3 years.
(ii) Usually after approx. 1 month children will go into remission
Prognosis is better for younger children
1 year and < 10 years; WBC < 50,000; B-progenitor-cell immunophenotype are average
risk.
(i) Girls do better than boys
(ii) Lower white counts = better prognosis
CNS prophylaxis
(i) Without prophylaxis, CNS leukemia may develop
(ii) Chemotherapy does not enter brain and brain is locus for cancer cells to grow
(iii) Initially radiation was used as prophylaxis decreased CNS leukemia rates from
50% to 5%
(iv) Now intrathecal chemotherapy is used as prophylaxis
Probably not any longterm sequelae from this route
(v) Radiation to young children can have some devastating effects
Supportive care
j) Risk assigned depending on age, type of cancer etc.
There are different protocols for each category
Very high risk children may be candidates for bone marrow transplant
k) Randomized trials for pediatric ALL
Prednisone vs Dexamethasone
(i) Oral vs IV of each
Patients on dexamethasone did better than prednisone (route did not matter)
(i) This trial changed standard of care for steroid therapy from prednisone to
dexamethasone


l) Infections associated with chemotherapy treatment
Patients are more prone to bacterial infections early in treatment
(i) Due to decreased levels of neutrophils
Pneumocystic carinii (jirovecii) seen during remission
(i) Every child with leukemia is given pneumocystic prophylaxis before this 5% of
patients would die from this pneumonia
Varicella zoster
(i) Very painful, seen often in children with leukemia due to immune suppression
Acute myeloid leukemia (AML)
a) Etiology
15-20% of leukemias
Distribution by age consistent throughout childhood
(i) No peak incidence
(ii) More common in children who are very young (<1 year)
(iii) May be secondary to chemotherapy treatment for another type of cancer (e.g.
Hodgkins)
Predominant neonatal/congenital leukemia
Associated with chromosomal abnormalities (trisomy 21, Fanconis anemia, chemotherapy
induced)
b) Clinical/lab findings symptoms may last longer before diagnosis is made
Signs/symptoms attributed to bone marrow failure
Pallor, bleeding, fever
Organomegaly, lymphadenopathy
Myelodysplastic syndrome presents with single cytopenia, presence of blasts in bone
marrow (< 30%), generally milder symptoms.
Morphologic, immunophenotypic and karyotypic evaluation to distinguish from ALL
c) FAB system, eight subtypes:
M0, myeloblastic, no maturation, common
M1, myeloblastic, no maturation, common


M2, myeloblastic, some maturation, common
M3, hypergranular promyelocytic, uncommon
M4, myelomonocytic, common
M5, monocytic, common
M6, erythroleukemia, rare
M7, megakaryocytic, uncommon
d) Generally all types are treated the same way except M3
M3 is treated with retinoic acid (a vitamin) which allows maturation of cells and cures
leukemia
e) Treatment
Chemotherapy is standard, currently utilize intensive timing induction.
(i) Much more aggressive than ALL treatment and side effects are greater
Consolidation: bone marrow transplant and/or chemotherapy
CNS prophylaxis
f) Poorer outcome than ALL
Survival is around 50%
Chronic myelogenous leukemia (CML)
a) This is more of an adult disease
b) Clonal malignancy characterized by the chromosomal translocation t(9;22)(q34;q1)
(Philadelphia chromosome)
c) Myeloid hyperplasia (> 100,000/mm
3
)
d) Hypercellular marrow
e) Chronic phase last 3-4 years, treat with imatinib
Cures this leukemia
f) Accelerate to blast phase.
g) Allogenic bone marrow transplant


