Paediatrics JC124: A Child With Cancer: Paediatric Cancers Flashcards
Epidemiology
- Rare (~150 per million children <15)
- <200 new cases in HK per year
- 2nd leading cause of death <15 (1st: accident)
Paediatric cancers
Different from adult cancers:
1. Types of cancer (Few carcinoma)
2. Biology (Lymphoid, **Embryonal, **Aggressive)
3. Prognosis (relatively ***good)
Cure rate:
- Depends on cancer type + staging (overall 70-80%)
**Chemotherapy + **RT:
- target rapidly dividing cells —> good for paediatric cancers (∵ generally aggressive)
- 45% occurs between birth and 4 yo
- Incidence is similar to other races except that
—> Hodgkin’s diseases, Wilm’s tumour, Ewing sarcoma (less frequent in HK)
—> more ***Germ cell tumour - M>F slightly
- No obvious ↑ / ↓ trend
- Childhood population: in and out of community (composition of population may change constantly)
Incidence (Descending):
1. **Acute leukaemia (myeloid / lymphocytic)
2. **Brain tumours
3. **NHL (less than overseas)
4. **Extracranial germ cell tumour (higher than overseas)
5. Neuroblastoma (less than overseas)
6. Rhabdomyosarcoma
7. Osteosarcocoma
8. Ewing sarcoma / Peripheral PNET
9. Hepatoblastoma (higher than overseas)
10. Nephroblastoma (Wilms’) (less than overseas)
***Paediatric vs Adult cancer
- Types
- Paediatric: **Lymphoid / **Haemic malignancy (others: ***Embryonal (i.e. Blastoma))
- Adult: Carcinoma (>95%) (from epidermal / glandular cells) - Sites
- Paediatric: ***Deep seated (deep / visceral organs e.g. Wilms’ tumour in kidney, Neuroblastoma in adrenal) —> discovered late
- Adult: Superficial + Visible - Stage at diagnosis
- Paediatric: ***Advanced usually
- Adult: Can be early - Screening
- Paediatric: ***Not effective (∵ aggressive, no timeframe for gradual development state)
- Adult: May help - Response to treatment
- Paediatric: ***Good
- Adult: Poor (except for selected targeted therapy) - Outcome
- Paediatric: 70-80%
- Adult: 30-40%
Etiology / Predisposition of Paediatric cancers
- Unknown in majority
- Genetic predisposition (also very important even without family history)
- **Oncogene
- **Tumour suppressor gene
- **DNA repair gene (e.g. BRCA gene)
- **Epigenetic control (Epigenetic marker / factors / elements)
—> any one have problem —> cancer
- Germline mutations in cancer-predisposing genes were identified in 8.5% of paediatric cancers
- **Family history did not predict the presence of an underlying predisposition syndrome in most patients (some may need secondary / tertiary genetic modifier)
—> Family history may **NOT be reliable - Problem with immunity surveillance (i.e. **Immunodeficiency: esp. **EBV related NHL)
- immunodeficiency are commonly X-linked —> ∴ paediatric cancers M>F - Environmental factors
- Physical (radiation: thyroid, haemic malignancy), Chemical, Biological
- Accounts for a ***minor proportion only (∵ short incubation period)
Conclusion: Difficult to prove etiology / predisposition
Familial Paediatric cancers
AD:
1. Retinoblastoma (some cases)
2. Neurofibromatosis
3. Familial polyposis
AR:
1. Xeroderma pigmentosa and Skin cancer
2. Bloom syndrome
3. Fanconi anaemia (X Fanconi syndrome)
X-linked:
1. Dyskeratosis congenita
Management issues in Paediatric cancers
- ***More responsive to therapy
- ***Tolerate therapy better (∵ organ function relatively new + strong)
- Requires family approach
- Multidisciplinary approach
- Concern on ***long term complications (e.g. secondary cancers to RT)
Treatment considerations:
Aim:
1. Maximise chances for cure (intensify treatment + adding other elements)
2. Minimises long term SE
Impact on:
1. Child: Development, Growth, School
2. Family members: Parents, Siblings
Supportive care in Paediatric cancers
- ***Blood product support
- ***Treatment of infection (e.g. antibacterial, antiviral, antifungals)
- ***Treatment of metabolic complications (e.g. tumour lysis syndrome by urate oxidase (Rasburicase))
- Symptoms control (e.g. pain, vomiting)
- Nutritional support
- Psychological support
- Family support
Combination modalities of therapy
- Chemotherapy
- Main form of therapy
- More intense in recent year
- Anti-toxicity regimen
—> **Folinic acid for MTX
—> **Mesna for Cyclophosphamide (Haemorrhagic cystitis —> Acrolein: neutralised by Mesna)
—> ***ICRF-187 for Anthracycline - Surgery
- Primary Rx for solid tumour
- More conservative in recent year, better tools
- 2nd look surgery is advocated - RT
- Mainly for brain + solid tumours
