Oncology Flashcards
5-fluorouracil
class: antimetabolite
mechanism: pyrimidine analogue
use: breast/GI
side effects: similar to MTX plus ataxia, esophagitis, stomatitis
6-Mercaptopurine
class: antimetabolite
mechanism: purine analogue
use: ALL
side effects: hepatotoxicity, mucositis, myelosuppression, pneumonitis
Acute GVHD
onset: 2-5wks but within 3 months
incidence: 30% HSCT from matched sibling, 60% unrelated donor
pathogenesis:
- recipient APC meets donor T cell and secrete cytokines
- donor T cells activated in response to cytokines and secrete TNF, IL2, IFN-g
- donor cytokines cause tissue famage and promote activation CD8 killer T cells
clinical:
- maculopapular rash, anorexia, N/V/D
- skin: erythema, pain, burning
- GIT: mucosal ulceration, destruction of crypts, abdominal pain, PR bleeding
- liver: jaundice
histology: endothelial damage and lymphocytic infiltrate, apoptotic bodies
management: prednisone (50% recover 20 days), MMF, monoclonal Ab
- poor outcome if steroid resistant
Age of malignancies
Age <1 yr:
- Neuroblastoma
- Leukaemia
- CNS tumours
- Wilm’s tumour
- Lymphoma
Age 1-14yrs:
- Leukaemia
- CNS tumours
- Lymphoma
- Wilm’s/Germ cell/NB
Age 15-19yrs:
- Lymphoma
- Germ cell tumours
- Leukaemia
- CNS tumours
- Thyroid cancer
ALL
incidence: peak 2-3yrs, M>F
risk factors: genetic (T21, Bloom, Ataxia-telangiectasia, Fanconi anaemia), high BW, radiation, drugs (cyclophosphamide, eposfomide), advanced mat age, MZ twin with ALL (70%)
Indications HSCT: Philadelphia, extreme hypoploidy, Tcell with relapse, ALL early relapse, ALL poor early response
PreBALL relapse: consider different chemo of BMT
AML/ALL
clinical/diagnosis
clinical:
initial: anorexia, fatigue, malaise, low grade fever
BM failure: anaemia (pallor/hypoxia), thrombocytopaenia (purpura/bleeding), neutropaenia (fever>5days)
blastic infiltration: hepatosplenomegally, LN, bone pain, CNS sx, testicular pain, subcutaneous nodules, respiratory distress (mediastinal disease)
emergencies: leucostasis AML>ALL, TLS, mediastinal compression (T cell ALL), coagulopathy (APML), febrile neutropaenia
diagnosis:
blood film
- ALL: monomorphic cells, large/small lymphoblasts with large nucleoli and minimal blue cytoplasm
- AML: polymorphic lymphoblasts with Auer rods, more cytoplasm
bone marrow: >25% BM are lymphoblasts
CSF: worse prognosis with CSF infiltration
Immunophenotype: FLOW cytometry
Cytogenics aids in prognostics: FISH, SNP microarray, gene expression profile
Aneurysmal bone cyst
etiology: benign expansive vascular lesion which grow rapidly and destroy bone
clinical: F>M, adolescents, any bone (femur, tibia), localised pain, pathologic fractures, swelling
XR: aggressive, expansile, ltyic metaphyseal lesions with eggshell sclerotic rim
Anthracycline
Daunorubicin
Doxorubicin
class: antitumour antibiotics
effect: inhibits topoisomerase II
use: ALL, AML, NB, NHL, Sarcoma, Wilm’s
side effects: cardiotoxicity, dermatitis, diarrhoea, myelosuppression, red urine
Asparaginase
class: enzymes
mechanism: catalyses hydrolysis of asparaginase to aspartic acid
- depletes asparaginase
use: ALL, AML
side effects: anaphylaxis, CNS depression, blood disoriders, pancreatitis
Beckwith-Wiedemann
Cancer
common tumours:
- Wilm’s tumour up to 15%
- hepatoblastoma
others: NB, adrenocortical carcinoma, rhabdomyosarcoma
Bleomycin
class: antitumour antibiotics
mechanism: binds to DNA and cuts
use: lymphoma, germ cell tumours
side effects: dermatitis, mucositis, pneumonitis/pulmonary fibrosis, Raynaud’s, stomatitis
Bone Marrow Transplant
allogenic: from another person
autologous: from oneself
preparative condition: myeloblative chemotherapy
- high dose immunosuppression
Day 0: BMT infusion
- IV donor cells
- intrabone injection of cord blood cells into marrow
Day 0- 19: aplastic phase
Day 20: engraftment
Brain tumours
supratentorial:
- pineoblastoma (PNET) (3%)
- craniopharyngioma (10%)
- choroid plexus carcinoma (4%)
- germ cell tumours (germinoma/teratoma) (5%)
