Oncology Flashcards
ALL overview
Most common childhood cancer
Peak onset 2-5 years
10-20x more likely in T21
Types include pre-B cell ALL and T cell ALL (10-15% of ALL)
ALL symptoms
Fevers (60%)
Bruising, epistaxis (50%)
Bone pain (20%)
Pallor, anorexia, fatigue
ALL examination
Hepatosplenomegaly (>60%)
Lymphadenopathy (50%)
Petechiae
Examine testes! (sanctuary site)
ALL investigations
Low platelets and Hb (due to bone marrow crowding with leukaemic cells)
WCC high/normal/low
CMP and LDH - monitor for TLS
CXR - for mediastinal mass
Bone marrow biopsy: >5% suggestive of leukaemia (>25% diagnostic), 5-25% ?lymphoma
LP - for CNS disease
ALL initial treatment
TLS prevention (hyper hydration, alkalinization, allopurinol
Induction: 28 days of treatment
- steroids, vincristine, intrathecal methotrexate and peg-asparaginase
- daunomycin in high risk patients
ALL maintenance treatment
Daily oral 6-mercaptopurine
Weekly oral methotrexate
Monthly pulses of steroid and vincristine
3 monthly intrathecal methotrexate
Duration = 2 years for girls, 3 years for boys
ALL favourable risk factors
1-10 years old
WCC <50 at presentation
TEL-AML1 (or ETV6-RUNX1), hyperdiploid
Negative for minimal residual disease
ALL high risk factors
<1 year or >10 years
WCC >50 at presentation
Corticosteroid exposure before diagnostic workup
CNS or testicular involvement
BCR-ABL1 (Philadelphia chromosome), mixed-lineage leukaemia rearranged, hypo diploid
Induction failure or positive minimal residual disease
ALL relapse
Most common sites: CNS and testes
If relapse, treatment often progresses to bone marrow transplant
AML overview
More aggressive and poorer prognosis than ALL
Associated with Down syndrome, Falcon anaemia, Kostmann syndrome and neurofibromatosis
AML good prognostic indicators
CBF mutations [inversion 16 (p13.1q22), t(16;16)(p13;q22), t(8;21)(q22;q22), or AML/ETO], CEBPa, NPM1
Down syndrome: 30% risk of AML presenting around 2 years, better prognosis and good response to chemo, but more treatment-related complications
AML worse prognostic indicators
Monosomy 5, monosomy 7
Infant AML
AML from myelodysplastic syndrome
FLT-3/ITD
Transient myeloproliferative disorder
A preleukaemic disorder that arises during fatal development and hematopoiesis in Down syndrome patients
- present in up to 30% (only clinically evident in 10%)
- diagnosed by presence of megakaryoblasts in peripheral smear
Majority (80%) regress by 3-7 months of life
20-30% of cases will develop AML by 4 years of age
AML symptoms
Fevers
Bone pain
Bruising, epistaxis
Pallor anorexia, fatigue
(similar to ALL)
AML examination
Hepatosplenomegaly
Pallor
Petechiae
Gingival hypertrophy (uncommon but unique)
AML investigations
High WCC (much more conducive to effects of hyper viscosity)
Higher risk of bleeding with coagulopathy
Bone marrow biopsy: >25% with blasts is diagnostic
LP to evaluate for CNS disease
(similar to ALL workup)
AML initial treatment
TLS prevention (hyperhydration, arlkalinization, allopurinol)
Correct coagulopathy
Usually will need 6 months of intensive chemotherapy (very immunosuppressive, will need admission until count recovery)
AML unique complications
Hyperleukocytosis (5-22%)
Neutropenia (more risk of prolonged neutropenia with AML) - opportunistic infections are the most common cause of death
Mediastinal mass - avoid sedation
AML chemotherapy
Induction with daunomycin/cytarabine/etoposide
Cardiac monitoring required due to daunomycin exposure
Due to risk of relapse, higher change of bone marrow transplant compared with ALL
