JC124 (Paediatrics) - Childhood cancer Flashcards
Compare cancer in adult and children
- Pathological types
- Sites
- Classification
- Stage at diagnosis
- Pathological types
Adult: mostly carcinoma
Children: Lymphoid malignancies, CNS tumors, Embryonal tumors
(rarely carcinoma) - Sites:
Adult: superficial or deep seated in visceral organ
Children: usually deep seated in organs - Classification:
Adult: by organ
Children: by tissue of origin - Stage at diagnosis:
Adult: Early or late
Children: Usually Late
Compare cancer in adults and children
- Efficacy of screening
- Treatment outcome/ prognosis
Screening:
- Adult: screening programs can be effective
- Children: Not effective screening due to aggressive nature of most paediatric cancers
Treatment:
- Adult: variable response
- Children: Usually good response with good prognosis
Paediatric cancers
- Typical age of presentation
- Demographics
- Typical age of presentation: birth to 4 years old
- Demographics: Sligh male predominance
- Ethnicity: More germ cell tumor in east Asians, less Hodgkin’s disease, Wilm’s tumor, Ewing’s sarcoma than Caucasians
List the top 10 most common paediatric cancers
Acute leukaemia Brain tumours Non-Hodgkin lymphoma Extracranial germ cell tumor Neuroblastoma Rhabdomyosarcoma Osteosarcoma Ewing sarcoma / peripheral PNET Hepatoblastoma Nephroblastoma
Etiologies of paediatric cancers
- Unknown in majority:
- Possible acquired spontaneous mutation during developmental stage
- Difficult to prove suspicion - Genetic predisposition
- Germline mutations in cancer-predisposing genes
- Mutation in epigenetic control mechanisms: Oncogenes, Tumor suppressor genes (e.g. P53) , DNA repair genes (e.g. BRCA1) - Immunodeficiency
- More common in male (X-linked PIDs)
- Increase susceptibility to cancer - Environmental (short exposure)
- Physical, radiation, chemical, biological agents
Family history is mostly unreliable for prediction of paediatric cancer
List familial paediatric cancers with autosomal inheritance
Difference in cancer treatment approach between paediatrics and adults
General difference from adults:
More responsive to therapy
Tolerate therapy better
Different volume distribution for infants
Long-term complications: effect on development, late complications
Long-term complications of paediatric cancer treatment
Learning disability (cranial irradiation)
Growth retardation (tumor in pituitary area)
Subfertility (high-dose alkylating agent, e.g. cyclophosphamide)
Organ dysfunction (e.g. ifosfamide - renal tubular damage)
Second malignancy (e.g. radiotherapy - 9-10% develop secondary neoplasm
on irradiation site after 20-25 years)
Supportive care options for paediatric cancer treatment
Blood product support
Treat infection (antibiotics, antifungals, antivirals)
Treatment of metabolic complications – tumour lysis syndrome (urate oxidase)
Symptoms control (i.e. pain, vomiting)
Nutritional support
Psychological support
Family support: empathetic approach to breaking bad news
Approach to breaking bad news about cancer in children
Be empathetic, prepare to listen
Provide affirmative diagnostic information, avoid using ambivalent terms
Do not provide too much information within a short time; just mention the framework of the
treatment plan & side effects
Provide “hope” but not “false hope” in prognosis
Help to pacify guilty feeling
Non-inherited nature of most childhood cancers
Non-contagious to other family members
Modalities of cancer treatment
General indication for each type
Chemotherapy - Mainstay therapy
Surgery - Mainstay treatment for solitary tumors