infratentorial:
- cerebellar pilocytic astrocytoma (5%)
- medulloblastoma (20%)
- ependymoma (10%)
- brainstem glioma (20%)
Brainstem glioma
incidence: 5-8yrs, 20% Paed BT
location: brainstem
features: cystic, well demarcated, non-infiltrating, non oedematous
clinical: long history, neck stiffness, CN symptoms, ataxia, N/V
associations: NF-1
treatment: resection, radiation, chemo
survival: 50%
Cell-cycle dependent chemotherapy
Phase-dependent drugs: kill cell at lower dose
- prolonged dosing to ensure maximum cells receive insult at right time in cycle
G1: L-asparaginase (enzyme)
S drugs:
- cytarabine: inhibits DNA polymerase
- steroids: suppress transcription factors
- antimetabolites:
- Folinic acid antagonists- methotrexate
- Pyrimidine antagonists- 5FU/ cytosine arabinoside
- Purine antagonists-mercaptopurine/ 6MP/ thioguanine
G2 drugs:
- topoismoerase inhibitors- etoposide
- bleomycin
M phase: vinca alkaloids
Chemo side effects
Chemotherapy agents
-secondary malignancy-
1. Alkylating agents + cisplatin: cyclophosphamide, ifosfamide
2. Topoisomerase inhibitors: etoposide
3. Anthracyclines: daunorubicin, doxorubicin
Chemotherapy pharmacokinetics
1st order kinetics: kill constant fraction of tumour cells at any one time
Chlorambucil
class: alkylating agent
mechanism: interfers DNA crosslinking by alkylating guanine
use: bladder, ovarian, testicular cancer
side effects: infertility, neuropathy, ototoxicity, pneumonitis, renal impairment
choroid plexus carcinoma
(supratentorial)
incidence: 12-16yrs, 4% Paed BT
location: choroid plexus
features: aggressive, focal necrosis, oedema
associations: Li Fraumeni
clinical: FTT, macrocephaly, headaches, N/V
treatment: resection, radiation
Chronic GVHD
definition: persistance >3m post transplant
- behaves like AI disease
incidence: 25% HSCT patients
risk factors: acute GVHD, HLA mismatch, HSV, peripheral SCT, female donor for male recipient, higher age, total body irradiation
pathophysiology:
- autoantibody production with collagen deposits/fibrosis
- due to persistent donor T cells not tolerant to recipient
clinical: limited or extensive
- skin: lichen planus, scleroderma, malar rash
- arthritis, joint contractures, obliterative bronchiolitis, bile duct degeneration
prognosis: skin/liver only is favorable
- extensive disease has high morbidity/mortality
- most resolve but may take 1-3yrs
- lower life expectancy, metabolic syndromes, secondary malignancy
treatment: as for GVHD + AB for prolonged immunosuppression
Cisplatin
mechanism: inhibits DNA synthesis
use: osteosarcoma, NB, CNS tumours, germ cell tumours
side effects: delayed N/V, neuropathy, ototoxicity, renal impairement/uraemic syndrome, SIADH
Other Renal Tumours
clear cell sarcoma: 3% kidney tumours, 1-4yrs, good prognosis
rhabdoid tumour of kidney: 80%<2yrs, poor prognosis, high metastatic rate, 15% synchronous brain lesion, clinical fever/haematuria/hyperglycaemia
renal cell carcinoma: 20% mets at diagnosis, age 10 yrs
CML
99% due to Philadelphia chromosome t(9;22) translocation leading to BCR-ABL fusion protein
pathogenesis
initial chronic phase (3-4yrs): malignant proliferation mature WBCs and increased immature cells
- associated splenomegally, anaemia, thrombocytopaenia
blast crisis: similar to ALL, increased risk TLS/hyperleukocytosis
- fever, malaise, lethargy, anorexia
diagnosis: blood/BM, cytogenics (philadelphia chromosome)
management: imatinib (70% cure), HSCT (80% cure)
Coagulopathy
(cancer)
incidence: AML esp acute promyeloblastic leukaemia
clinical: DIC/fibrinolysis
treatment: FFP (maintain >1), platelets (maintain 30-50)
prognosis: 30% die haemorrhage in <2 weeks and often before starting treatment
Coloid cyst
etiology: rare developmental lesion with outer fibrous later and inner epi of mucin producing cells
location: 3rd ventrical
- can block foramen of Munro causing hydrocephalus
clinical: symptoms raised ICP 30-60yrs
treatment: surgery +/- shunt
craniopharygioma
(supratentorial)