Acute promyelocytic leukaemia treatment
Alltrans retinoid acid (ATRA) - 80% survival
AML relapse predictors
Karyotype, FLT2 status, response to induction
Neuroblastoma overview
Most common extra cranial solid tumour, and most common solid tumour of infancy
Median age 18 months (90% at <10 years)
ALK gain of function mutation in most familial cases (rare)
Neuroblastoma pathophysiology
Arises from sympathetic nerve progenitor cells
- 50% arise from the medulla of the adrenal gland, but neuroblastoma can arise anywhere along the sympathetic nerve chain
Neuroblastoma - metastatic disease
50-70% have metastatic disease at diagnosis - common site include regional lymph nodes, bone marrow, bone (e.g. orbits), liver and skin sites are more common in young infants
Neuroblastoma clinical presentation
Fever, weight loss, abdominal distension, bone pain (high risk disease)
Clinical features of neuroblastoma in the abdomen
Abdominal organ compression:
- bowel = constipation
- urinary = retention, UTI
- renal artery = hypertension
Clinical features of neuroblastoma (abdominal)
Abdominal organ compression:
- bowel = constipation
- urinary = retention, UTI
- renal artery = hypertension
Clinical features of neuroblastoma (orbital lesion)
Proptosis or raccoon eyes
Clinical features of neuroblastoma (paraspinal with nerve root invasion)
Weakness, paraplegia
Clinical features of neuroblastoma (cervical chain)
Horner syndrome (ptosis, mitosis, anhidrosis)
Clinical features of neuroblastoma (mediastinal)
Respiratory symptoms, laryngeal nerve compression, hoarse voice
Clinical features of neuroblastoma with large liver metastases
Respiratory distress (from abdominal competition), coagulopathy, renal impairment
Opsoclonus-myoclonus syndrome
Caused by antineural antibodies attacking the cerebellum, usually associated with low risk tumours
Opsoclonus: rapid involuntary conjugate movement of the eyes in all directions
Myoclonus: irregular jerking of limbs/trunk
Ataxia and irritability are common
Neuroblastoma paraneoplastic syndromes
Opsoclonus-myoclonus syndrome
High-volume secretory diarrhoea (due to excessive vasoactive intestinal polypeptide secretion)
Secretion of catecholamines may cause flushing, headaches, palpitations and hypertension
Neuroblastoma bloods
Anaemia, thrombocytopenia or pancytopenia from metastatic disease
Abnormal LFTs/coags if liver mets
Elevated ferritin and LDH
Neuroblastoma specific diagnostic tests
Urine or serum catecholamines (HVA, VMA)
MIBG scan - similar in structure to noradrenaline and taken up by tumour (90% of neuroblastoma are MIBG avid)
Biopsy of primary tumour
Bone marrow biopsy for mets
Neuroblastoma treatment
Low-risk disease: monitor for regression
Intermediate disease: limited chemotherapy, and surgery if able
High-risk disease: chemo, surgery, radiation, autologous stem cell transplant, and immunotherapy with GD2-directed antibody (dinutuximab)
Relapse rate 50%
Subtypes of paediatric brain tumours
Neuroepithelial (gliomas, ependymomas)
Embryonal
Meningeal
Cranial and paraspinal nerve tumours
Choroid plexus tumours
Also described based on location (supratentorial, infratentorial, parasellar, spinal)
NF1 and brain tumours
Optic pathway and other low-grade gliomas, malignant peripheral nerve sheath tumours
Other features = cafe-au-lait spots, axillary and groin freckling, neurofibromas on skin, Lisch nodules on iris
NF2 and brain tumours
Acoustic sschwannomas, meningiomas, ependymomas
Other features = juvenile cataracts