Radiation therapy - Mainly for brain tumors, solid tumors, palliative therapy
Targeted therapy - Novel technique for selected cancers
Cellular therapy: Stem cell (e.g. HSCT), Gene therapy, Immune modulation
Immune checkpoint inhibitors - selected cancers
Hormonal therapy (e.g. ER/PR+ breast cancer)
Examples of anti-toxicity regimens for cancer treatment
Anti-toxicity regimen:
Methotrexate + folinic acid (leucovorin)
Cyclophosphamide + Mesna
Anthracycline + ICRF-187
Examples of immune modulation treatment for cancer
Monoclonal Ab for activation of NK cells and complement activation
Leukapheresis for synthetic proliferation of Cytokine-induced killer cells (CIK), lymphokine-
induced killer cells (LIK) and reinjection
Ex-vivo dendritic cells mix with cancer lysate and reinjection
Genetically modify Cytotoxic T-cells with cancer antigen sequence, co-stimulatory domains and signalling domain for hyperactive response against cancer
Myeloproliferative disorders (MPD)
- Haematological abnormality
- Disease entities
Abnormal proliferation of haematopoietic cells: High cell count but normal morphology (abnormal morphology in late stage/ severe MPD)
PRV (polycythaemia vera)
ET (essential thrombocythaemia)
MF (myelofibrosis)
CML (chronic myeloid leukemia)
Myelodysplastic syndrome
- Haematological abnormality
- Disease entities
Abnormal differentiation of haematopoietic cells
RA (refractory anemia)
RARS (refractory anemia with ring sideroblasts)
RAEB-I (refractory anemia with excess blast)
RAEB-II
CMML (chronic myelomonocytic leukemia)
/JMML (juvenile myelomonocytic leukemia)
Types of leukaemia that occur in children
ALL - most common
AML - second most common
CML and MDS (rare)
CLL (ultra rare)
Origin: marrow, lymph node, thymus
Clinical features of paediatric leukaemia
Marrow failure
Pallor
Multiple petechiae and bruises (over limbs, H&N)
Constitutional symptoms
Fever, LOA, LOW
Organ infiltration
Scattered lymphadenopathy
Moderate hepatosplenomegaly
Bilateral shin tenderness (bone pain more common in ALL than AML because infiltrate marrow space and necrosis)
Non-tender testicular swelling (more common in ALL than AML)
Leucostasis (involvement of CNS)
Headache (uncommon)
Nuchal rigidity
Paediatric leukaemia
- Investigations for diagnosis
Peripheral blood: CBC with differential, Blast count, Electrolytes and urate and LDH for TLS
Peripheral blood smear
- Morphology
- Cytochemical staining (e.g. PAS, acid phosphatase for ALL)
Immunophenotyping: find lineage based on CD expression by flow cytometry
Bone marrow
- Cytogenetics: FISH and Karyotyping
- Molecular genetics: RT-PCR
Genetic abnormalities in paediatric ALL and AML
ALL:
Translocation t(12;21) (TEL-AML1 fusion transcript):
Found in 23% children, uncommon in adult (2.8%)
Translocation t(9;22) Philadelphia chromosome (worse prognosis)
Uncommon in children (3%), but found in 23.6% adult
AML: de novo AML – common fusion transcript:
t(15;17)
t(8;21)
Inversion 16
Treatment scheme for childhood ALL
First 4-6 months:
- Induction»_space; consolidation»_space; CNS prophylaxis
- Bone marrow transplant for high- risk group, not upfront
- 2nd consolidation
Following 1.5-2 years:
- maintenance (3rd consolidation)
Treatment scheme for childhood AML
Short and intensive (toxic) as compared to ALL:
First 4-6 months:
1. Induction and consolidation
2. CNS prophylaxis (intrathecal chemotherapy)
3. Bone marrow transplant performed upfront +/- maintenance therapy
Prognosis and outcome of paediatric ALL and AML
ALL: Berlin-Frankfurt-Munster (BFM) protocol
Event-free survival of 75-80%
Overall survival of 80-90%