incidence: 5-14yrs, 10% Paed BT
location: suprasellar region (remnant Rathke’s pouch)
features: benign, solid, fluid filled cysts, calcification
clinical: long history of symptoms, visual sx, endocrine sx, headache, N/V
treatment: resection, radiation
survival: 90%
Cyclophosphamide
class: alkylating agent of the nitrogen mustard type
- adds alkyl group to DNA interferes with DNA crosslinks
use: cancers (ALL, AML, Burkitt’s, NHL, Ewing’s sarcoma), autoimmune disorders, amyloidosis
side effects:
- alopecia, N/V, BM suppression, stomach ache, haemorhagic cystitis, pulmonary fibrosis
- AML, bladder cancer, haemorrhagic cystitis, infertility
Cyclophosphamide
class: alkylating agent
mechanism: interfers DNA crosslinking by alkylating guanine
use: ALL, AML, lymphoma, sarcoma
side effects: myelosuppression, hyperuricaemia, haem cystitis, pneumonitis/fibrosis, SIADH, secondary malignancy
Cytosine arabinoside
(ara-c)
class: antimetabolite
mechanism: pyrimidine analogue
use: ALL, AML, lymphoma
side effects: similar to MTX, conjunctivitis, neurotoxicity
Dactinomycin
class: antitumour antibiotic
mechanism: binds DNA inhibiting transcription
use: Wilm’s, rhabdo, Ewing’s
side effects: dermatitis, diarrhoea, myelosuppression, tissue necrosis on extravasation
Delayed onset emesis in chemotherapy
associated agents: cisplatin, doxorubicin + cyclophosphamide
treatment: corticosteroids, ondansetron, precipitant (NK1R antag)
Diencephalic syndrome
pathogenesis: syndrome caused by tumour located in the diencephalon juve above the brainstem in the hypothalamus (glioma or astrocytoma)
clinical: FTT and emaciation/weakness
- behave in happy and outgoing manner
- vomiting, visual changes, headache and pallor can develop
treatment: surgery, radiation, chemotherapy
ependymomas
(infratentorial)
incidence: 2-9yrs, 10% Paed BT
location: ependymal lining (cranial 90%, spine 10%)
features: slow growing, well demarcated, calcification, haemorrhage, ependymal rosettes
associations: NF2
clinical: ataxia/vertigo, papilledema, CN VI-X palsy, seizures, increased ICP, headache, N/V
treatment: resection, RTX, +/- chemo
survival: 50%
Etoposide
mechanism: topoisomerase inhibitor
use: ALL, lymphoma, germ cell, sarcoma
allergic reaction, constipation/diarrhoea, mycositis, secondary leukaemia
Ewing’s sarcoma
incidence: more common <10yrs
location: diaphysis of long bones of extremities: femur, tibia, humerus
associations: t(11:22), EWS gene
clinical: fever, weight loss, pain, swelling, mass
- more systemic sx than osteosarcoma
histology: small round blue cells
XR: poorly marginated destructive lesion with permeative/moth eaten appearance in association with soft tissue mass and periosteal reaction (onion skinning)
treatment: chemo, RTX, +/- resection
prognosis: 60% survival
Febrile neutropaenia
neutropaenia: nadir 7-10 days post chemo
definition:
fever >38.5 or sustained >38
neutropaenia <0.5
- consider <0.1 v.low, cell quality, duration of neutropaenia
- high risk >7 days or altered BM, low risk <7 days AND normal BM
clinical: fever may be only sign of infection
- look EVERYWHERE for source
organisms: bacteraemia most common
- can rapidly progress to septic shock
- due to gut translocation of flora in 80%
gram positive: S.aureus, S.pneumo, S.viridans, VRE, CONS
gram negative: Pseudomonas, Ecoli, Klebsiella, Enterobacter, Acinetobacter, ESBL
fungal: increased with prolong AB/neutropaenia (>5days)
- candida (entry GIT), aspergillus (via lungs, assoc steroids), cryptococcus, fusarium
- treatment: amphotericin
viral: HSV, VZV, resp viruses
management: AB <60 mins of fever
- empiric: Amikacin/Gent, Tazocin/Timentin, Vancomycin
germ cell tumours (germinoma/teratoma)
(supratentorial)
incidence: 11-16yrs, 3-5% Paed BT
location: pineal, suprasellar
features: high bHCG/AFP
clinical: hormone sx, visual sx, headache
treatment: radiation, chemo
survival: 90%
Gonadal/Germ cell tumour
incidence: rare
pathogenesis:
- GCT (most malignant gonadal): primordial germ cell