Tuberous sclerosis and brain tumours
Subependymal nodules and giant-cell astrocytomas
Other features = Ash leaf spots and shagreen patches on skin, angiofibromas on the face, angiomyolipomas in kidney, developmental issues, seizures
Turcot syndrome and brain tumours
Most often gliomas, but can also have medulloblastomas, ependymomas, astrocytomas
Other features = polyps in colon
Gorlin syndrome and brain tumours
Medulloblastomas
Other features = increased risk of BCC, pits in palms and soles, skeletal abnormalities, macrocephaly
Li Fraumeni and brain tumours
Astroytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas
Other features = increased risk of breast cancer, osteosarcoma and other sarcomas, leukaemia and adrenocortical carcinoma
von Hippel-Lindau syndrome and brain tumours
Hemangioblastomas
Other features = pancreatic and genitourinary tract cysts, increased risk of RCC and pheochromocytoma
Cause of early morning vomiting with brain tumours
Vasodilation of cerebral vessels overnight leads to increased cerebral blood volume, followed by increased CSF production
Clinical presentation of brain tumours
Headache, nausea and vomiting (morning), macrocephaly in infants, irritability, obstructive hydrocephalus, neurological symptoms based on location
Features of obstructive hydrocephalus
Papilloedema, vomiting, obtundation
Clinical features of supratentorial lesion
New seizures, visual changes, diencephalic syndrome (severe emaciation and FTT in otherwise happy infant, due to tumours in hypothalamus)
Clinical features of infratentorial lesion
Ataxia, gait abnormalities
Nystagmus (especially with cerebellar tumours)
Parinaud syndrome
Head tilt
Obstructive hydrocephalus
Parinaud syndrome
Paralysis of up gaze, pupils are mid-dilated and poorly reactive to light, convergence or retraction nystagmus, and eyelid retraction (from pineal or dorsal midbrain tumours)
Complication of resection of intratentorial tumour?
Cerebellar mutism syndrome = mutism, irritability, ataxia, and hypotonia which lasts a few weeks to 6 months, followed by a period of dysarthria that eventually self resolves
Clinical features of parasellar lesion
Endocrine dysfunction: either under or over producing hormones
Visual field defects from growth upwards into the optic nerve
Investigation of brain tumour
Brain and spinal MRI
CSF evaluation to look for mets
Screen TSH, GH, prolactin and other hormone levels as needed if pituitary involved
AFP and HCG for germ cell tumour
Biopsy for definitive diagnosis
Low grade gliomas
Most common brain tumour
Neuroepithelial cell of origin
Slow growing, but can have significant symptoms depending on location
e.g. pilocytic astrocytoma, optic nerve gliomas
Pilocytic astrocytoma
Low grade glioma
Infratentorial, usually arising in cerebellum
Most common glioma in children
High grade gliomas
Neuroepithelial cell of origin
Infratentorial: most often diffuse intrinsic pontine glioma (DIPG)
Supratentorial: anapaestic astrocytoma, glioblastoma multiforme (GBM)
Medulloblastomas
Most common malignant brain tumour
Embryonal cell of origin
Arise in cerebellum
Can be metastatic to bone marrow
Craniopharyngioma
Parasellar tumour
Arises from ectodermal remnants of Rathke cleft
Endocrine issues are common (is near pituitary and hypothalamus), visual changes if optic chasm involved
Skull film can show calcification in the sella turcica
Excellent prognosis (>90% survive)
Pituitary adenoma
Parasellar tumour
Anterior pituitary gland tumour
Benign