High-risk: survival still >50%
AML: Survival mostly 40%
Overall survival of 60% for low-risk, 50% for high-risk
Causes of ALL relapse in children
Survival of relapsed ALL
7% unrelated second leukemia (new)
8% same as diagnosis (retain abnormal original clone)
34% clonal evolution from diagnosis
51% clonal evolution from a preleukemic clone
Survival of relapsed ALL patients:
50-60% still salvaged
The later the relapse, the better the outcome; late relapses may only be treated by chemotherapy instead of transplant
Common childhood brain tumors
Gliomas:
- Astrocytoma (e.g. cerebellar astrocytoma)
- Ependymoma
- Others (e.g. brainstem glioma, optic glioma)
PNET (primitive neuroectodermal tumor)
- Medulloblastoma
- Others (e.g. pineoblastoma)
CNS germ cell tumor (60% at pineal gland) - Germinoma (73%) - Non-germinoma (27%): o Yolk sac tumor o Choriocarcinoma o Teratoma (16%) o Mixed
Others:
- Craniopharyngioma
- Atypical teratoid rhabdoid tumors (ATRT)
Childhood medulloblastoma
- Presentation
May obliterate 4th ventricle: progressive obstructive hydrocephalus
On-and-off headache and vomiting especially upon waking up
Unsteady gait
Motor incoordination
Cerebellar signs
Tumor markers for childhood brain tumors
Non-germinoma:
- Yolk sac tumour ↑αFP in CSF, serum
- Choriocarcinoma ↑β-HCG
Classification of astrocytoma and prognosis
Childhood astrocytoma:
Grade I, II: good survival (90-100%); functional impairment depends on location of tumor
Grade III, IV, brainstem: poor outcome (usually fatal)
Modalities of treatment for childhood brain tumor
- Surgery
- Radiotherapy:
- IMRT (intensity-moderated
radiotherapy)
- TOMO
- Proton Beam - Chemotherapy
- Targeted therapy: Avastin, bevacizumab – VEGF inhibitor, Nimutuzumab, m-TOR inhibitor…
5, +/- ventriculo-peritoneal shunt
Prognosis of childhood medulloblastoma
Prognosis of childhood germ cell brain tumor
Germinoma:
Good survival (~90%)
Late mortality may not be due to relapse but secondary complication related to previous treatment e.g. cranial radiotherapy
Secondary complications: secondary brain tumor, progressive vascular anomaly in brain/ laminar necrosis
Non-germinomatous GCT:
overall survival not as great (~70%)
Radiological feature of cortical laminar necrosis (secondary complication of cranial radiotherapy)
MRA (angiogram): serpingineous hyperintensity along the cortex - lesions due to neuronal loss
a/w high lactate and low NAA/tCr (N-acetylaspartate/total creatine) due to anaerobic glycolysis
Long-term neurological impairments in childhood brain tumor survivors
Risk factors of higher impairment
> 1 neurological impairment in 70% (due to treatment, or original tumor causing brain dysfunction):
a) Motor impairment (56%)
b) Subnormal IQ (30%)
c) Visual impairment (24%)
d) Brain atrophy (21%)
e) Epilepsy* (21%)
Risk factors:
<3 years
High initial IQ
Form of treatments: posterior fossa radiotherapy/ craniospinal irradiation +/- chemo
3 clinical presentations of childhood non-hodgkin lymphoma
Lymphoblastic NHL
Diffuse bulky LN
Mediastinal enlargement (airway/ SVC obstruction)
Hepatosplenomegaly
Burkitt’s NHL (sporadic form)
Enlarged cervical/ supraclavicular LN
Intussusception (abdomen)
Anaplastic Ki-1 NHL Thin-looking Skin nodules Pleural effusion Hemophagocytic lymphohistiocytosis
Non-Hodgkin lymphoma (NHL)
Diagnostic investigations
Diagnosis – tissue biopsy:
excisional/incisional biopsy (resect the whole LN)
** avoid needle biopsy c.f. adults - single cell isolates can be lymphoma/ neuroblastoma/ rhabdomyosarcoma and has no bearing on treatment planning **
Classification of Childhood non-Hodgkin Lymphoma