- non germ cell gonadal tumour: coelomic epithelium
GCT types: teratoma/germinoma/endodermal sinus tumour, embryonal carcinoma
sacrococcygeal tumours: infant girl
testicular germ cell tumours: boys<4yrs
Non-GCT types (UNCOMMON): epithelial carcinoma (ovary), sex cord stromal tumours (ovary/testis)
associations: del Ch 1p/6q, gain 1q, T21, undescended testis/inguinal hernia/testicular atrophy
diagnosis: AFP/bHCG, imaging, pelvic exploration
management: resection, chemo, RTX
prognosis: 80% cure, >12yrs increased x4 risk death
Graft failure
etiology: rejection usually due to different btw major/minor MHC
definition:
primary failure: failure to reach neutrophil count 0.2x109 within 21 days
secondary failure: loss of peripheral blood counts after initial engraftment
causes:
- residual recipient T cells causing rejection of donor cells
- inadequate SC dose
- infections: CMV, HHV-6
risk factors: HLA disparity, T cell/stem cell deplete graft, reduced intensity conditioning, prophylaxis with MTX/bactim
diagnosis: BMA/biopsy (persistence of host lymphocytes suggests immunologic rejection)
treatment: remove myelotoxic drugs, G-CSF, second transplant
Graft verus Host Disease (GVHD)
etiology: engraftment of donor lymphocytes with T cell activation again recipient MHC
risk factors: BMT, nonmatched donor, high T cell vol. received, disparities in HLA groups, disparities in sex chromosome (female donor recognise male recipient), advanced disease, cell source (peripheral blood>BM>CB)
prophylaxis for GVHD:
T cell deplete donor: but increased immunocompromise/systemic infection post tx
post transplant immunosuppressants: methotrexate, MMF, calcineurin inhibitors
pathophysiology:
- tissue damage
- T cell mediated immune response
- apoptosis
Growth fraction
definition: proportion of cells dividing at any one time
tumours: have high GF (1-10%)
Hepatic Sinusoidal Obstructive Syndrome
definition: severe syndrome with hepatic vein obstruction, portal HTN, 3rd spacing, IV hypovolaemia
pathophysiology:
- fibrous obliteration of venules/veins with damage to surrounding hepatocytes/sinusoids with hepatic necrosis/haemorrhage
- not associated thrombus formation
etiology: post HSCT/chemo/alkaloid toxins/radiation/liver tx
- high risk chemo drugs: alkylating agents, platinum complexes, thiopurines
incidence: <10% post HSCT, F>M
clinical: 3 weeks post HSCT
- weight gain, hepatosplenomegally, RUQ pain, jaundice, ascites
diagnosis: high AST/ALT/conj bilirubin, prolonged PTT, renal insufficiency
management: avoid hepatic damage, diifibrotide, monitor
prognosis: often resolvied but can lead to progressive organ failure, mortality<4%
Hepatoblastoma
incidence: <3yrs
associations: BWS, trisomy 18, trisomy 21, Acardia syndrome, Li-Fraumeni syndrome, Goldenhar syndrome, Von-Gierke’s dusease, FAP
pathology 2 types:
- epithelial type (embryonal malignant cells): better outcome
- mixed (mesenchymal/epithelial elements)
clinical: large asymptomatic mass right lobe liver
diagnosis: AFP (ALWAYS elevated), bilirubin/LFTs (normal), anaemia/thrombocytopaenia (common)
management: resection, chemo (Cisplatin/Vincristine/5-FU/Doxorubicin), liver transplant if unresectable
prognosis: 90% survival complete resection, 60% partial resection
Hepatocellular carcinoma
incidence: adolescence
etiology: secondary to HepB/HepC infection
associations: tyrosinaemia, galactosaemia, GSD, alpha-1 antitrypsin deficiency, biliary cirrhosis
treatment: partial resection, chemotherapy
High/Low grade gliomas
incidence: 40% all braintumours
etiology: arise supportive tissues (astrocytes/oligodendrocytes)
subtypes: astrocytoma, oligodendroglial, ependymoma
low grade: pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, mixed oligoastrocytoma, ganglioglioma, subepenpendymal giant cell astrocytoma
- tx: resection, +/- chemo/RTX
high grade: anaplastic glioma (astrocytoma/oligodendroglioma/oligoastrocytoma), diffuse intrinsic pontine glioma, GBM, pilomyxoid astrocytoma
- tx: resection, chemo, RTX
