Pediatric Oncology 2019 Flashcards
To prepare for College Exam
6 MP
What is mechanism of action/excretion, uses, short and long term toxicity?
A Cancer What is the incidence of pediatric cancers by age group?
ALL Epedimiology?
Most common type of childhood cancer; 1/3 of childhood ca, of which ¾ is ALL
85% of all childhood leukemia; incidence 3/100,000
Peak 2-6yrs, boys>girls
ALL Etiology?
8 conditions, and 4 environmental associations?
- Unknown,
- genetic conditions
Ataxia-telangiectasia, Bloom, Down, Fanconi, Klinefelter, NF-1, SCID, Turner
- environmental associations -benzene, drugs (alkylating agents),3ionizing radiation, ,
ALL What are the High risk features?
what are the survival outcomes?
Name one bad translocation?
- NACI High risk (Age 10 - 13), WBC >50 = 75% survival
- Testicular disease AND
- SR but MRD+ at D29 +/- other features
ALL Rx What are the Induction drugs and maintainance Rx for Treatment of standard risk ALL?
What additional Rx for high risk?
- Induction with:
-Intrathecal chemo (Cytarabine + MTX)
- P: Prednisone & PEG asparaginase
- Vincristine, methotrexate
…and Possible if High risk: Daunorubicin
- Maintainence with Mtx and 6-MP
ALL What are flow cytometry + and -ve markers?
flow cytometry
Positive
CD19 B cell
CD10
Tdt
Negative
CD3
MPO
Myeloperoxidase
ALL What are the 4 phases of Rx?
1) Induction – goal is to attain remission (<5% blasts in bone marrow), attained in 95% of children
2) CNS prevention – eradicate subclinical CNS leukemia via intrathecal chemotx
3) Consolidation – goal is to decrease relapse
4) Maintenance
ALL What are the common types of ALL?
- Pre-B ALL
-“Common”
- Infant
- Philadelphia positive
2. T-ALL
- Mature B-cell
Commonest are in BOLD
ALL What are the flow cytometry markers?
Flow cytometry:
CD19 = B-cell marker
CD10 = Early B-cell marker
CD3 = T-cell marker
CD33 = myeloid marker
MPO = myeloid marker
Tdt = Terminal deoxynucleotidyl transferase
ALL What are the Sx?
Reflect degree of bone marrow infiltration by leukemic cells and extent of disease outside the marrow.
Common:
- Pancytopenia symptoms, bruising, palllor & Fatigue
- Other: Fever, Bone pain/limp, Hepatosplenomegaly, Lymphadenopathy
Less common:
- CNS: Cranial nerve palsies, signs of papilledema,
- Mucous/skin: Gum hypertrophy/ skin cutis
3. GUT:
a. Testicular enlargement
3. Nephro: Renal failure
4. MSK: Solid mass (chloroma in spine), vertebral #
5. Complications of SVC syndrome or airway compression 2º mediastinal mass (esp T-cell ALL)
ALL What are the very high risk features?
- Age : > 13 years
- CNS +, Hypodiploidy (<44), iAMP21, KMT2a rearrangement,
BCR-ABL,
- Induction failure, MRD + at D29 (SR or HR)
Are these essential?
Presence of t(9:22) (Philadelphia +), t(4:11),
ALL What are the 3 DDx categories for ALL?
-
Hemato-oncology:
a. Other malignancies (AML, NBL, Ewings Sarcoma, etc.),
b. 1° bone marrow failure (aplastic anemia),
c. Hematology: Transient erythroblastopenia of childhood (TEC), ITP - Infections: EBV,
- Rheum: JIA.
ALL What does this slide show? -
List 5 slide features
Blasts visible with:
a. Large nuclei & Scant cytoplasm (High N:C ratio)
b. Fine chromatin
ALL What factors make a child standard risk?
Age & White cell count?
Trisomy, diploidy, translocation?
- Age >1 & <10 years, WBC < 50,000 = 85% survival
- No unfavourable features AND MRD negative at D29
ALL What Inv do you do?
-
Blood:
a. CBC shows abnormalities of ≥2 cell lines; lymphoblasts on smear
b. Flow cytometry-Cytochemical analysis, Immunophenotyping, Cytogenetic analysis - Bone marrow aspirate –blasts confirms diagnosis (>25%)
- CXR to screen for mediastinal adenopathy
- Lumbar puncture to screen for CNS disease (present <5% children at diagnosis)
ALL What is standard low risk?
- NCI Standard Risk (Age 1 – 10, WBC <50)
- Favourable cytogenetics
a. ETV-RUNX1 (TEL-AML)
b. Trisomy 4 and 10...96% :).
• AND
- MRD negative at D29
ALL What studies of tumor cells are useful for determining a patient’s prognosis?
- The cytogenetics and DNA index (ratio of DNA content in abnormal cells compared to normal reference cells) determines:
a. The number and structure of chromosomes and
chromosomal material in tumor cells. > 50 chromosomes (hyperploidy) or a DNA index > 1.16 is favorable.
b. Certain chromosomal translocations are unfavorable.
2. Immunophenotyping is also useful and involves the determination of B- or T-cell lineage, with maturity or immaturity of cells
AML What are the Dx features?
Bone marrow aspirate –blasts confirm diagnosis (<25%)
Fab subtyping based on histology
AML What are the favourable Fx?
Favorable:
- chromosomes: t(8:21), inv(16), t(9:11), t(15:17),
- remission after 1 cycle,
- Fab-M4 w eosinophilia
AML What are the Rx phases?