Micro <1cm, macro >1cm
Non-secreting tumours (30%), secreting tumours (70%)
Hormone secreting tumour features
Prolactinomas cause milk production and inhibit GbRH, resulting in diminished testicular/ovarian function
Gigantism/acromegaly from GH
Cushing disease from ACTH
Hyperthyroidism
Germ cell tumours
Germinomas: most common, good outcomes
Nongerminomas: some produce hormones - choriocarcinoma (bHCG), yolk sac tumour (AFP)
Ependymoma
Derived from ependymal cells that secrete CSF
65-75% are infratentorial in childhood
Can be low or high grade
Choroid plexus carcinoma
Mass in region of the choroid plexus
Often causes hydrocephalus because it arises in ventricles
High grade tumour, poor prognosis
Atypical teratoid/rhabdoid tumours (ATRT)
Aggressive tumour that can arise anywhere in the CNS, usually in patients less than 3 years old
Caused by mutations in SMARCB1 (often result in multifocal tumours, usually renal)
Treatment of brain tumours
Dexamethasone for symptom relief
Surgical resection when able (plus often VP shunt needed)
Chemotherapy
Radiation
Pituitary adenoma treatment
No need to treat microadenoma if not symptomatic
Medical management of prolactinomas: dopamine agonist (decreases size of adenoma and decreases prolactin), if prolactin levels do not normalise, proceed to surgical debulking
Wilms tumour
2-5 years
Painless abdominal mass
Metastatic sites: regional lodes, lungs, liver
Rx: surgery and chemotherapy, radiation if advanced
Mesoblastic nephroma
<1 year (median age 1-2 months)
Abdominal mass (may be noted prenatally), haematuria
No metastatic sites (benign)
Rx: nephrectomy
Clear-cell carcinoma
1-6 years
Abdominal mass
Metastatic sites: lungs, brain, bone
Rx: surgery, chemotherapy and radiation
Rhabdoid tumour
<3 years
Fever, haematuria
Metastatic sites: lungs, brain (atypical teratoid/rhabdoid tumour)
Rx: surgery, chemotherapy and often radiation
Renal cell carcinoma
Adolescents
Haematuria, flank pain, abdominal mass
Metastatic sites: regional nodes, lung, liver
Rx: complete surgical resection including affected nodes
Conditions associated with hepatoblastoma?
Beckwith-Wiedemann/hemihypertrophy
Very low birth weight/prematurity
Glycogen storage diseases
Familial adenomatous polyposis
Trisomy 18
Conditions associated with hepatocellular carcinoma
Chronic hepatitis B and C
Alagille syndrome
Glycogen storage diseases
Tyrosinaemia
Progressive familial intrahepatic cholestasis
Wilson disease
Haemochromatosis
Autoimmune hepatitis
Osteosarcoma
Adolescent
Most common malignant bone tumour, M>F
Femur > tibia > humerus
Metaphysis (with “sunburst” appearance)
No genetic findings
Treatment: surgery and chemotherapy
Ewing sarcoma
10-20 year olds
Lower extremity > pelvis > chest wall
Diaphysis affected (with “onion skin” appearance)
Genetics: EWSR1-FLI1 fusion (t11,22)
Rx: surgery or radiation, and chemotherapy
Clinical presentation of osteosarcoma
Unilateral bone pain
Pathological frature
Palpable hard mass/swelling
Rarely erythematous
Investigation of osteosarcoma
XR: periostea new bone formation (“sunburst”)
MRI
CT chest for metastatic spread - mets in lung in 15% at time of diagnosis
PET scan
Biopsy required for diagnosis
Treatment of osteosarcoma
Surgical resection - amputation vs limb sparing surgery, radiation is not effective in fully eradicating
Neoadjuvant and adjuvant chemotherapy are necessary for cure as 80% have micrometastatic disease
- methotrexate, doxorubicin, cisplatin
Presentation of Ewing sarcoma
Pain (dependent on site)
Pathologic fracture