Hodgkin Lymphoma
incidence: rare, age 15-19yrs, 7% of ALL childhood cancers
pathology: Reed-Sternberg cells (<1% of LN)
- large/multiloculated nuclei with prominent central nucleolus with surrounding clearance
- arise from germinal B cells
etiology: EBV found in 25-50% Reed-Sternberg cells
histology:
- classic HL (95%): nodular sclerosing, mixed cellularity, lymphocyte rich or deplete
- nodular lymphocytc predominant (5%): malignant cells different from Reed-Sternberg
clinical: lethargy, malaise, anorexia, lymphadenopathy rubbery/firm/painless (cervical, supraclav, axillary), hepatosplenomegally, mediastinal mass (75%)
** B symptoms (<20% of children), weight loss >10% in 6/12, fevers >38 for <3/7, night sweats
diagnosis: tissue biopsy, BMA
treatment:
- low risk (stage IA/IIA): OEPA (vincristine/etoposide/prednisone/doxorubicin)
- intermediate risk (stage IB/IIB): same as above but more cycles
- high risk (stage IIIB/IVB): more chemo BEACOPP (bleomycin, etoposide, doxorubicin, cyclophophamide, vincristine, procarbazine, prednisone), MBT
prognosis:
- low risk: >95%
- high risk: 90%
poor prognosis: males, IIB/IIIB/IV, bulky mediastinal disease, high WCC, anaemia
Hypercalcaemia
(cancer)
incidence: leukaemia/lymphoma (osteolytic), alveolar rhabdomyosarcoma (osteolytic), Non-Wilm’s renal tumour
clinical: confusion → dehydration → renal failure
management: hyperhydration, frusemide, bisphosphonates
Hypothalamic hamartoma
definition: most common brain lesion to cause precocious puberty
etiology: congenital malformation of ectopic neural tissue
pathogenesis: glial cells in lesion produce GF beta that activates GnRRH pulse
MRI: penduculated mass attached to tuber cinereum of the hypothalamus
clinical: gelastic seizures, precocious puberty
Ifosfamide
class: alkylating agent
mechanism: interfers DNA crosslinking by alkylating guanine
use: lymphoma, Wilm’s, sarcoma, germ cell tumours
side effects: cyclo effects + cardiotoxicity, neurotoxocity, nephrotoxicity, SIADH
Indications for HSCT
non-malignant disease
congenital BM failure: Fanconi’s anaemia
single lineage deficiency: sickle cell, thalassemia, Kausman
blood cell dysfunction: chronic granulomatous disease
immune deficiencies: SCID (all), CVID (some)
immune dysfunction: hyper inflammation (HLH)
metabolic disease: enzyme replacement (Hurler, Gaucher, metachromatic leujodystrophy)
acquired organ failure: aplastic anaemia
stem cell replacement: osteopretrosis, epidermolysis
Indications for HSCT
malignant disease
AML: cytogenic/molecular high risk group or poor MRD
ALL: Philadelphia chromosome, extreme hypoploidy, poor MRD, early relapse, T cell relapse
myelodysplastic syndrome
myeloproliferative syndromes: JMML, polycysthaemia vera, CML
Juvenile Myelomonocytic Leukaemia
JMML
incidence: the only myeloproliferative disease in childhood
clinical: rash, LN, splenomegally, haemorrhage
blood film: elevated WCC, anaemia, thrombocytopaenia
diagnosis: monocytosis>1x109/L, blasts<20%
- increased HbF, WBC, neutrophils
cytogenetics: nil distinctive
associations: NF1 (10% cases), Noonan syndrome
treatment: HSCT
Kaposiform Haemangioendothelioma
KHE
definition: locally aggressive vascular tumour
epidemiology: 50% at birth, otherwise <1yr
location: extremities, 10% don’t involve skins (retroperitoneum, mediastinum, internal organs)
clinical: raised subcutaneous mass with purpuric appearance and occassional telangiectasias, increased hair growth over tumour
complications: Kasabach-Merrit phenomenon
- rapid enlargement of tumour with low platelets/fibrinogen, high D-dimer/fibrin
diagnosis: biopsy, MRI
management: excission, laser, chemo
prognosis: can undergo regression but necer completely resolve, long term oedema/pain/ortho issues
Histiocytosis Syndrome Class I
Langerhan’s cell histiocytosis (LCH)
diseases: eosinophilic granuloma, Hand-Schuller-Christian disease, Letterer-Siwe disease
pathology: proliferation of cells from the monocyte lineage (including Langerhan’s cells with Birbeck granules) causing accumulation of granulomatous materials throughout the body