1) Induction – goal is to attain remission (<5% blasts in marrow)
2) CNS prevention
3) Consolidation – goal is to decrease relapse
4) Intensification & BMT – high risk of mucositis, infection, prolonged bone marrow suppression
5) Aggressive supportive care, esp w blood products, empiric abx, anti-fungal, nutritional
AML What are the Sx?
- Marrow failure symptoms as in ALL
-
Other symptoms seen in AML
- Subcutaneous nodules or blueberry muffin lesions,
- gingival hypertrophy,
- DIC,
- chloromas or granulocytic sarcomas (discrete masses associated with AML-M2);
- more often see CNS symptoms
AML What are the unfavourable Fx?
Unfavorable:
- chromosomes: monosomy 7,
- initial WBC > 100,000,
- secondary AML,
- myelodysplasia
AML What is the epidemiology and etiology?
Epidemiology: 11% of all childhood leukemia
Etiology:
- Unknown, but several associated chromosomal abn,
- Syndromes (Bloom, Diamond-Blackfan, Down, Fanconi anemia, , Kostmann, Li-Fraumeni , NF-1, Schwachman-Diamond,
- environmental RFs (ionizing radiation, chemotherapy, organic solvents, PNH)
AML What is the prognosis of AML?
What is the remission rate from chemo alone?
What is the remission rate after BMT?
Why do you BMT these guys and not ALL?
- Remission in 80% of patients from chemo alone
- matched-sibling BMT after remission = 60-70% long-term survival;
- graft-versus-leukemia effect from allogeneic transplantation (not seen in ALL)
Aneurysmal bone cyst What are the features?
Reactive lesion of bone
Xray = cavernous spaces filled with blood and solid aggregates of tissue, mostly femur, tibia & spine
Biopsy necessary to confirm diagnosis; treated with excision; recurrence rate 20-30%
Anthracycline (Doxo/Dauno)
What is mechanism of action/excretion, uses, short and long term toxicity?
Extra S/E of doxorubicin
Hair loss, Hand/foot syndrome, u Skin discolouration
Ara C
What is mechanism of action/excretion, uses, short and long term toxicity?
Asparaginase What is mechanism of action/excretion, uses, short and long term toxicity?
Bleomycin
What is mechanism of action/excretion, uses, short and long term toxicity?
Blood formation How are RBCs, white cells and platelets made?
Bone tumor
Brain tumor How do you manage acute hydrocephalus?
- Definitive = divert CSF, or remove block
- Emergent = dexamethasone to reduce oedema
- Can “hold” until gets to a neurosurgeon
Brain tumor How does acute hydrocephalus and cerebral edema present?
Common with aggressive tumours
Tumour may invoke oedema
Blockage of drainage channels – acute hydrocephalus
-Severe hydrocephalus gives cerebral oedema too
Brain tumor medulloblastoma what is the classification?
Pathology
- Classic
- Large cell/anaplastic
- Nodular/desmoplastic
Molecular
Group 1 – WNT
Group 2 – SHH
Group 3
Group 4
Brain tumor What is the commonest malignant brain tumor in children?
How does it present?
Medulloblastoma
Presents:
- Headache, Vomiting, Ataxia
- Cranial nerve palsies & Developmental regression
Brain tumors Epidemiology?
Brain tumors Etiology?
Brain tumors How do you Dx them?
Emergency!!
- Ophthalmology,
- neuroimaging (head MRI),
- neuroendocrine evaluation,
- lumbar puncture
Brain tumors What are the Sx (3/6)
Increased ICP – lethargy, irritability, macrocephaly, headache, papilledema, vomiting
Supratentorial/cortical – subtle personality/speech changes, motor weakness, sensory changes, seizures, reflex abnormalities, infants can present with early handedness(<1yr is pathologic)
Infratentorial – abnormal gait, torticollis, blurred vision, diplopia, nystagmus
Brain tumors What are the Sx (2nd 3/9)
Brainstem – gaze palsy, multiple cranial nerve palsies, UMN defects (hemiparesis, hyperreflexia, clonus)
Optic pathway – decreased visual acuity, Marcus Gunn pupil (RAPD), visual field defect
Suprasellar – neuroendocrine deficits, e.g. DI, galactorrhea, abn puberty, hypothyroidism
Brain tumors What are the Sx (3rd 3/9)
Diencephalic syndrome: FTT, emaciation, increased appetite, euphoria
Pineal region: Parinaud syndrome: paresis of upward gaze, nystagmus, eyelid retraction
Spinal cord: long nerve tract motor and/or sensory deficits, bowel/bladder deficits, back pain
Brain tumors What 4 categories constitute 80% of all pediatric brain tumors?
astrocytoma (Juvenile pilocytic and Diffuse),
PNET (medulloblastoma),
Ependymoma,
Craniopharyngioma
Brain tumors What are the Sx, Rx and Progx of the 4 common types?
Brain tumors What is the epidemiology and origin of the 4 common types?
Cancer etiology What % of childhood cancer are associated with a genetic and/or congenital condition?
15%
Cancer etiology What is the 1st mechanism that genetic conditions predispose to cancer?
1. Gene alteration disrupts normal genetic repair:
Ataxia telangiectasia = lymphoma
Bloom syndrome = leukemia;
Xeroderma pigmentosa = skin cancer;
2. Dysfunctional cellular growth:
Beckwith-Weidemann = Wilms tumor, hepatoblastoma, rhabdo, adrenal tumor;
MEN = Hepatic tumors;
Neurofibromatosis = optic glioma, CNS tumors & rhabdomayosarcoma
3. Inactivation of tumor suppressor gene:
Familial retinoblastoma & Li Fraumeni = osteosarcoma
Cancer etiology What is the role of cancer stem cells?
- May have a role in certain malignancies such as CML, AML, ALL, gliomas, and breast cancer.