- More refined field + dose control (**less SE but efficacy remain **same)
- Palliative therapy - Targeted therapy
- Small molecule blockers / Monoclonal Ab
- **Much less system SE
- Has to have **known target (but not too much paediatric cancer has tumour specific Ag / targets)
- e.g. Immune-checkpoint inhibitor - Cellular therapy
- HSCT
- NK cells, MSC cells (CIK, LIK, T cells)
- Stem cells (repair deranged organs)
- Gene therapy (improve chemo-resistant of BM —> can tolerate higher dose of chemotherapy)
—> nowadays technology can ***minimise Graft-vs-host effect —> don’t have worry about not having donor in family —> can just use Haploid (i.e. Half-matched) donor
Immune checkpoint inhibitors
Usual role of immune system in cancer cell killing
1. Release of cancer cell Ag
2. Cancer Ag presentation (Dendritic cells to T cells)
3. Priming + activation
4. Trafficking of T cells to tumours
5. Infiltration of T cells into tumours
6. Recognition of cancer cells by T cells
7. Killing of cancer cells
Immune checkpoint: prevent excessive immune response to normal cells (to avoid autoimmunity)
—> Immune checkpoint inhibitors —> allow immune response to continue to kill cancer cells (e.g. Melanoma, Hodgkin lymphoma)
Examples:
- Anti-CTLA-4
- Anti-PD1, Anti-PDL1
Immune therapies: CIK, LIK, DCs
CIK: Cytokine-induced killer cells
LIK: Lymphokine-induced killer cells
DC: Dendritic cells
CTL: Cytotoxic T lymphocytes
Collection of self lymphoid cells
—> Expose them under a cocktail of cytokines / cancer Ag
—> Stimulate expansion of CIK, LIK, DC, CTL that recognise cancer
—> Put it back into patient
In general do NOT work very well ∵
1. Immune checkpoint
2. Cells cannot recognise the cancer from very beginning
More effective way:
Genetic-modified T cells (**CAR T cells)
**Chimeric Ag Receptor contains:
1. Ag-binding domain
- extracted from Ab which **recognise tumour Ag
- **not restricted to MHC-presented Ag
- created from a single-chain variable fragment
- Co-stimulatory domain
- from ***co-stimulatory receptor
- ↑ T cell activation
- ↑ cytolytic function of T cells - Signaling domain
- from CD3-zeta (TCR accessory protein)
- induces ***T cell activation
Haemic malignancy vs CT disease
Inflammatory conditions:
- ↑ ANC (absolute neutrophil count)
- ↑ Platelet (∵ acute phase reactant)
Malignancy:
- ↓ ANC (absolute neutrophil count)
- ↓ Platelet
- +/- Blast cells
- ↑ Urate (by-product of purine, component of DNA), LDH (cell breakdown + rapid cell turnover), K, PO4 (intracellular electrolyte: but may be low in rapid-growing cancer ∵ suck in K, PO4)
Leukaemia
- ***ALL»_space; AML (5:1)
- CML, MDS rare
- CLL almost non-existing
Origin:
- BM
- LN
- Thymus
Clinical features:
- BM failure
- Constitutional symptoms
- Organ infiltration
—> **Bone pain: more common in ALL than AML ∵ Lymphocyte infiltrate into BM space —> marrow necrosis)
—> **Testicular swelling: more common in ALL
—> CNS disease (e.g. Kernig’s sign): ALL = AML
- ***Leukostasis
Diagnosis:
1. PB, BM examination
2. Morphology (e.g. high NC ratio)
3. Cytochemistry (for myeloid lineage)
4. Immunophenotyping
- **IHC —> determine lymphoid (B vs T) vs myeloid lineage + cell stage (early vs mature B)
- **Flow cytometry —> can quantify number of cells carrying specific Ag
- Cytogenetics + Molecular genetics
- **Karyotyping (tell whether there is novel cytogenetics abnormality)
- SKY (SpectroKaryotyping)
- **RT-PCR
- **FISH (detect fusion transcript)
—> for **Risk stratification + Treatment + Monitor progress
Rmb: almost 100% of children ALL have genetic abnormalities in abnormal cells
- mostly Fusion transcript (i.e. translocation)
- abnormality in Chromosome number (hyperdiploid, hypodiploid)
t(9;22) abnormality (associated with poorer prognosis):
- not same Philadelphia chromosome as CML
- common in adult
- rare in children
**t(12;21) abnormality (responsive to treatment —> associated with **good prognosis (>95% have durable remission))
- ***common in children
- rare in adult
—> ALL has good prognosis in children compared to adults
Pre-leukaemia + Leukaemia
Myeloproliferative disorder (MPD):
- Abnormal proliferation of Haematopoietic cells
- High cell number
- Morphology is ***normal (unless severe like CML, MF)
- PV, ET, MF, CML
Leukaemia:
- Abnormal proliferation + differentiation of Haematopoietic cells (Blasts)
- ALL / AML
MDS:
- Abnormal differentiation of Haematopoietic cells (Myelodysplastic features in blood cells)
- CMML etc.