VI. Lymphoma
Hodgkins disease
a) Etiology
Industrialized countries bimodal age peak, early peak in middle to late 20s and late peak
after 50 years
Males > females, whites > other races, immunodeficiency higher
EBV implicated in pathogenesis
Cell of origin unknown
(i) Probably a B lymphocyte
b) Clinical/lab findings
Cardinal histologic feature is Reed-Sternberg cell
c) 4 histologic subtypes
Nodular sclerosing: most common, 50% of childhood cases, 70% of adolescent cases, broad
bands of collagen divide node into nodular, cellular areas.
Mixed cellularity: second most common form, 40-50% of patients, inflammatory
background of mixed cells, abundant Reed-Sternberg cells, present with advanced disease.
Lymphocyte predominant: most cells are mature lymphocytes, 10-20% of patients, more
common in younger males, localized disease, best prognosis.
(i) Treated with radiation only
Lymphocyte depletion: least common, least favorable, < 10% of patients, few lymphocytes,
bizarre malignant cells, widespread disease
(i) Most unusual type
d) Clinical/lab findings
Painless enlargement of lymph nodes in cervical, supraclavicular, occasionally axillary or
inguinal areas
(i) Supraclavicular node enlargement is Hodgkins until proven otherwise
(ii) Generally the lump is what brings them in to the office
33% systemic symptoms (fatigue, pruritis, lethargy, anorexia, pain increased with alcohol)


B symptoms are unexplained fever, 10% plus weight loss in previous six months, night
sweats
Biopsy of enlarged nodes, extensive staging, evaluating above and below the diaphragm
Staging laparotomy rarely done now
(i) Due to effectiveness of therapy
e) Treatment
Chemotherapy and radiation therapy either alone or in combination
Stage I/II 95%+ cure
Stage III 75-90% cure
Stage IV 60-85% cure
Late sequelae (malignancy, sterility) a concern
(i) Patients that were treated very aggressively in 70s and 80s have developed secondary
malignancies (breast cancer etc.) in area of radiation
f) Very important that these children are treated at pediatric cancer centers
Want to minimize sterility, avoid secondary malignancies
Non-Hodgkins lymphoma (NHL)
1) More aggressive than Hodgkins lymphoma
a) Can occur explosively in any node
2) Etiology
a) Increased in inherited immunodeficiency states or HIV
b) 25% marrow involvement designated leukemia
3) 3 primary subtypes
a) Small noncleaved cell (SNCC), Burkitts lymphoma, B-cell tumors, characteristic chromosomal
translocations: t(8, 14), t(2, 8), t(8, 22), each involves C-myc oncogene (8) and an
immunoglobulin gene.
First chromosomal translocation to be identified
Chromosomal translocation is universally diagnostic
b) Lymphoblastic, T-cell origin, may have T-cell receptor gene translocation
c) Large cell, T-, B-, or non -B/non -T cell phenotypes


4) Clinical/lab findings
a) Most frequent sites are abdomen (31%), mediastinum (26%), head/neck (29%).
Burkitts often occurs as a diffuse abdominal malignancy
(i) Very rapid growth, but also very chemosensitive
Mediastinal sites tend to be T-cell lymphomas while abdominal sites tend to be B-cell
lymphomas
b) Diagnose quickly due to rapid growth rate
c) CT, bone scan, gallium scan
5) Treatment
a) Chemotherapy
b) Tumor lysis syndrome common (hyperkalemia, hyperphosphatemia, hypocalcemia)
Because of rapid growth
c) Stage I/II 90% survival
Malignant cells are very chemosensitive
d) Stage III/IV 70% survival
II Neuroblastoma
1) Often occurs in the abdomen
2) Very aggressive and lethal (compared to Wilms tumor which is very curable)
3) Etiology
a) Most common extracranial solid tumor
b) 8-10% of childhood cancer
c) 90% diagnosed before 5 years
4) Clinical/lab findings
a) 60-75% of patients have metastatic disease at diagnosis.
Majority do not survive this disease even with marrow transplantation
b) Mass in abdomen, chest or head/neck. Metastases to liver, bone marrow, bone, skin, orbits may
be presenting signs.
May present like leukemia
c) N-myc oncogene amplification has prognostic significance (poor).
About of children with metastatic disease have this oncogene amplification