- These tumor-initiating cells have self renewal and proliferative properties similar to nonmalignant stem cells.”
Cancer etiology What other factors cause cancer?
- Viruses
EBV – Burkitt’s , Hodgkin + T-cell lymphoma
HBV – Hepatocellular carcinoma
HCV – Hepatocellular carcinoma, splenic lymphoma
HPV – Cervical cancer
HHV-8 – Kaposi sarcoma
- Genomic imprinting (selective inactivation of ½ gene alleles) à Wilms tumor – loss of normal inactivation of maternal gene
- Telomerase (enzyme that adds telomeres on xsomes = “immortal” cell lines
Cancer etiology What 2 major gene classes are implicated in development of cancer?
1) Mutation that converts Proto-oncogenes into oncogenes. These mutations can be:
a. Amplification, e.g. N-MYC in neuroblastoma
b. Point mutation, e.g. 10q RET in MEN2
c. Translocation, e.g. Philadalphia xsome t(9:22) BCR/ABL in ALL
2) Mutation that disables Tumor suppressor genes
Cancer etiology Alterations in which cellular processes can cause cancer?
Cancer is a complex of diseases arising from alterations that can occur in a wide variety of genes.
Alterations in the following normal cellular processes can result in a malignant phenotype:
- signal transduction,
- cell cycle control, DNA repair,
- cellular growth and differentiation,
- translational regulation, senescence and apoptosis (programmed cell death)
Cancer predisposition syndromes Features of Lynch syndrome?
MLH1, MSH2, MSH6, PMS2
non-polyposis Colorectal carcinoma, endometrial, gliomas, ovary, ureteric
Cancer predisposition syndromes Features of Neurofibromatosis type 1?
NF1 gene – complex mutations
Benign nerve sheath tumours, gliomas, MPNST, plexiform neurofibroma
Cancer predisposition syndromes Features of Li Fraumeni Syndrome
Germline p53 mutation
Adrenocortical carcinoma, sarcomas, breast cancer, brain tumours
Cancer predisposition syndrome features of Gorlin Syndrome?
- PTCH mutation – SHH pathway mutation *GROUP 2*
- Naevoid basal cell carcinoma syndrome
Basal cell carcinomas
Medulloblastoma
Odontogenic cysts
Skeletal and cutaneous abnormalities
Carbplatin
What is mechanism of action/excretion, uses, short and long term toxicity?
Chemotherapy side effects Which ones are the most concerning?
- leukoencephalopathy after high-dose methotrexate therapy; 2. infertility in male patients treated with alkylating agents (e.g., cyclophosphamide);
- myocardial damage caused by anthracyclines;
- pulmonary fibrosis caused by bleomycin;
- pancreatitis caused by asparaginase;
- renal dysfunction due to ifosfamide, nitrosourea, or platinum agents; and
- hearing loss from cisplatin
Chemotherapy side effects
What are the most important side effects from:
Mtx
Alkylating agent
Anthracycline
Bleomycin
Asparaginase
Ifosfamide
Cisplatin
Mtx
Alkylating agent
Anthracycline
Bleomycin
Asparaginase
Ifosfamide
Cisplatin
Chemotherapy What are the Late Effects Assessment and Management for lung, urologic and liver?
Chemotherapy What are the Late Effects Assessment and Management for Renal and gonadal?
Chemotherapy What are the Late Effects Assessment and Management for secondary malignancies?
Chemotherapy What are the Late Effects Assessment and Management for heart, lung and thyroid?
Chemotherapy What are the Late Effects Assessment and Management for gonadal?
Chemotherapy What are the Late Effects Assessment and Management for secondary malignancies and other organs?
Chemotherapy What are the Late Effects Assessment and Management for CNS, Cardiac and hearing?
Cisplatin
What is mechanism of action/excretion, uses, short and long term toxicity?
Cisplatin:
Immediate side effects
Nausea/vomiting
Acute renal tubular dysfunction + Hypomagnesaemia
Long-term side effects
Hearing loss
Renal impairment with low GFR
Electrolyte disturbances with low Mg, âK
CML What are:
- What is the incidence of all childhood leukemia?
- What chromosome and translocation is present?
- How long is the chronic phase and what features and what acute phase may happen?
- How is CML Treated?
- 2-3% of all childhood leukemia;
- 99% w Philadelphia chromosome t(9:22) BCR-ABL
- 3-4 yrs of chronic phase (high WBC, low Hb, high Plt, splenomegaly) leading to a “blast crisis” phase
- Treated with busulfan, hydorxyurea & interpheron-alpha; stem-cell transplant the only cure
Cyclophosphamide
What is mechanism of action/excretion, uses, short and long term toxicity?
Dactinomycin
What is mechanism of action/excretion, uses, short and long term toxicity?
Downs ALL and AML
How much commn is acute leukemia in Downs kids?
Which leukemia is more common?
What is the long-term survival?
Which (AML vs ALL has better prognosis?
In Downs kids What is the sensitivity to methotrexate & other metabolites and toxicity?
20x increased frequency of acute leukemia;
ALL>AML except first 3 years of life
prognosis >80% long-term survival.
ALL prognosis slightly worse than others,
AML prognosis slightly better.
More sensitive to methotrexate & other metabolites – higher risk of toxicity
Downs Kids Transient myeloproliferative disorder
- What is theincidence in kids with Down syndrome?
- What are the clinical and lab features?
- What is the Management?
- What is the Chance of leukemia?
- Occurs in 10% of neonates with Down syndrome ; lasts up to 1 year
- High WBC, blasts, anemia, thrombocytopenia, hepatosplenomegaly.
