Paediatrics JC124: A Child With Cancer: Paediatric Cancers Flashcards

1
Q

Epidemiology

A
  • Rare (~150 per million children <15)
  • <200 new cases in HK per year
  • 2nd leading cause of death <15 (1st: accident)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Paediatric cancers

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

***Paediatric vs Adult cancer

A
  1. Types
    - Paediatric: **Lymphoid / **Haemic malignancy (others: ***Embryonal (i.e. Blastoma))
    - Adult: Carcinoma (>95%) (from epidermal / glandular cells)
  2. Sites
    - Paediatric: ***Deep seated (deep / visceral organs e.g. Wilms’ tumour in kidney, Neuroblastoma in adrenal) —> discovered late
    - Adult: Superficial + Visible
  3. Stage at diagnosis
    - Paediatric: ***Advanced usually
    - Adult: Can be early
  4. Screening
    - Paediatric: ***Not effective (∵ aggressive, no timeframe for gradual development state)
    - Adult: May help
  5. Response to treatment
    - Paediatric: ***Good
    - Adult: Poor (except for selected targeted therapy)
  6. Outcome
    - Paediatric: 70-80%
    - Adult: 30-40%
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Etiology / Predisposition of Paediatric cancers

A
  1. Unknown in majority
  2. 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
  3. Problem with immunity surveillance (i.e. **Immunodeficiency: esp. **EBV related NHL)
    - immunodeficiency are commonly X-linked —> ∴ paediatric cancers M>F
  4. Environmental factors
    - Physical (radiation: thyroid, haemic malignancy), Chemical, Biological
    - Accounts for a ***minor proportion only (∵ short incubation period)

Conclusion: Difficult to prove etiology / predisposition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Familial Paediatric cancers

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Management issues in Paediatric cancers

A
  1. ***More responsive to therapy
  2. ***Tolerate therapy better (∵ organ function relatively new + strong)
  3. Requires family approach
  4. Multidisciplinary approach
  5. 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Supportive care in Paediatric cancers

A
  1. ***Blood product support
  2. ***Treatment of infection (e.g. antibacterial, antiviral, antifungals)
  3. ***Treatment of metabolic complications (e.g. tumour lysis syndrome by urate oxidase (Rasburicase))
  4. Symptoms control (e.g. pain, vomiting)
  5. Nutritional support
  6. Psychological support
  7. Family support
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Combination modalities of therapy

A
  1. 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
  2. Surgery
    - Primary Rx for solid tumour
    - More conservative in recent year, better tools
    - 2nd look surgery is advocated
  3. RT
    - Mainly for brain + solid tumours
    - More refined field + dose control (**less SE but efficacy remain **same)
    - Palliative therapy
  4. 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
  5. 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Immune checkpoint inhibitors

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Immune therapies: CIK, LIK, DCs

A

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

  1. Co-stimulatory domain
    - from ***co-stimulatory receptor
    - ↑ T cell activation
    - ↑ cytolytic function of T cells
  2. Signaling domain
    - from CD3-zeta (TCR accessory protein)
    - induces ***T cell activation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Haemic malignancy vs CT disease

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Leukaemia

A
  • ***ALL&raquo_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

  1. 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Pre-leukaemia + Leukaemia

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Treatment of ALL in children

A

***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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

AML

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Childhood brain tumours

A
  1. Astrocytoma (most common)
  2. **Medulloblastoma (under **PNET: Primitive neuroectodermal tumour) (most common as a single disease)
  3. Germ cell tumour / Pineoblastoma (common in Chinese) (much higher than overseas)
17
Q

Treatment of Paediatric Brain tumours

A
  1. Surgery
  2. 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)
  3. Chemotherapy
    - new agents: Temozolomide
  4. Targeted therapy
    - Avastin, Nimutuzumab, mTOR inhibitor
  5. +/- VP shunt
18
Q

Medulloblastoma

A
  • 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
19
Q

Astrocytoma

A

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

20
Q

CNS Germ cell tumours

A
  • 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%)

21
Q

Vascular anomalies

A

Cortical laminar necrosis
- serpingineous hyperintensity along cortex
- only detected by MRI

22
Q

Neurological disability in Paediatric Brain tumour survivors

A
  • 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
23
Q

Non-Hodgkin Lymphoma

A

3 types:
1. ***Lymphoblastic NHL
- diffused bulky LN, mediastinal enlargement (airway / SVC obstruction), hepatosplenomegaly

  1. ***Burkitt’s NHL (sporadic form) (vs endemic form in Africa, associated with EBV, jaw enlargement)
    - intussusception, enlarged cervical LN
  2. ***Anaplastic Ki-1 NHL
    - pleural effusion, skin nodules, haemophagocytic syndrome (HPS) / haemophagocytic lymphohistiocytosis (HLH)
  3. Diffuse Large B cell lymphoma
  4. 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)

24
Q

Neuroblastoma

A
  • 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%)

25
Q

Other solid tumours in children

A
  1. Kidney
    - ***Wilms’ tumour (aka Nephroblastoma) (good survival) (surgery + chemo)
    - Other types (e.g. Clear cell, PNET)
  2. 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
  3. ***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
  4. Liver
    - ***Hepatoblastoma (more common) (chemo —> surgery) (good survival: 70-80%)
    - HCC (↓ incidence ∵ Hep B vaccination)
  5. 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%)
26
Q

Long Term Complications of Paediatric cancers

A

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
27
Q

Breaking bad news (upon diagnosis / relapse)

A
  1. Empathy + prepare to be listener
  2. Don’t try to provide too much information within a short time
  3. Has to provide affirmative diagnostic information, avoid using ambivalent (含糊不清) terms
  4. Just mention the framework of treatment plan + SE
  5. Provide “hope” but not “false hope” in prognosis
    - should be realistic to disease nature
  6. Help to pacify guilty feeling
    - non-inherited nature of most childhood cancers
    - non-contagious to other family members