d) Cytogenetic abnormalities present in 80%, include partial deletion of short arm of 1,
chromosome 17 anomalies
5) Treatment
a) Stage A (I) - surgery only
b) Stage B (II)- surgery/chemotherapy
c) Stage C (III) - surgery/chemotherapy
d) Stage D (IV) - chemotherapy
e) Stage DS (IV-S) - no treatment or chemotherapy
6) Localized disease is likely to be cured while metastatic disease is usually lethal
7) IV-S: seen in very young children (<1 year) with metastatic disease all over
a) These children often cure themselves may be a developmental abnormality
b) Unsure why this occurs
VII. Neoplasms of the Kidney
Wilms tumor (nephroblastoma)
c) Often these children are very active and do not seem sick except for the huge abdominal mass
(as compared to neuroblastoma where the children appear very sick)
1) Etiology
a) Deletions involving loci on chromosome 11 in 33%
b) Association with two syndromes with constitutional deletions of 11p13
WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, mental
retardation)
Denys-Drash syndrome (Wilms tumor, nephropathy, genital abnormalities)
c) Association with deletion of 11p15
Beckwith-Wiedemann syndrome (embryonal neoplasm, hemihypertrophy, macroglossia,
visceromegaly)
d) Wilms tumor is the pediatric tumor with the most genetic abnormalities associated with it.
2) Clinical/lab findings
a) Median age 3 years
b) Asymptomatic abdominal mass


Usually mother or physician notices that belly is growing and feels a lump
c) Hematuria 10-25% of cases
d) Intrarenal mass on imaging
3) Staging system of National Wilms Tumor Study (NWTS)
a) I - limited to kidney, completely excised
b) II - extends beyond kidney, completely excised.
c) III - postsurgical residual confined to abdomen (nonhematogenous)
d) IV - hematogenous metastases (lungs most common)
e) V- bilateral disease
4) Treatment
a) Surgical removal of affected kidney if possible (even if metastatic) by experienced pediatric
surgeon
Adult kidneys are removed posteriorly
In this type of tumor they need to examine other kidney as well to make sure it is normal
before removing cancerous kidney (should use a midline incision)
(i) If both are abnormal than chemotherapy is used do not want to remove one abnormal
kidney if the other is abnormal as well
b) Combination chemotherapy
c) Radiation therapy in advanced disease
5) Survival rate is around 80% with metastatic disease and 90% if localized
VIII. Soft Tissue Sarcomas - Rhabdomyosarcoma
1) Etiology
a) Pay attention to these types of tumors
Lumps/bumps in muscle in absence of trauma
b) Most common pediatric soft tissue sarcoma
c) 5-8% of childhood cancers
d) Any site: head and neck (40%), genitourinary (20%), extremities (20%), trunk (10%),
retroperitoneal/other (10%)
e) Arise from embryonic mesenchyme that gives skeletal muscle


2) Clinical/lab findings
a) Mass with/without pain
b) Symptoms due to displacement or obstruction
With obstruction may present with abdominal emergency
c) Metastases to lung, bone, bone marrow
d) Most kids are caught in the early stage of disease
e) Pathology
Embryonal - 60% of cases
Botryoid - embryonal variant in a body cavity (bunch of grapes), 6% of cases
Alveolar - 15% of cases, characterized by t(2;13) translocation
(i) poorest prognosis
Pleomorphic - adult form, rare in children (1%)
Undifferentiated - 20% of cases
f) Rhabdomyosarcoma
3) Staging
a) I local, complete excision
b) II local, microscopic residual
c) III local, gross residual
d) IV metastatic (25%-50% prognosis)
4) Treatment
a) Surgical excision, completely whenever possible
b) Chemotherapy for all patients
c) Radiation for local control
Try to avoid radiation as much as possible because of longterm effects



IX. Neoplasms of Bone
Osteosarcoma
a) Etiology
Adolescence, metaphyseal region, associated with rapid bone growth
Increased risk seen with:
(i) Hereditary retinoblastoma (loss of normal Rb tumor-suppressor gene)
(ii) Li-Fraumeni syndrome, germline p53 mutations
(iii) Paget disease
(iv) Osteogenesis imperfecta
(v) Local irradiation to bone
b) Clinical/lab findings
Highly malignant spindle cell neoplasm, produces osteoid - sunburst on x-ray
Pain and swelling localized
History of trauma (usually coincidental)
Metastases to lungs
(i) Metastasis occurs fairly early
Most often long bones (distal femur, proximal tibia, proximal humerus)
(i) Look for painful lumps around knee and upper arm
c) Treatment
Chemotherapy - very aggressive
Complete surgical resection many children have amputation of extremity
(i) Radiation and chemo do not control cancer very well