- Management: usually supportive w transfusions
- Chance of leukemia: 20-30% develop acute leukemia by 3 yrs old
Etoposide What is mechanism of action/excretion, uses, short and long term toxicity?
Ewing sarcoma Epidemiology and Etiology?
Second decade, Highest risk during adolescent growth spurt
Undifferentiated bone sarcoma that may arise from soft tissue
Ewing sarcoma What are the DDx?
Other small round cell tumors –
neuroblastoma,
rhabdomyosarcoma,
Non-Hodgkin lymphoma
histiocytosis,
osteomyelitis
Ewing sarcoma What are the Dx features on Xray?
Onion skin
Ewing sarcoma What are the Rx options?
Chemotherapy
+/- surgery
+/- radiotherapy
Ewing sarcoma What are the Sx?
Pain, swelling, limitation of motion, localized tenderness
Spinal cord compression if tumor is paraspinal or vertebral
Often have systemic symptoms – fever, weight loss
Ewing sarcoma What is the progx?
Ewings sarcoma Where does it metastasize to?
Lungs, Lymph nodes, bone marrow
Ewings sarcoma Which are the most common bones involved?
Long bones – diaphysis
Axial skeleton & chest wall
Febrile neutropenia What are the answers?
- Importance in emergency events for children with cancer?
- Importance in mortality cause?
- Why are cancer patients prone to infections?
- Commonest oncological emergency
- Commonest non-cancer cause of death
- Reason for increased risk: breakdown” of infective protection mechanisms
- Low neutrophils/phagocytes
- Impaired mucosal barriers
- Indwelling catheters
- Impaired immune response
Febrile neutropenia What are the common organisms?
Gram positive (most common)
Staph aureus & epidermidis, Strep viridans
Gram negative (can be life threatening)
Pseudomonas
E coli
Klebsiella
Fungal
Candida
Cryptococcus
Febrile neutropenia What is the critical ANC level?
How is the clincal presentation differnt from normal kids?
- Patients are at particular risk if the ANC is < 500 but < 1000 also incur some risk
- Lack of neutrophils leads to a loss of the inflammatory response and fever may be the only manifestation of infection and the need for empiric abx
Febrile neutropenia When should you start thinking of an antifungal?
[Z1]
Patients without an identifiable source and persistent fever after > 5 days with progression of symptoms, the addition of an antifungal agent is generally warranted
Fibroma What are the features?
Occurs in 40% of children > 2yrs old; represent ossification defect, usually discovered incidentally
Occasional pathologic fractures; xray = lucency, may be multilocular, long axis runs parallel to bone
Spontaneous regression after skeletal maturity; excision if >50% of bone diameter
Germ cell tumors What are the answers to?
What are 2 syndromes and 4 signs that make germ cell tumours more common?
How do you manage electrolytes problems in TLS?
- Px with HR K+ or HOCa+ -cardiac monit & lytes q 4hrly
- K+ > 7-7.5 or or widening of QRS complex requires immediate intervention.9,10 Standard therapies to lower the potassium
Rx for HR K+:
a. loop diuretics, insulin and glucose, inhaled bagonists, polystyrene sulfate, and calcium gluconate for
symptomatic hyperkalemia or electrocardiographic changes.
b. hemodialysis.
2. Hyperphosphatemia is treated with phosphate
binders.
- The presence of secondary hypocalcemia can be
life-threatening and generally necessitates the use of
hemodialysis. Asymptomatic hypocalcemia should not be
treated with calcium administration because of the risk of
increasing calcium phosphate deposition in the rena
Ifosphamide
What is mechanism of action/excretion, uses, short and long term toxicity?
Infant leukemia What are the answers to the folowing?
- What % of childhood leukemia cases occur < 1 year?
- What is the ALL:AML ratio ?
- What are thePoor prognosis Fx?
- What is the Rx?
- 2% of childhood leukemia cases occur < 1 year
- ALL:AML ratio 2:1
- Poor prognosis – hyperleukocytosis, organomegaly, CNS disease, leukemia cutis (subcut nodules), diffuse pulmonary infiltration
- Intense chemotherapy + stem cell transplant
How does Rasburicase work?
-Urate oxidase oxidizes uric acid to the water-soluble and
readily excreted metabolite allantoin.
- Rasburicase (urate oxidase) reduces uric acid levels without
increasing the levels of uric acid precursors, and therefore
does not risk xanthine nephropathy.
Lymphoma Epidemiology?
What is the % of childhood cancer;?
What are the risk factors?
- 3rd most common type of childhood cancer;
- 6% of childhood cancers; peak in adolescence; rare in children < 10 years
- Increased risk with immunodeficiency,
- acquired (HIV) &
- congenital (e.g. Ataxia-Telangiectasia)
Lymphoma Hodgkins How do you Dx and rx SVC syndrome?
Lymphoma What are the risk factors?
- Unknown
- genetic (risk 100-fold for monozygotic twin)
- infectious (EBV, CMV, HHV-6) factors
- Post chemo and radiotherapy
Lymphoma What are the symptoms?
- Painless, non-tender, firm cervical lymphadenopathy;
- B symptoms (fever, wt loss, night sweats)
3. Mediastinal adenopathy common -
- airway compromise,
- SVC syndrome,
- pleural/ pericardial effusion
Lymphoma Hodgkins What is the characterisitc histology finding?
Reed Sternberg cells (owls eye cell)
Lymphoma How do you Dx it?
- Chest x-ray
- excisional lymph node biopsy -Reed-Sternberg cell– clonal B cells
Lymphoma staging Based on this PET scan, what Stage
would Melissa’s lymphoma be?
Stage 3
Lymphoma What are th types seen on biopsy?
Types:
- nodular,
- lymphocyte-rich,
- mixed cellularity,
- anaplastic large cell,
- lymphocyte-depleted
Lymphoma What are the causes of mediastinal masses?