clinical: multisystemic deposits everywhere
- malaise, lethargy, irritability
- bone (80%): commonly the skull
- skin: scaly, popular, seborrhoeic dermatitis, gingival infiltrates
- LN, hepatosplenomegally
- eyes: retroorbital infiltrates/proptosis
- pituitary dysfunction
diagnosis: tissue biopsy, skeletal survey
treatment:
- single system disease if benign: low dose RTX
- multisystem disease: systemic multiagent chemo
Histiocytosis Syndrome Class II
Haemophagocytic Lymphohistiocytosis (HLH)
pathology: non-malignant proliferative condition with accumulation of APC (macrophages) and uncontrolled activation of inflammatory cytokines
etiology:
- AR (mutations in perforin or Munc 13-4 proteins)
- infection associated: better outcome
clinical: <4yrs, fever, maculopapular rash, weight loss, irritability, severe immunodeficiency, hepatosplenomegally, LN, resp distress, aseptic meningitis
diagnosis: BM biopsy or clinical features plus
- hyperlipidaemia, hypofibrinogenaemia, elevated LFTs/IL2/ferritin, pancytopaenia
treatment:
- familial: chemo with IT MTX, fatal with relapse, HSCT cures 60%
- infectious: treat cause
LEAST myelosuppressive chemotherapy
Prednisone
Asparaginase
Bleomycin
Vincristine
Leucostasis/Hyperleucocytosis
leucostasis: WCC>50
hyperleucocytosis: WCC>50 PLUS white cell plugs in microvasculature
incidence: occurs in AML>ALL and CML blastic crisis
- present in 20% newly diagnosed AML
clinical:
- CNS: altered GCS, headache, dizziness
- resp: hypoxia, dyspnoea
- fever in 80%
RISK OF HAEMORRHAGE
treatment: cytoreduction, prophylaxis for TLS, platelet transfusion
Leukaemias
30% of paediatric cancers
ALL 77% (PreB 85%, T cell 15%, B cell <1%)
AML 11%
CML 2-3%
JMML (Juvenille myelomonocytic leukaemia) 1-2%
Leukaemias
Cell morphology
ALL: blasts >25%
- small to intermediate blasts
- basophilic, rarely granules
- B cells: CD19, T cells: CD3
AML: blasts>20%
- larger/irregular blasts
- auer rods, granules
- myeloperoxidase
Leukaemias
genetics
ALL:
- hyperdiploidy, t(12:21): good
- hypodiploidy, t(BCR ABL): bad
AML:
- >3 abnormalieis, t(9:11, t(9:22): bad
Li-Fraumeni syndrome
SBLA cancer syndrome
- Sarcoma
- Breast
- Leukaemia
- Adrenal gland
genetics: AD, abnormality tumour protein p53 gene
diagnosis: proband with a sarcoma <45yrs + a 1st degree relative with cancer <45yrs + a 1st/2nd degree relative cancer <45yrs OR sarcoma
lifetime cancer risk: 100%
Long term effects post transplant
CAD: 75% at 5 yrs due to chronic rejection (vasculopathy)
hypertension: 60% 5yrs due to steroids/cyclosporin
neoplasm: 20% 6m-6yrs usually lymphoproliferative
renal dysfunction: 25% at 5yrs assoc MMF/sirolimus
osteoporosis: 100% due to steroids/calcineurin inhib
behavioural issues: 33% at 5 yrs
Mediastinal compression
(cancer)
etiology: vena caval/bronchotracheal tree compression
incidence: T cell ALL
clinical: facial oedema, dyspnoea, wheeze, orthopnoea
- must exclude pericardial effusion
medulloblastoma
(infratentorial)
incidence: 5-9yrs, 20% Paed BT (most common malig)
location: ONLY in cerebellum
features: evolves weeks-months, 1/3 metastasise to CSF
clinical: altered GCS, ataxia/poor coordination, visual sx (CN VI), headache, N/V, increased ICP
associations: FAP, NBCCS
treatment: resection, RTX, chemo
survival: 50%
Methotrexate
class: antimetabolite
mechanism: folic acid antagonist (inhibits DHFR)
use: ALL, lymphoma, medulloblastoma, osteosarcoma
side effects: hepatotoxicity, infertility, mucositis, myelosuppression
Neuroblastoma
origin: arise from primitive sympathetic ganglion cells
sites: adrenal 40%, abdo 25%, thoracic 15%, pelvic 5%, cervical 5%
symptoms:
- abdominal pain
- proptosis/periorbital echymosses
- Horner’s syndrome
- opsoclonus myoclonus syndrome
- bone pain
- scoliosis
- HTN
Neuroblastoma
definition: embryonal cancer of peripheral SNS
epidemiology: 40% cancer in infancy, 90% <5yrs, M>F
etiology: 1-2% familial (Phox28/ALK genes)
