Oncology Flashcards
Cancer mutations: germline vs somatic mutations
Germline = mutations at conception
- Inherited from parents as mutation present in parent’s germ cells OR
- De novo - acquired during mieosis, conception or very early embryonic development
- Cancer predisposition come from germline mutations
Somatic = mutations acquired after conception in a subset of cells
Solid tumours that can invade bone marrow
Paediatric small round blue cell tumours can invade marrow to cause bone marrow failure
- Ewings sarcoma
- Anaplastic hepatoblastoma (not foetal or embryonal subtypes)
- Medulloblastoma
- Neuroblastoma
- Alveolar rhabdomyosarcoma
- Retinoblastoma
- Wilm’s tumour
Genetics associated with Wilm’s tumour
Hereditable disorders (germline/hereditary genetic mutations):
- WAGR syndrome: WT1 deletion (11p13)
- Denys-Drash syndrome: WT1 missense mutation (11p13)
- Beckwith Wiedeman syndrome: 11p15 (imprinting defect)
- Familial forms: FWT1 (17q12-q21) and FWT2 (19q13)
- Worse prognostic indicator: loss of heterozygosity at 1p and 16q
Treatment of Wilm’s tumour
Stage 1: nephrectomy only if tumour wt <550g and <2yo
Stage 1 or 2: nephrectomy with chemotherapy - vincristine and dactinomycin for 18 weeks
Stage 3 or 4: nephrectomy with chemotherapy - vinc, dact, doxorubicin for 24wks, radiation to abdopelvis/lungs if mets
Stage 5: aggressive chemotherapy, partial nephrectomy or bilat nephrectomy, 1-2yrs of bridging dialysis with consideration of transplant if in remission
If anaplastic histology: intensive CTX and radiation - V and doxo, cyclophosphamide, ifosfamide, etoposide and carboplatin
Risk factors for osteosarcoma
- Cancer predisposition: Li Fraumeni syndrome (TP53 germline mutation), hereditary retinoblastoma
- Previous radiation therapy
- Benign conditions: paget dz, enochondromatosis, fibrous dysplasia, hereditary exostoses
Major differences between osteosarcoma and Ewing sarcoma
OS:
- Primary = bone only
- Metaphyseal distribution of long bones e.g. prox humerus, knee
- Pathological #
- XR: mixed lytic/blastic appearance, sclerotic, sunburst appearance
- Tx: no radiation
ES:
- Primary = bone AND/OR soft tissue
- Diaphyseal distribution including flat bones (e.g. pelvis, ribs)
- Systemically unwell, fevers, anorexia, anaemia
- Metastasis: lung, bone, MARROW (therefore, work up includes bone marrow aspirate)
- XR: lytic lesions, onion skinning (local periosteal rxn)
- Tx: radiation
Genetics in Ewing sarcoma
t(11:22) is 90% diagnostic - ESWR1:FLI1
Remainder can have t(21:22)
ESWR1 = 22q11
Genetics in rhabdomyosarcoma
Alveolar:
- Worse prognosis, if metastatic disease - incurable –> palliative chemotherapy
- t(1:13) or t(2:13) = PAX-FKHR
Clinical manifestations of rhabdomyosarcoma
Most common sites of involvement:
- Head and neck esp orbit (favourable), parameningeal sites (unfavourable) such as nasopharynx
- Orbit: proptosis, ophthalmoplegia - Genitourinary tract: pelvic mass or urinary retention
- Bladder or prostate involvement is unfavourable; female genitalia or paratesticular are favourable - Extremity (unfavourable) and truncal tumours
Risk stratification for rhabdomyosarcoma
- Histology: alveolar vs embryonal
- Initially given a stage, then assigned a “surgical” group
Stage depends on: site (favourable vs unfavourable), size, local invasiveness (T1 - confined, T2 - extension/fixative to surrounds), LN involvement, metastases
Group is assigned after resection: - Group 1: complete resection; Group 2: microscopic residual disease; Group 3: gross residual disease; Group 4: distant mets
Good prognosis (80-90%): stage 1 pre-op and group I/II/III post-op, embryonal histology
Genetics in rhabdoid kidney or brain tumour (ATRT)
Loss INI1 = SMARCB1 - germline mutation 35%
Poor prognosis
Li Fraumeni Syndrome
TP53 germline mutation
- Germline loss of TP53, autosomal dominant predisposition to solid tumours and leukaemia
- Screening exam, bloods, whole body MRI, USS etc required
Genetics in neuroblastoma
Bad prognostic indicators:
- MYCN amplification (>8-200 copies)
- 11q aberrations or LOH 1p
Others: ALK mutation, PHOX2 (if breathing problem)