Anterior Mediastinal mass?
Middle Mediastinal mass?
Posterior Mediastinal mass?
Anterior Mediastinum:
- Lymphoma,
- Thymoma,
- Thyroid
Middle Mediastinum
- Lymphdenopathy –
- lymphoma, metastatic disease,
- Germ cell tumour
Posterior Mediastinum
- Neuroblastoma, neurofibroma,
- Ewings,
- Rhabdomyosarcoma
Lymphoma What are the favourable and non favourable factors?
Unfavorable:
- tumor bulk,
- stage at diagnosis,
- B symptoms = 90% survival
- Relapse > 12 mos after therapy = 60-70% survival
Favorable prognostic factors
+ early-stage disease = 95% survival
Lymphoma What is the Ann Arbor staging ?
Ann Arbor Staging - Lymphoma
Stage 1
Single nodal group
Stage 2
2 or more nodal groups on SAME side of diaphragm
Stage 3
2 or more nodal groups on BOTH sides of diaphragm
Stage 4
Involvement of extra-lymphoid tissues
B- Symptoms
Present vs Absent
Lymphoma What is the Rx?
- Combined chemotherapy & radiotherapy
Chemo eg:
ABVD”
(A) Doxorubicin
Bleomycin
Vincristine
Dacarbazine
- Autologous stem cell transplant in those who never achieve remission or relapse after < 12mos
Lymphoma Non-Hodgkin What is the Epidemiology and etiology?
Epidemiology
- 60% of all lymphomas in children & adolescents; 10% of all malignancies
- >70% present with advanced disease. RFs include immune deficiency, viral infection, syndromes.
- Represents 50% of all pediatric malignancies in equatorial Africa (endemic Burkitt’s lymphoma)
- Usually in younger children
Etiology:
EBV present in 95% of cases of endemic (African) Burkitt’s lymphoma
Lymphoma Non-Hodgkin How do you Dx it? What are the 4 types?
- Burkitt 40% (small nocleaved B cell),
- Lymphoblastic 30% (TCell),
- Diffuse large B/T-cell 20%,
- Anaplastic large cell 10%
Lymphoma Non-Hodgkin What are the Sx?
Masses: head & neck, intrathoracic, mediastinal, abdominal, cutaneous. Can spread to marrow.
Site specific findings: SVC syndrome, airway compression, intussusception, spinal cord compression, TLS
Lymphoma Non-Hodgkin. What is the prognosis?
90-95% survival for localized disease;
60-90% with advanced disease
Lymphoma Non-Hodgkin What is the Rx?
Systemic & intrathecal chemotherapy
Surgery for diagnostic biopsy; rarely for debulking large masses
Methotrexate
What is mechanism of action/excretion, uses, short and long term toxicity?
Monitoring blood tests?
- Get baseline analyte values prior to Rx:
uric acid, electrolytes, LDH, and creatinine,
HIGH RISK: every 4 to 6 hours
INTERMEDIATE RISK: every 6-8 hours
LOW RISK: every 24 hours
N.B.
- uric acid levels may remain normal in patients with an emerging TLS ON ALLOPURINOL
- For rasburicase, laboratories must develop
protocols to collect uric acid samples in prechilled tubes that
are placed immediately on ice and kept on ice throughout
rapid transport to the laboratory for immediate run on the
instrument to prevent rapid in vitro uric acid breakdown,
and a spuriously low assay result.
Neuroblastoma Epidemiology?
Epidemiology
3rd most common pediatric cancer ~8%; 90% diagnosed by 3yrs old
Most common neoplasm in infants - 1/3 of cases
Neuroblastoma How do you Dx it?
- Abdo and chest CT
- BMA w/ biopsy (bilateral!)
- 95% have elevated urine HVA & VMA
- Bone scan/MIBG scan
- Mass biopsy
Neuroblastoma What are the DDx?
Other small round cell tumors –
- rhabdomyosarcoma,
- Ewing sarcoma,
- Non-Hodgkin lymphoma
Neuroblastoma What are the Sx and signs?
What are the symptoms that present with each location?
Can develop at any site of sympathetic nervous tissue, S&S reflect location & extent of tumor
- Thoracic: dyspnea/horner syndrome
- Abdominal: abdo pain, vomiting, palpable mass
- Pelvic: constipation and urinary retention
- Paraspinal: back pain, limp, leg weakness, hypotonia
Where can neuroblastoma develop?
Neuroblastoma What are the Sx and signs?
Where does it like to spread and 2 examples?
What are 4 paraneoplastic syndromes?
Funny METS to bone marrow and skin:
- Periorbital bruising (raccoon eyes),
- blue berry muffin spots (skin nodules)
Paraneoplastic syndrome:
- Opsoclonus-myoclonus,
- intractable watery diarrhea,
- hypertension,
- sweating
Neuroblastoma What is the etiology?
- Embryonal cancer of the peripheral sympathetic nervous system; variable neural differentiation from undifferentiated (neuroblastoma) to mature ganglion (ganglioneuroma)
- Amplification of n-MYC gene, 11q and 1p deletions associated with poor outcome
Neuroblastoma What is the prognosis?
Factors include
- amount of stroma,
- degree of differentiation,
- presence of enlarged nucleoli,
- mitosis index
Depends on stage:
stage 1 > 90%;
stage 2 80%,
stage 3 50%;
stage 4 30%;
stage 4S (<1yr) >80%
Neuroblastoma What is thr Rx?
Surgery, chemotherapy, radiotherapy
4S = special!
- <1year of age,
- localized primary tumour w/ spreading limited to liver, skin, bone marrow.