locations: adrenals 40%, abdominal 25%, thoracic 15%, cervical 5%, pelvic 5%
pathology:
neural type cells
- neuroblastoma: undifferentiated, poorly differentiated, most aggressive, small blue cells
schwann-type cells:
- ganglioneuroblastoma (schwann cells/neuroblasts): intermediate malignant potential
- ganglioneuroma (schwann cells/mature ganglion cells): benign
- ganglionneuroblastoma nodular
clinical: mass related symptoms, fever, periorbital echymoses (orbital mets), proptosis, Horner’s, abdo pain, constipation, bladd/bowel dysfunction
paraneoplastic syndromes: opsoclonus-myoclonus ataxia sx, VIP secretion (diarrhoea), HTN
diagnosis:
- urine catecholamine intermediates: neuroblastoma cells can’t synthesis catecholamines so intermediates (homovanillic acid, vanillymandelic acid, dopamine) accumulate
poor prognostic: MYCN protooncogene (25% tumours), chromosomal deletions, ALK mutations, age>18months, neuroblastoma, nodular neuroblastoma, high mitosis-karyorrhexis (MKI)
good prognosis: low MK, ganglioneuroma
treatment
- low risk: surgery
- intermediate risk: 96% survival, chemo (cyclo/carbo/cisplatin/etoposide/doxorubicin), surgery
- high risk: <40% survival, induction chemo, surgery, SCT, radiation, immunotherapy
- relapsed NB is incurable
NF-1 cancer
genetics: 17q11 NF1 gene
types:
optic pathway gliomas (15% <6yrs): low grade pilocytic astrocytomas
brain tumours: astrocytomas, brainstem gliomas
soft tissue sarcomas: rhabdomyosarcoma, GISTs, MPNSTs, glomus tumours
other: JML, phaeochromocytoma
NF-2 cancer
genetics: AD 22q12, NF2 gene
types:
bilateral vestibular schwannomas
intracranial meningiomas
spinal tumours
Non Hodgkin Lymphoma
clinical/diagnosis/treatment
clinical:
- rapid onset 1-3 weeks, enlarging non tender LN, compression of surrounding structures, CNS involvement
- emergency: TLS, SC compression, SVC obstruction, hyperviscosity sx, hyperleukocytosis
diagnosis: anaemia, thrombocytopaenia, leukopaenia, increased uric acid/LDH
staging: CT +/- PET (neck, chest, abdo, pelvis), BMA, LP
treatment: chemotherapy, radiation rarely, NO surgery
prognosis: 90% survival
Non-cell cycle dependant chemotherapy
non-phase dependent drugs:
- inactivate DNA: procarbazine
- alkylating agents: cyclophosphamide, ifosfamide
- platinum analogues: cisplatin
- anthracyclines
Non-Hodgkin Lymphoma
epidemiology/pathology
epidemiology: 5th most common paediatric malignancy, median age 10yrs
genetics: de novo
etiology:
- congenital: Wiskott-Aldrich, ataxia-telangiectasia, X-linked lymphoproliferative syndrome
- aquired: HIV, EBV etc.
types:
Burkitt Lymphoma: highly aggressive B cell NHL
- age 4-6yrs, M>F
- translocation/deregulation of c-MYC proto-oncogene on chromosome 8
- moth eaten appearance to LN
- 3 variants: endemic 50% (Africa-New Guinea), sporadic 30% (Western), Immunodef (HIV)
- endemic: ALL EBV receptor positive
- sites: abdomen, head, neck
Diffuse Large B Cell Lymphoma
- most common NHL
- denovo transformation of other low grade B cell lymphoma
- film: big cells, multiple nuclei, scant cytoplasm
- location: neck, abdomen, mediastinum, B symptoms in 30%
- TLS is UNCOMMON
Lymphoblastic T and B cell lymphoma/Leukaemia pre-T and pre-B ALL
- age 12yrs, M>F
- lymphoma if mass lesion and <25% blasts in BM
- leukaemia if >25% blast BM with or without mass lesion
- cytology: polymorphic lymphoblasts, CD7/CD3 positive, TCR rearrangements 30%
- location: peripheral LN, neck
- clinical: resp distress, SVC syndrome, >60% get BM infiltration
Anaplastic Large Cell Lymphoma
- aggressive peripheral T cell lymphoma
- assoc translocation of ALK (anaplastic lymphoma kinase gene on Ch2p23)
- clinical: fever, painless LN, skin/subcutaneous involvement
Osteochondroma
etiology: bony spur from external surface of bone
- cartilaginous cap overlies the spur and causes growth
genetics: AD germline mutation tumour suppressor genes EXT1/EXT2
clinical: 2nd decade M>F, painless mass near a joint, functional problems, deformity, pathological fracture