Risk stratification in neuroblastoma
Risk is based on combination of both:
- Clinical features
- Worse: >18mths (embryonal cancers easier to treat in younger pts), large unresectable tumours, metastatic disease - Histological features
- Worse: MYCN amplification, 11q deletion
High risk neuroblastoma
- Highly malignant and aggressive
- ~70% survival (long term survival 25-35%)
- MYCN amplification: intensive chemotherapy for 13-18mths regardless of local vs metastatic dz
- Tx: intense high dose CTX, autologous stem cell rescue, surgery, radiation, MIGB radioactive isotope, immune therapy with Ch 14.18, retinoic acid for differentiation therapy
Intermiediate risk neuroblastoma
- Local (in older pts) or metastatic (<18mth of age)
- 95% survival
- 2-8 cycles of moderate intensity chemotherapy and surgery
- No transplant, no immune therapy, rarely require radiation
Low risk neuroblastoma
- Localised disease in young pts
- 97-99% survival
- Small tumours in infants usually resolve spontaneously
- Larger ones are cured with resection, do not require chemotherapy
Neuroblastoma 4S disease
a. k.a. MS = Metastatic Special - can remit spontaneously or kill rapidly
- Age <12mths
- Adrenal mass and metastases limited to liver, skin nodules (multiple subcut blueberry nodules) and bone marrow (<10%; does not involve cortex)
- 2 possible outcomes: spontaneous resolution (highest rate of any cancer) OR can rapidly grow –> expanding liver, respiratory embarrassment, subsequent death
- Tx: usually supportive cares, but if massive liver involvement - small dose cyclophos +/- hepatic radiation
- Survival >90%; 81% if treatment required
Klinefelters is associated with which malignancy?
Increased risk of mediastinal germ cell tumours and breast cancer
HSCT for solid tumours
Only autologous stem cell transplant is used in solid tumours as there is no graft vs disease (only relevant in leukemia and lymphoma), therefore risks associated with allogeneic HSCT are not worth it.
Autologous stem cell rescue is considered for HR-neuroblastoma, metastatic or large volume Ewing sarcoma and/or refractory Wilms tumour
Beckwith Wiedemann Syndrome
- Common cancers
- Surveillance
5-10% get cancer
- Wilms tumour
- Hepatoblastoma
- Adrenocortical carcinoma
- Neuroblastoma
- Rhabdomyosarcoma
- AFP 3mthly for 4yrs
- Abdo USS 3mthly until 8yrs of age
Li Fraumeni Syndrome
- Common cancers
- Surveillance
TP3 mutations
- Osteosarcoma age <30yrs - 3-10%
- Rhabdomyosarcoma in age <5yrs
- ALL hypodiploid
- Hepatoblastoma
- Medulloblastoma
Child has increased risk of second cancer
Surveillance for relations:
- Genetic testing for parents and siblings +/- whole body MRIs
PTEN Syndrome
- Common cancers
- Surveillance
PTEN Harmatoma Tumour Syndrome
- Macrocephaly, autism/ID, skin lesions, lipomas, AVMs
- Thyroid, breast and endometrial cancer
- Colon cancer
- Melanoma
- RCC
Surveillance:
- Thyroid Ca - start at 10-12yrs
- Breast and colon - start at 25yo
Rhaboid tumour syndrome
- Common cancers
Mutations in SMARCB1/INI1 gene
Atypical teratoid/rhabdoid tumours
- ATRT in CNS
- Malignant rhaboid tumours - renal and extra-renal
- Incomplete penetrance, most tumours occur <5yo
- 35% have germline mutation
No standard surveillance guidelines
Risk factors for hepatoblastoma
Prematurity/LBW (<1000g) Beckwith Wiedemann Syndrome FAP Li Fraumeni Syndrome Trisomy 18 Neurofibromatosis type 1 Ataxia-telangiectasia Fanconi anaemia Tuberous sclerosis
RB1 gene
Chromosome 13q14
Tumour suppressor gene: controls cell cycle by restricting cell’s ability to progress from G1 to S phase
Germline RB1 mutations can lead to development of other malignancies e.g. osteosarcoma, soft tissue sarcoma, breast cancers
RB1 gene
Chromosome 13q14
Tumour suppressor gene: controls cell cycle by restricting cell’s ability to progress from G1 to S phase
Germline RB1 mutations can lead to development of other malignancies e.g. osteosarcoma, soft tissue sarcoma, breast cancers
Role of corticosteroids in CNS tumours
Pre-operative steroids are given to reduce both intracranial pressure and tumour oedema
Tapered slowly post-operatively
Chemotherapy agents that cross the blood brain barrier