Very good prognosis!
Osteoblastoma What are the features?
Locally destructive, progressively growing bone lesion, prefers vertebrae
Insidious onset of dull, aching pain; may have neurological deficits at presentation
Biopsy necessary to confirm diagnosis; treated with excision
Osteochondroma (exostosis)
What does osteochondroma look like on xray? (mushroom according to Amanda)
Arise in metaphysis of long bone, esp distal femur, proximal humerus, proximal tibia
Bony, painful mass; Xray = stalks or broad-based projections from bone surface
Malignant degeneration in 1% of adults, surgical resection if symptomatic
Osteoid osteoma What are the features?
Unremitting, gradually increasing pain that is worse at night, relieved by analgesic
Most common sites proximal femur & tibia; vertebral lesion = scoliosis or neurological deficits
Xray = round or oval lucency surrounded by ring of sclerosis
Surgical resection; some resolve spontaneously with skeletal maturity
Osteosarcoma Epidemiology?
What 2 syndromes are asociated with it?
Malignant spindle cell tumour.
Second decade, Highest risk during adolescent growth spurt
Etiology:
hereditary retinoblastoma,
Li-Fraumeni
Osteosarcoma How do you Dx it?
What are the characteristic X-ray findings in osteosarcoma
where does osteosarcoma metastasize to?
-
Radiology:
a. Xray = sunburst pattern (ossification of soft tissue) & Codman triangle (cortical elevation) - primary site
b. MRI primary site & CT chest
u Bone scan
- Biopsy of tumor & metastatic workup to lung + bone marrow
- Blood work up: Normal CBC and chemistry, but may have elvated LDH & ALP
Osteosarcoma What are the DDx?
What is your differential for a lytic bone lesion?
Lytic bone lesion ddx =
histiocytosis,
Ewing sarcoma,
lymphoma,
bone cyst
Osteosarcoma What are the metastatic spread patterns?
Indicative of highly aggressive or advanced tumour
- Local invasion
- Lymphoid spread -Locoregional, distant
- Haematogenoous spread
u Distant sites (e.g. lungs, brain, bone marrow)
- CNS tumours & CSF dissemination
Osteosarcoma What are the Sx?
- Pain, limp, swelling most common. May be attributed to sports injury or growing pains
- Deep bone pain that causes nighttime awakenings; May also see decreased ROM, joint effusion, tenderness, warmth
Normal CBC and chemistry, but may have elvated LDH & ALP
Locations: long bone metaphysis – 50-80% are in proximal tibial / distal femur
Osteosarcoma What is the progx?
75% survival in non-metastatic disease;
25% survival in metastatic (lung) disease
Osteosarcoma What is the Rx?
1. Neo-adjuvant chemo (Cisplatin, Doxorubicin, Methotrexate (high dose)..then
- complete surgical resection (ESSENTIAL) (may need amputation) ….then more chemo
Note: this tumour is more chemo resistant
**NOT radiosensitive
Osteosarcoma Which are the most common bones involved?
Ends of long bones (usually solitary)
Pelvis, others
Prednisone What is mechanism of action/excretion, uses, short and long term toxicity?
Radiation Rx What are the long-term side effects?
- Growth delay (cranial or vertebral irradiation)
- Endocrine (midbrain irradiation)
- Pulmonary or cardiac insufficiency (chest)
- Strictures and adhesions (GI)
- Infertility (pelvic
Radiation Rx What are the Short-term side effects?
- Dermatitis of adjacent tissues
- Mucositis anywhere from mouth to anus
- Somnolence (Cranial irradiation)
- Alopecia
Radiotherapy What are the Late Effects Assessment and Management for CNS and eye?
Retinoblastoma Diagnosis?
What 2 investigations must you do?
Opthalmology,
MRI to r/o intracranial tumor
Retinoblastoma Epidemiology?
BILATERAL:
Rare, bilateralinvolvement highest if presents <1yr old
25% bilateral/hereditary
UNILATERAL:
60% unilateral/non-hereditary;
15% unilateral/hereditary;
Retinoblastoma Etiology
Hereditary form due to 2-hit hypothesis:
1st inherited germ cell mutation then
2nd somatic mutation
Increased risk in Li-Fraumeni
Retinoblastoma How is it managed?
What are the Primary + secondary goals?
What are your treatment options?
What do you need to do for first degree relatives?
Primary goal = cure; secondary goal = preserving vision
- Enucleation (eyeball resection),
- chemotherapy + focal therapy (laser or cryo),
- radiation
- All 1st-degree relatives need to be screened
Retinoblastoma Progx?
95% cure rate; poor prognosis if metastatic
Retinoblastoma Sx ?
Leukocoria– white papillary reflex
Strabismus;
with advanced disease = orbital inflammation, hyphema, pupil irregularity
Retinoblastoma What are the DDx?
What other 4 things can give you leukoria?
Cataract,
retinopathy of prematurity,
visceral larva migrans,
coloboma
Retinoblastoma What is the relevance of the RB1 gene carrier?
- If RB1 gene carrier – depending on the mutation 10-100% risk of retinoblastoma, and
- increased risk for other tumours (osteosarcoma, glioma, glioblastom multiforme, melaninoma, lung, bladder) and need to have optho exams until 9 yo
Rhabdomyosarcoma How do you Dx it?
Requires high index of suspicion
Biopsy required, cytogenetics to determine prognosis
Rhabdomyosarcoma How do you Rx them?
- Neo-adjuvant chemotherapy then
- complete resection if possible,
- followed by XRT & chemo
Rhabdomyosarcoma What are the DDx?
What 3 other small round tumors are DDx?