Constitutional symptoms are more common in metastatic disease
Due to marrow involvement, can have pancytopenia
Investigations in Ewing sarcoma
LDH - offers prognostic information
XR: destructive diaphysial bone lesion, sometimes accompanied by periosteal reaction (onion skinning)
MRI, CT chest, PET scan
Bone marrow aspirate and biopsy
Treatment in Ewing sarcoma
Surgery preferred, radiation used in patients with non-resectable disease
Chemotherapy necessary as all patients are assumed to have micrometastatic disease
- vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide
Prognostic factors: improved outcomes in young, in females, and extraskeletal tumours, high LDH is worse prognosis
Tumour syndromes - inactivation of tumour suppressor genes
Li-Fraumeni (p53) syndrome
NF1 and NF2
Familial retinoblastoma
Von Hippel-Lindau disease
Tuberous sclerosis
Tumour syndromes - defects in DNA repair
Bloom syndrome
Fanconi anaemia
Xeroderma pigmentosum
Ataxia-telangiectasia
Alkylating agents
Disrupt double helix of DNA by adding aryl groups -> leads to DNA breakage and cell death
Most active in resting phase of cell cycle
Cyclophosphamide
MoA: alkylating agent - alkylates guanine -> inhibit DNA synthesis
Indication: ALL, NHL, HL, soft tissue sarcoma, Wilms, neuroblastoma
AE: hemorrhagic cystitis, pulmonary fibrosis, SIADH, infertility
Other: Mesna prevents hemorrhagic cystitis
Ifosfamide
MoA: alkylating agent - alkylates guanine -> inhibits DNA synthesis
Indication: NHL, Wilms, soft tissue sarcoma
AE: SIADH, renal tubular acidosis, ifosfamide encephalitis, infertility
Other: Mesna prevents hemorrhagic cystitis
Ifosfamide encephalopathy
Wears off once the drug is cleared - treat with thiamine or methylene blue
Antimetabolites
Folic acid, pyridine and purine analogues
Similar structure to naturally occurring molecules in DNA/RNA synthesis but interfere with normal cellular function
Cause cell death during S phase of cell growth, or inhibit enzymes needed for nucleic acid production
Methotrexate
MoA: antimetabolite, folate antagonist; inhibits dihydrofolate reductase
Indication: ALL, NHL, osteosarcoma, HL, medulloblastoma
AE: common (N/V, hepatitis, photosensitive dermatitis), renal and CNS toxicity (can cause effusions, low IQ), IT arachnoiditis, leukoencephalopathy
Other: if toxic - carboxypeptidase given
Can’t give with penicillin, PPIs or Bactrim
6-mercaptopurine/6-thioguanine
MoA: antimetabolite, purine analog; inhibits purine synthesis
Indication: ALL
AE: myelosuppression
- 6MP: hypoglycaemia
- 6TG: VOD
Other: allopurinol inhibits metabolism/increases toxicity
Cytarabine (Ara-c)
MoA: antimetabolite, pyrimidine analog; inhibits DNA polymerase
Indication: ALL, AML, NHL, HL
AE: cytarabine fevers/flu like symptoms
Other: can be given intrathecal
5-flurouracil (5-FU)
MoA: antimetabolite, pyridine base
Indication: multiple solid tumours
Vinca alkaloids
Cytotoxics; halt division of cells and cause cell death - bind to tubular and inhibit formation of spindle fibres (microtubules) during MITOSIS
Vincristine
MoA: vinca alkaloid, inhibits microtubule formation
Indication: ALL, NHL, HL, Wilms, Ewing, neuroblastoma, rhabdomyosarcoma
AE: constipation, neuropathy (peripheral, sensorimotor, autonomic), jaw pain
Other: given IV only, must not be allowed to extravasate (can cause severe injury)
Vinblastine
MoA: vinca alkaloids, inhibits microtubule formation
Indication: NHL, HL, Langerhans cell histiocytosis, CNS tumours
AE: cellulitis, leukopenia
Other: IV only, must not extravasate