Treatment of ALL in children
***Long duration
More intensive treatment (first 4-6 months)
1. **Induction
2. **Consolidation
3. CNS prophylaxis
4. **BMT (only for high risk group after achieved good remission with initial treatment)
5. 2nd consolidation
1.5-2 years
6. 3rd consolidation
7. **Maintainence (on oral medications, can go to school)
Very good survival: 70-80%
HK: German Berlin, Frankfurt, Muenster (BFM) treatment:
- 80+%
Relapse of ALL:
1. Clonal evolution from a pre-leukaemic clone (51%)
2. Clonal evolution from same clone of diagnosis (34%)
3. Same clone as diagnosis (8%)
4. Unrelated second leukaemia (7%)
—> Implications: retain same genetic abnormalities —> can salvage relapsed patients
—> Prognosis: the later they relapse from original diagnosis —> better outcome
AML
Similar to adult de novo AML (NOT MDS-related AML):
- Genetic abnormalities: common fusion transcript (e.g. t(15;17), t(8;21))
Treatment of AML (***Short + Intensive compared to ALL):
4-6 months
1. Induction
2. Consolidation
3. BMT (usually at remission state)
4. +/- Maintenance
Paediatric AML Chemotherapy:
- **Intrathecal chemotherapy for **CNS prophylaxis (kill cancer cells in CNS to prevent relapse in CNS, not done in adults)
Acute Promyelocytic Leukaemia (APL) (i.e. M3-AML):
- ATRA + ATO
Prognosis:
- Depend on genetic abnormalities
- Overall 30-40% survival
Childhood brain tumours
- Astrocytoma (most common)
- **Medulloblastoma (under **PNET: Primitive neuroectodermal tumour) (most common as a single disease)
- Germ cell tumour / Pineoblastoma (common in Chinese) (much higher than overseas)
Treatment of Paediatric Brain tumours
- Surgery
- RT
- newer form of RT: IMRT (Intensity-moderated), TOMO, Proton beam
—> much less scattered irradiation than conventional RT
- ∵ medulloblastoma tend to spread along leptomeninges —> need irradiation of both brain + ***spine (i.e. Craniospinal irradiation) - Chemotherapy
- new agents: Temozolomide - Targeted therapy
- Avastin, Nimutuzumab, mTOR inhibitor - +/- VP shunt
Medulloblastoma
- always derived from cerebellum (mostly ***Vermis)
- ***Cerebellar symptoms
-
**Obliterate 4th ventricle
—> **obstructive hydrocephalus
—> gradual ↑ frequency of headache + vomiting - treatment outcome: ~70-80% survival
- 4 main groups (with different gene expressions, pathways, prognosis)
—> future treatment can be based on risk / types
—> minimise SE + treatment efficacy
Astrocytoma
WHO classification:
Grade 1-4 (NOT staging —> will NOT progress to next grade)
Grade 1: Pilocytic astrocytoma
Grade 2: Low grade glioma
Grade 3: Anaplastic astrocytoma
Grade 4: Glioblastoma multiforme (GBM)
Grade 1, 2: Very Good outcome (90-100%) (can just use low dose chemotherapy to arrest growth of tumour)
Grade 3, 4: Very poor outcome
CNS Germ cell tumours
- 60% at pineal / suprasellar region, sometimes in thalamus / basal ganglia
- often along midline
2 main groups:
1. Germinoma (73%)
2. Non-germinoma (27%)
- Embryonal carcinoma (↑ AFP + βhCG)
- Yolk sac tumour (↑ AFP)
- Choriocarcinoma (↑ βhCG —> pseudo-precocious puberty)
- Teratoma
- Mixed
Prognosis:
- Germinoma (90%) > Non-germinoma (70%)
Vascular anomalies
Cortical laminar necrosis
- serpingineous hyperintensity along cortex
- only detected by MRI
Neurological disability in Paediatric Brain tumour survivors
- 70% >=1 neurological impairment (∵ tumour / treatment), 25% moderate to severe:
1. **Motor impairment
2. **Visual impairment
3. ***Subnormal IQ - Slow down in deterioration after 2-3 years
- Risk factors: <3 yo, high initial IQ, form of treatments
- Higher dose of **Craniospinal irradiation —> Worse deterioration of IQ
4. **Brain atrophy
5. ***Epilepsy
Non-Hodgkin Lymphoma
3 types:
1. ***Lymphoblastic NHL
- diffused bulky LN, mediastinal enlargement (airway / SVC obstruction), hepatosplenomegaly
- ***Burkitt’s NHL (sporadic form) (vs endemic form in Africa, associated with EBV, jaw enlargement)