Other small round cell tumors –
neuroblastoma,
Ewing sarcoma,
Non-Hodgkin lymphoma
Rhabdomyosarcoma What are the Sx?
- retroperitoneal & other 35%
- Head & neck 25%,
- genitourinary tract 22%,
- extremities 18%,
Mass that causes displacement or obstruction of normal structures – symptoms are specific to site
Orbit = proptosis,
middle ear = chronic otitis media,
larynx = hoarseness,
bladder = hematuria
Rhabdomyosarcoma What is the prognosis?
80-90% survival with complete resection;
70% with incomplete resection,
25% with disseminated
Rhabdomyosarcoma Where do these tumors arise from?
Arise from striated skeletal muscle
Rhabdomyosarcoma What syndrome is associated with this? Epidemiology?
(Soft tissue sarcomas)
3.5% of childhood cancers, increased risk in neurofibromatosis
Role of high K+ in TLS?
K+ is an ICF electrolyte regulated through renal excretion.
TLS HR K+ …cardiac dysrhythmias and sudden death.
Ca+ stabilizes the cardiac membrane, Low Ca+ exacerbates HR Ca+- induced cardiotoxicity and cardiac dysrhythmias.
HR Ca+ > 7.0 mEq/L(hyperkalemic emergency) and can be potentiated by ongoing TLS, Low Ca+, and/or renal failure
Role of hydration in TLS?
- Maintaining a high urine output with adequate hydration
- most important aspect of TLS prevention and
management, because this improves renal perfusion and
glomerular filtration, and minimizes acidosis, all of which
serve to prevent the precipitation of uric acid and calcium
phosphate crystals in the renal tubules.
- intermediate-to-high risk & for established TLS: hyperhydration with NS to maintain equal
fluid balance and a high urine output.
- K+, PO4, and Ca+ should NOT be added to the hydration solution.
- Monitored Volume status to prevent volume overload, particularly in patients with renal failure or cardiac dysfunction, and diuretics may be necessary to maintain urine output.
Role of Rasburicase in TLS?
What are the benefits and limitations of rasburicase?
Preferred prophylactic agent for patients at high risk for TLS and the treatment of choice for established TLS.
Benefits:
- rapidly reduces uric acid levels and breaks down deposits of uric
- Reduces PO4 + serum creat levels
- does not require renal dosing;
however, there is a risk for
Problems:
- severe hypersensitivity reactions (anaphylaxis)
particularly with repeat dosing
- contraindicated in pregnant/lactating F & G6PD Def’y , (severe hemolytic anemia) - Screen for G6PD
Role of Acute Renal Injury in TLS?
AKI - independent predictor of short + long-term TLS mortality
Mecnms:
Crystal-dependent and crystal-independent mechanisms.
-
Crystal-dependent mechanisms
- obstructive uropathy.
- Decreased urinary outputcan result in volume overload and cardiac failure, which can exacerbate crystal precipitation.
Urine alkalinization to > pH 6.5 not in use now
2. Crystal-independent mechanisms
-loss of autoregulation, renal vasoconstriction,
and local inflammation
-Tumor lysis–induced hypercytokinemia can result in hypotension, systemic inflammation, and multiorgan failure
Secondary malignancyWhat is the incidence and how should you screen for it?
- The risk appears to be cumulative, increasing by about 0.5% per year, resulting in approximately a 12% incidence at 25 yr after treatment.
- Patients should be examined annually, with particular attention to second malignancies.”
Supportive care How do you manage the immunocompromised host?
Supportive care Miscelleneous problems:
Supportive care WHow do you treat each of the following oncological emergencies?
- Increased ICP
Spinal cord compression
Hyperleukocytosis
Tracheal compression
SVC syndrome
Tumor lysis syndrome
SIADH
GVHD
Supportive care What organ toxicities are of concern?
Techniques for safe administration of chemotherapy What are 4 methods?
[Z1]List 6 techniques for safe administration of chemotherapy.
- Safe storage and labelling
- Appropriate handling and protective equipment
- Careful identification of patient and dosage (double checked) AND ROUTE
- Appropriate administration
How does Allopurinol work?
Allopurinol blocks uric acid synthesis leading
to accumulation of the uric acid precursors xanthine and
hypoxanthine, of which hypoxanthine is more soluble and
more easily excreted than uric acid.
How do Allopurinol and Rasburicase work?
Pathogenesis- Hyperuricemia
Hyperuricemia with hyperphosphatemia, can lead to acute kidney injury.
Mecanism:
-Purine containing nucleic acids released
into the serum are catabolized to uric acid and, when
present in excess, surpass the renal tubular capacity for uric
acid excretion.
-Uric acid is poorly soluble in water, and the solubility is markedly reduced in the physiologically acidic environment of the distal tubules and collecting system. Thus, uric acid crystals readily precipitate when concentrated in the renal circulation, leading to renal tubule obstruction and obstructive uropathy, with compromised glomerular filtration and reduced
urine output.
TLS What are the CLINICAL FEATURES of TLS?
Timing?
Symptoms (4)?
Cplxns (3)?
Timing:
- Within 12 to 72 hr > initiation of cytotoxic therapy
- Can occur 72 hrs - Can occur before Rx
Symptoms include:
- nausea, vomiting, diarrhea, anorexia,
- weakness, lethargy and syncope.
- hematuria,
- muscle cramps, tetany,
Cplxns:
- Cardiac dysrhythmias,
- seizures,
- sudden death
What is the Diagnostic Criteria for TLS
(Cairo Bishop grading for Lab & Clinical TLS)
What is Tumor lysis syndrome (TLS)?
What are the lab findings and Cplxns?
Deftn: Acute, life-threatening disease among children that is associated with the initiation of cytoreductive therapy in the treatment of malignancy.