Topoisomerase inhibitors
Disrupt topoisomerase I and II, which play biggest role in uncoiling DNA for replication
Etoposide
MoA: topoisomerase inhibitor
Indication: ALL, NHL, germ cell tumour, Ewing
AE: secondary leukaemia
Anthracyclines
Increase oxygen free radicals, risk of cardiac toxicity
Doxorubicin
MoA: binds to DNA, intercalation
Indications: ALL, AML, osteosarcoma, Ewing, HL, NHL, neuroblastoma
AE: cardiomyopathy, red urine, necrosis on extravasation
Other: dexrazoxane reduces risk of cardiotoxicity
Danorubicin
MoA: affects DNA
Indications: ALL
AE: cardiomyopathy, red urine, necrosis on extravasation
Other: dexrazoxane reduces risk of cardiotoxicity
Carboplatin
MoA: inhibit DNA synthesis
Indications: osteosarcoma, neuroblastoma, CNS tumours, germ cell tumours
AE: N/V, myelosuppression, anaphylaxis
Other: aminoglycosides may increase nephrotoxicity
Cisplatin
MoA: inhibit DNA synthesis
Indications: osteosarcoma, neuroblastoma, CNS tumours, germ cell tumours
AE: N/V +++, ototoxicity, renal impairment
Other: amifostine is given as otoprotection, sodium thiosulfate is also protective
L-asparaginase
MoA: depletion of L-asparagine, specific to leukaemia cells
Indication: ALL, AML in combo with cytarabine
AE: anaphylaxis, pancreatitis, coagulopathy, hyperglycaemia, cerebral sinus thrombosis
Other: PEG-asparaginase now preferred to L-asparaginase
PEG-asparaginase
MoA: polyethylene glycol conjugate of L-asparagine
Indications: ALL
Other: usually only given once
Bleomycin
MoA: binds to DNA, cleaves DNA strands
Indications: HL, NHL, germ cell tumours
AE: pneumonitis, pulmonary fibrosis, mucocutaneous reactions (often affects palms)
Other: arrest at G2 phase, no myelosuppression
Dactinomycin
MoA: binds to DNA, inhibits transcription
Indications: WIlms, rhabdomyosarcoma, Ewing
AE: myelosuppression, mucosal ulceration, tissue necrosis on extravasation
Tretinoin
MoA: enhances normal differentiation
Indications: acute promyelocytic leukaemia, neuroblastoma
AE: dry mouth, hair loss, pseudotumour cerebri, birth defects, premature epiphyseal closure
Prednisolone and dexamethasone (as chemo)
MoA: lymphatic cell lysis, unclear mechanism
Indications: ALL, HL, NHL
AE: Cushing, cataracts, diabetes, HT, myopathy
Other: can suppress fever, avoid in brain tumours
Side effects for chemo agents preventing DNA replication
All cause the same side effects: myelosuppression, nausea, mucositis, hair loss, loss of fertility
Intrathecal chemotherapy?
Methotrexate
Cytarabine
Key side effects - bleomycin
Pulmonary fibrosis
Key side effects - bulsulfan
Seizures
Key side effects - cisplatin
Hearing loss, nephrotoxic, nausea
Key side effects - cyclophosphamide
Haemorrhagic cystitis, secondary leukaemia, sterility, herpes zoster
Key side effects - cytarabine
Nausea and vomiting, mucositis, myelosuppression
Key side effects - daunorubicin
Radiation recall reactions, cardiotoxicity
Key side effects - doxorubicin
Cardiotoxicity
Key side effects - etoposide
Secondary leukaemia, myelosuppression
Key side effects - methotrexate
High dose: mucositis, LFT derangement, renal failure, third space accumulation
Key side effects - ifosfamide
Proximal RTA, Fanconi
Key side effects - procarbazine
Sterility
Key side effects - vincristine
Neurotoxicity, jaw pain, constipation, foot drop (don’t give to neuropathic patients), extravasation burns, CYP450 substrate
FATAL if intrathecal
Chemo agents that cause minimal/no myelosuppression
Vinca alkaloids
Enzymes (asvparaginase)
Bleomycin
Steroids