Ewings sarcoma/peripheral neuroepithelioma (PNET)
a) Etiology
Chromosomal translocation t(11;22)(q24;q12),
(i) This translocation is diagnostic
Adolescence, Male predominance
Rare in black children
Most often in flat bones (pelvis, ribs, scapula, skull)
(i) Rib tumors are not osteosarcomas
(ii) If seen in long bones they are mid shaft
b) Clinical/lab findings
Pain, swelling, tenderness localized
Metastases to lungs, bone, bone marrow
c) Treatment
Chemotherapy - aggressive
Radiation therapy
(i) Controls local site which decreases amputation rate
Complete surgical resection
(i) Radiation controls spread better than osteosarcoma and amputation is usually not
necessary



Retinoblastoma
1) Etiology
a) 1/16,000 live births
b) 30% AD predisposition/bilateral involvement, median age 11 months
2
nd
hit (for whatever reason) causes disease development
Youngest presenting age of any pediatric tumor
c) 70% unilateral, random, median age 23 months (20% have a genetic predisposition).
d) Retinoblastoma gene on 13q
e) Children should undergo an exam by an ophthalmologist at birth if there is a family history of
retinoblastoma
Look for red reflex if not seen this could be presenting sign of retinoblastoma
2) Clinical/lab findings
a) Diminished/absent vision
b) Mother may notice there is not red eye or a whitish spot on eye
c) Metastases to CNS, bone, bone marrow
This is pretty unusual
3) Treatment should be done by ophthalmologist that specializes in these types of cancers
a) Surgery (survival > 90%)
Enucleation
Cryotherapy
Laser therapy
b) Radiation therapy
c) Chemotherapy (generally for bilateral)
d) Most do not need radiation or chemotherapy


X. Brain Tumors
1) Etiology
a) Second only to leukemia in prevalence
b) Most common solid tumors
c) Present at any age
d) 66% occurring in children 2-12 years are infratentorial (posterior fossa).
Most adult brain tumors are supratentorial
e) < 2 years, > 12 years equal between infratentorial and supratentorial
2) Two major histologic types
a) Glial cell;
most common; include astrocytoma, ependymoma, glioblastoma multiforme
These are not malignant and grow very slowly
Brainstem location makes them difficult to treat (radiation, chemo do not work well)
b) Primitive neuroectodermal cell,
Undifferentiated cell line; seen throughout the CNS; cerebellum (medulloblastoma),
cerebrum, spinal cord, pineal gland (pineoblastoma)
These tumors need radiation and chemotherapy for treatment
3) Association with both types of neurofibromatosis, radiation treatment
4) Clinical/Lab findings
a) Signs/symptoms of increased intracranial pressure (ICP)
b) Focal neurological signs
c) Alterations in personality
d) Morning headache typically associated with vomiting
Any child who wakes up in the morning, vomits and then feels better has a brain tumor
until proven otherwise
e) Diplopia, cranial nerve signs
f) Ataxia, gait abnormalities
g) Head tilting, nuchal rigidity
h) Papilledema (cardinal sign)


5) Infratentorial tumors
a) Cerebellar astrocytoma - most common
b) Medulloblastoma
Most malignant most children receive chemotherapy and radiation
c) Brain stem gliomas
Poor prognosis because these are usually inoperable
d) Ependymomas
6) MRI best evaluation technique
7) Treatment
a) Surgical resection whenever possible
Cannot operate on brainstem tumors
b) Radiation therapy for inoperable/recurrent tumors and as adjuvant
c) Adjuvant chemotherapy for some types (eg, medulloblastoma)
XI. Late Effects
1) Caused by disease process
2) Caused by treatment
a) Surgery
b) Radiation
c) Chemotherapy
3) Treatment summary and long-term follow-up plan
4) Remember: children of patients that had these cancers will very infrequently have tumors with
similar symptoms etc.
a) NOT prone to congenital malformations or malignancies