Characteristic findings:
Raised: uric acid, phosphate, K+, urea, creatinine
Low: Ca+,
Cplxns: cardiac arrhythmia, seizures, renal failure,
and sudden death.
Tumor markers What tumors produce the following tumor markers?
- Alpha-fetoprotein
- Beta-HCG
- Urine catecholamines
- Alpha-fetoprotein: Hepatoblastoma, germ cell tumours
- Beta-HCG: Germ cell tumours
- Urine catecholamines: Neuroblastoma, Phaeochromocytoma
Unicameral bone cyst What are the features?
Usually occur b/w 3-12 yrs, fluid-filled lesion, mostly asymptomatic until pathologic fracture
Xray = solitary, centrally located lucency, proximal humerus or femur
Treatment with aspiration and injection of bone marrow or steroids
Vinblastine What is mechanism of action/excretion, uses, short and long term toxicity?
Vincristine
What is mechanism of action/excretion, uses, short and long term toxicity?
What are the toxic effects?
Special side effects: (vincristine, vinblastine, vindesine)
Vincristine
Vinca alkaloid
Severely neurotoxic
Severe vesicant – extravasation damage
Intrathecal administration ( WILL DIE….)
Severe demyelination
Severe encephalopathy
Severe pain..extravasation burn..
Death, usually
What are the classes of chemotherapy?
- Antimetabolites: MTX, 6 MP, Ara C
- Alkylating agents: cyclophosphamide, ifosphamide, cisplatin, carboplatin
- Antibiotics: Anthracyclines (Doxorubicin, daunomycin), Dactinomycin, Bleomycin
4. Plant alkaloids; Vincristine, vinblastine, etoposide VP 16
5. Miscellaneous: Prednisone, PAG Asparaginase
Alkylating agents
u e.g.
u Anthracyclines
u e.g. doxorubicin
u e.g. Methotrexate
u Antibiotics
u e.g. bleomycin
u Enzymes
u e.g. asparaginase
u Microtubule inhibitors
u e.g. vincristine
u Nucleoside analogues
u e.g. 6-mercaptopurine
u Platinum agents
u e.g.
u Small-molecule inhibitors
u e.g. imatinib
u Topoisomerase inhibitors
u e.g. etoposide
What are the indication for hemodialysis in TLS?
- refractory volume overload
- AKI: oliguria or anuria,
- persistent HR K+, HR uric acid despite above measures
- hyperphosphatemia-induced symptomatic hypocalcemia, and a calcium phosphate product of greater than 70 mg2/dL
N.B. Prophylactic hemodialysis in patients at risk for TLS may be appropriate in the setting of preexisting renal disease or acute renal injury at presentation, and further studies are needed
What are the Risk factors in TLS?
What is the role of Allopurinol in TLS?
“Preferred prophylactic in low-to-intermediate risk patients”
- *Limitations:**
1. As it it does not break down preexisting uric acid, urate nephropathy can develop in the 3 days it takes to have a therapeutic effect. SO is NOT the preferred agent in the presence of hyperuricemia.
Furthermore, xanthine nephropathy must be considered in patients who develop TLS while receiving appropriate prophylactic therapy with allopurinol.
- allopurinol is excreted by the kidneys and must be dose reduced or discontinued in patients with renal insufficiency.
- hypersensitivity reactions have occurred. Asian populations have a higher frequency of the HLAallele, which is associated
with severe adverse cutaneous reactions with allopurinol
use.
- because allopurinol reduces purine degradation,
chemotherapeutic agents, such as 6-mercaptopurine
and azathioprine, must be dose reduced by 50% to 70%
when concurrently administered.
N.B. Any patient who develops TLS while receiving allopurinol prophylaxis should be switched to rasburicase
What is the role of Hyperphosphatemia and Hypocalcemia in TLS?
- Tumor cells have higher (PO4) than their normal cells
- In TLS renal tubular excretion of (PO4) becomes saturated. - excess serum phosphate
- Excess (PO4) binds to Ca+– low (Ca) + Ca PO4 deposition - - Low (Ca) Sx:
- Arrythmias, seizures, Nephrocalcinosis -renal tubulular nephrolithiasis and cause or further provoke an obstructive
uropathy.
What is the Cairo-Bishop Grading of Clinical Tumor Lysis Syndrome (TLS)?
Wilms tumor Epidemiology ?
How often is unilat vs bilat?
Epidemiology
6% of pediatric cancers, usually between 2-5 years; unilateral 90%
Etiology:
Most sporadic; 1-2% AD;
increased risk in syndromes
- Beckwith-Wiedemann
- Denys-Drash – Glomerulopathy/Pseudohermaphrodism
- Neurofibromatosis
- Sotos
- WAGR- (W-ilms, A-niridia, G- GU anomalies, R- MR,
Wilms tumor Etiology?
Complex mixed embryonal tumor
Wilms tumor How do you Dx it?
- CT scan: Diagnostic imaging to confirm intrarenal origin & determine local & m_etastatic spread_ ( claw sign)
- Biopsy if diagnosis uncertain (Look at both kidneys!) - risk of biopsy!!
Wilms tumor How do you Rx it?
Nephrectomy, chemotherapy, radiotherapy
Wilms tumor Sx and Signs?
1. Renal specific Sx:
a. Hematuria 25%, hypertension (renal ischemia),
b. Mass effect:
- Abdominal mass, generally discovered fortuitously while parent bathing child
- rapid abdominal enlargement (hemorrhage into renal pelvis),
2. develop acquired bleeding diasthesis (VWD)
3. polycythemia
Wilms tumor What is the progx?
- Depends on DNA content;
- Staging:
>60% survival across all stages;
>90% survival if stages 1-3