- intussusception, enlarged cervical LN - ***Anaplastic Ki-1 NHL
- pleural effusion, skin nodules, haemophagocytic syndrome (HPS) / haemophagocytic lymphohistiocytosis (HLH) - Diffuse Large B cell lymphoma
- Small non-cleaved cell (SNC) lymphoma
Diagnosis:
Required ***tissue biopsy for confirmation, preferably Excisional / Incisional biopsy rather than needle biopsy
Staging:
- Imaging
- Radioisotopes scan
Prognosis:
- 70-80% survival (∵ aggressive in nature)
Neuroblastoma
- Common in children, rare in adult
- Arise from **Neurocrest cells (progenitor cells of **sympathetic nerves)
—> Tumour along sympathetic chain, adrenal gland (65%), kidney
Specific investigations:
1. **MIBG scan (sensitive to pick up neurocrest cells in origin e.g. neuroblastoma, phaeochromocytoma)
2. Urine **VMA, HVA (catecholamine-related chemicals)
Treatment:
Early stage neuroblastoma (Stage 2a / 2b, Symptomatic 4s (s: spontaneous regression —> regress without treatment)):
**Surgical resection
—> **5 courses of chemotherapy (Cyclophosphamide + Doxorubicin)
—> **2nd look surgery
—> No residual disease —> Follow up
—> Residual disease —> **Salvage chemotherapy (VP16 + Carboplatinum)
Prognosis:
- 90-100% survival
High stage / Metastatic neuroblastoma (65%):
Need every treatment possible:
- Chemotherapy
- Surgery
- Stem cell transplant
- RT
- Targeted therapy (***Anti-GD2 monoclonal Ab)
- Retinoic acid
—> Poor prognosis (50-60%)
Other solid tumours in children
- Kidney
- ***Wilms’ tumour (aka Nephroblastoma) (good survival) (surgery + chemo)
- Other types (e.g. Clear cell, PNET) - Soft tissue Sarcoma
- Rhabdomyosarcoma (a group of tumours arise from skeletal muscle, most common: Embryonal type (1/3 found in parameningeal area, 1/3 in pelvic cavity, associated with chromosome gain / loss) + Alveolar type (found in trunk, forelimbs, in older children, unique fusion transcript)) (poor outcome: 50-60% ∵ poor total resection ∵ HN region)
- Non-Rhabdomyosarcoma
- PNET - ***Germ cell tumour (Peripheral / Extracranial) (good survival) (surgery + chemo) (NOT CNS germ cell tumour)
—> Also have Germinoma vs Non-germinoma
- Choriocarcinoma
- Yolk sac tumour
- Malignant teratoma
- Dysgerminoma - Liver
- ***Hepatoblastoma (more common) (chemo —> surgery) (good survival: 70-80%)
- HCC (↓ incidence ∵ Hep B vaccination) - Bone tumour
- Osteosarcoma (metaphyseal areas: periosteum lifted up —> **Codman triangle, **Sunray appearance) (good survival if no metastasis: 80-90%) (treatment: may need limb salvage e.g. allograft / prosthesis)
- Ewing’s sarcoma (diaphyseal areas: ***onion skin) —> in Chinese mainly as peripheral PNET (found in various parts of body) rather than extremities (in Caucasians) —> cannot totally resect —> poorer outcome (survival 40%)
Long Term Complications of Paediatric cancers
Related to disease / treatment
1. **Learning disability (esp. Craniospinal irradiation)
2. **Growth retardation (e.g. pituitary tumour, irradiation of pituitary)
3. **Subfertility (high dose alkylating agents e.g. Cyclophosphamide)
4. **Organ dysfunction (e.g. Adriamycin causing Cardiomyopathy, Ifosfamide causing renal tubular damage)
5. Second malignancy (9-10% 25 years after at site of irradiation)
- Late effects of therapy may manifest many years later
- Developmental period more prone to damage caused by therapy
Breaking bad news (upon diagnosis / relapse)
- Empathy + prepare to be listener
- Don’t try to provide too much information within a short time
- Has to provide affirmative diagnostic information, avoid using ambivalent (含糊不清) terms
- Just mention the framework of treatment plan + SE
- Provide “hope” but not “false hope” in prognosis
- should be realistic to disease nature - Help to pacify guilty feeling
- non-inherited nature of most childhood cancers
- non-contagious to other family members