Staging methods and treatment prognosis of childhood non-hodgkin lymphoma
Staging:
Imaging e.g. MRI
Radioisotopes scan
Treatment outcome: good survival (70-80%)
Burkitt lymphoma (BL), DLBCL: up to 90%
Lymphoblastic lymphoma (LBL): 80%
Anaplastic large cell lymphoma (ALCL): 75%
Primary mediastinal large B-cell lymphoma (PMLBCL): 50% **
Neuroblastoma
- Cell of origin
- Organs affected
- Clinical presentation
- Confirmatory Ix
- Cell of origin: neural crest cells (progenitor cells of sympathetic nerve)
- Organs affected: neuroblastoma can be found along the path of neural crest cell migration:
Sympathetic chain (trunk, ganglia)
Adrenal gland (medulla) - Clinical presentation:
Abdominal mass
Cachexia - Confirmatory Ix:
MIBG scan detects neural crest cells in neuroblastoma, pheochromocytoma
Elevated catecholamines, urine VMA (vanilylmandelic acid) and HVA (homovanillic acid)
Treatment for early-stage neuroblastoma
Early-stage neuroblastoma:
- Surgical resection
- 5 courses of chemotherapy (cyclophosphamide + doxorubicin)
- Second look surgery to find residual disease»_space; salvage chemotherapy with Etoposide + carboplatinum
Treatment for late-stage neuroblastoma
Do everything:
1. Chemotherapy
- Surgery
- Stem cell transplant
- Local irradiation
- Targeted therapy (monoclonal antibodies):
Anti-GD2 attacks GD2 (tumor-specific antigen) on surface of neuroblastoma cells
GM-CSF priming to increase opsonization of neutrophils, monocytes, macrophages - Differentiating agent (isotretinoin (13-cis-retinoic acid))
Types of extracranial germ cell tumor and organs affected
Germinoma: Dysgerminoma
Non-germinomatous GCT:
Yolk sac tumour
Choriocarcinoma
Malignant teratoma (e.g. sacrococcygeal teratoma)
Distribution: Thyroid and Pineal gland Mediastinum Retroperitoneal Gonads Sacrococcygeal
Treatment and prognosis of extracranial germ cell tumor
Mainly treated with JEB (carboplatin, etoposide & bleomycin) for 4-6 courses
Good overall survival with surgery (90-100%)
Rhabdomyosarcoma
Types and organs affected
Embryonal type - chromosomal gain/ loss
1/3 in head and neck (e.g. parameningeal area, jaw)
1/3 in pelvis
Alveolar type (usually older children, adolescents) - specific fusion transcript
Trunk
4 limbs
Treatment outcome of childhood rhabdomyosarcoma
Survival not good (50-60%)
H&N, pelvis: hard to resect, poor resection margin - not removed completely by surgeon
Residual disease treated by radiation and chemotherapy
(not perfect cure)
Compare osteosarcoma and Ewing’s sarcoma
- Location
- X-ray feature
Osteosarcoma:
- Metaphysis (near proximal/ distal end of long bone, e.g. femur)
- X-ray: Sunburst/ sunray appearance at Codman’s triangle
Ewing’s sarcoma:
- Diaphysis (middle part of long bone)
- X-ray: Onion skin (grows layer by layer)
Compare osteosarcoma and Ewing’s sarcoma
- Treatment options
- Outcome
Osteosarcoma;
1. Excision
2. Limb salvage: prosthesis (total joint replacement)/ allograft
3. Amputation
4. Rotationplasty
Prognosis: Localized - good survival (60-80%); metastasized - poor survival (20-30%)
Ewing’s sarcoma:
1. Excision
Resectable - good survival (85%)
Unresectable - poor survival (40-50%)
Name 2 childhood liver cancers
A. Hepatoblastoma (chemo + surgery, good survival 80%)
B. Hepatocellular carcinoma (HCC) (uncommon due to universal vaccination program)
List types of childhood kidney tumor
Wilms’ tumour (nephroblastoma): 2/3 (huge proportion) of childhood kidney tumor
Others: Clear cell sarcoma PNET Mesoblastic nephroma inflammatory myofibroblastic tumor, mesoblastic fibroadenoma, RCC ...etc