Lomustine (nitrosurea; alkylating agent)
Vincristine (vinca alkyloid; antimicrotubules)
Cisplatin (platinum; alkylating agent)
Cyclophosphamide (nitrogen mustard; alkylating agent)
Etoposide (topoisomerase II inhibitor)
ATRT
Highly malignant grade IV tumour that can be found most commonly in brain, spine or abdomen
Disseminated disease in 20%
INFANTS (<3yo)
Genetics: Biallelic inactivation of SMARCB1, INI1 loss (chrom 22q11.2)
Imaging: tumours are large, rapidly growing, cystic areas and calcifications
Poor prognosis: GTR associated with longer median survival of 12.5mths
T cell CD markers
CD1a, CD2, CD3, CD4, CD5, CD7, CD8
B cell CD markers
CD10, CD19, CD20, CD22, CD 79a
Myeloid cell CD markers
CD15, CD33, myeloperoxidase
Characteristics of a malignant lymphoblast
- Immature
- T or B cell differentiation
- Abnormal intensity of CD marker expression
- Abnormal expression of non-lymphoid cell markers
Immature cell CD markers (indicative of blasts on flow cytometry)
CD34, CD117, HLA-DR, TdT
Low risk B-ALL
- Age: 1-10yrs
- WBC: <50
- Favourable cytogenetics: hyperploidy, ETV6-RUNX1 translocation
- MRD at D8 (PB) <0.01%
MRD at D29 (BM) <0.01% - rapid response to treatment - No CNS2 or CNS3, no testicular involvement
- 5yr EFS >95%
Standard risk B-ALL
- Age: 1-10yrs
- WBC: <50
- Neither favourable or unfavourable genetics
- MRD at D8 (PB) <0.01%
MRD at D29 (BM) <0.01% - rapid response to treatment - No CNS3 or testicular leukemia
OR - Favourable genetics
- MRD at D8 (PB) >0.01% or CNS 2 status
MRD at D29 (BM) <0.01% - rapid response to treatment - No CNS3 or testicular leukemia
- 5yr EFS 90-95%
High risk B-ALL
- Age: >10yo
- WBC: >50
- Unfavourable cytogenetics: hypoploidy, Ph+, MLL rearrangements, iAMP21
- MRD >0.01% at day 28-36 of induction
- CNS positive leukemia
- Testicular positive leukemia
- -> Those with HR features at start of induction with poor response to Tx (positive MRD at end of induction) are recategorised to very high risk
- 5yr EFS 88-90%
Very high risk B-ALL
- Age: <1yo or >13yo
- Unfavourable cytogenetics: extreme hyperploidy, MLL rearrangements, iAMP21
- Failure to achieve remission at end of induction therapy (MRD >0.01%)
- 5yr EFS <80%
Predictors of outcome in relapsed ALL
- Timing of relapse - later the better
- Site of relapse - extramedullary, marrow, testes, CNS, mixed –> EM alone is better
- T vs Pre-B - Pre-B is better
- Response to relapse therapy (MRD)
- Availability of stem cell donor
Depending on risk assignment, treatment will be CTX alone vs CTX and HSCT
Prognosis of relapsed ALL
- Late relapse (>18mths off Tx) isolated extramedullary disease - 70% survival with CTX alone (if early achievement of MRD negative status)
- Early relapse (<18mths since Dx, <6mths off Tx) - 50% with transplant
- Very early (<18mths since Dx) - 20-30% with transplant
- T-cell ALL - very poor 10-30%
What has changed the outcome of Ph+ ALL?
Addition of tyrosine kinase inhibitor (imatinib) with intensive chemotherapy regime has significantly improved outcomes
7yr EFS ~70%
Unfavourable cytogenetics for AML
- Monosomy 7
- Complex karyotype (3 or more aberrations, at least 1 structural aberration w/o favourable genetics or MLL)
- MLL rearrangements - t(9;11) w/ other aberrations or MLL other than t(9;11) or t(11;19)
- Monosomy 5 or del(5q)
- FLT3-ITD (chrom 13q12.2) - relapse risk proportional to allelic ratio (>0.4)
What type of AML is ATRA and arsenic used for?
APML
- Cellular arrest at promyelocytic stage
- PML-RARa oncoprotein blocks transcription of genes that allow differentiation of PM cells, promotes enhancement of self renewal. RARa = retinoic acid receptor alpha and PML is a nuclear regulatory protein that controls differentiation
- 30% present in DIC which can be fatal - therefore, important Dx to make
- Induction therapy with ATRA and arsenic can cure disease
- Very good prognosis if pt survives induction
Prognosis of AML
Reasonable - depends on risk group
Overall survival 60-70%
Favourable cytogenetics for AML
- t(8;21)(22q:22q) = AML1-ETO
- t(15;17)(q22:q21) = PML-RARa
- NPM1 mutation
- CEBPA
- Inversion of chromosome 16