locations: distal femur, knee, proximal humerus
XR: bony spur from surface of cortex away from joint
Osteoid osteoma
pathology: small benign bone tumour
clinical: 5-20yrs, M>F, proximal femur/tibia, increasing/unremitting pain worse at night, limp, atrophy
XR: round/oval lucency in the metaphysis/diaphysis surrounded by sclerotic bone
Osteosarcoma
incidence: most common bone cancer 10-16yrs
location: distal femur, metaphysis, vertebrae
etiology: associated rapid growth
- pleomorphic spindle cell neoplasm with malignant osteoid bone
4 subtypes: osteoblastic, fibroblastic, chondroblastic, telangiectatic
associations: RB1, Li-Fraumeni, Rothmund-Thomson, Paget’s, fibrous dysplasia
clinical: pain, limp, swelling, soft tissue mass, joint effusion/warmth
- assumed to be secondary to injury
- 10% metastatic disease at presentation (lung, bone, LN)
diagnosis: histology (malignant cells produce osteoid), XR (sunburst appearance of secondary ossification in tissue), MRI
management: chemo (Cisplatin, Doxorubicin, MTX), resection
prognosis: 65-75% survival non metastatic
Pilocytic astrocytoma
low grade glioma
(infratentorial)
incidence: MOST common, 20% paed BT, age 5-14yrs
location: cerebellum, 3rd ventricle
features: low grade, slow growing, well circumscribed, cystic
histology: tight fibrillary bundles around spongy areas
radiology: contrast enhancing nodule with cystic mass
clinical: torticollis, ataxia/poor coordination, visual sx, N/V, headache, FTT, increased ICP
treatment: resection, +/- chemo/RTX
prognosis: total resection 87%, partial 50-95%
Pineoblastoma (PNET)
(supratentorial)
incidence: 1-12yrs, 3% Paed BT
location: pineal gland
features: highly malignant, large, lobulated, poorly demarcated
associations: RB1
clinical: hydrocephalus, headache, lethargy, neuroocular sx
treatment: resection, radiation, chemotherapy
Pituitary adenoma
anterior: TSH, ACTH, FSH, LH, GH, prolactin
posterior: vasopressin/oxytocin
clinical: depends on adenoma and hormones prosuced
- most common hormones: GH/prolactin
- visual: bitemporal hemianopia, raised ICP
Post HSCT infections
etiology: no neutrophils from donor and no/function of T cells remains low for several months
risks: low cell counts, immunosuppressants, GVHD
organisms:
- invasive fungal infections: aspergillosis, candida
- viral: CMV most common (1-4 months post)
- EBV lymphoproliferative disease: deficiency of T cells to attack EBV
treatment: IVAB
Post transplant CMV infection
pathogenesis: common post renal tx due to immpaired T cell immunity
onset:
primary (sero +ve organ): 4-12 weeks post transplant
reactivation by immunosuppresants: more common, usuallly asymptomatic
clinical:
- early: fever, decreased WCC, rash, joint pain, high ALT
- GI: oesophagitis, gastritis/ulcers, gastroenteritis, pyloric stenosis, hepatits, pancreatitis, cholecytsitis, colitis
- eye: CMV retinitis
- late: impaired function of transplanted organ/fungal infection
prognosis: tissue damage may lead to renal rejection
- 90% asymptomatic, 10% lead to death
Post transplant lymphoproliferative disease
etiology: rare, malignant condition, associated CMV/EBV
clinical: fever, LN, GIT (abdo mass, pain, bleeding, obstruction, perforation, ascites), seizures, CNS abnormalities, mediastinal mass
Posterior fossa syndrome
etiology: injury to the cerebellar vermis/dentate nuclei
clinical: impaired language production, emotional lability, inattention, difficulty initiating movement
onset: 1-2 days post op and resolve over weeks to months
Pre B ALL
NCI standard risk (65%) cure rate 90%
- age 1-9yrs AND WCC<50
- favorable cytogenics: diploidy, hyperdiploidy (50-67 chromosomes), trisomies 4, 10, 17, TEL AMI t(12:21)
NCI high risk (25%) cure rate 75%
- age <1yr OR** >10yrs **OR WCC >50
- adverse cytogenies: t(9:22) Philadelphia with ABL-BCR fusion protein, t(4:11), t(1:19), iAMP21 amplification, MLL gene rearrangement, iKZF1 gene deletion, hypodiploidy of blasts (<45 chromosomes)
Radiation Recall
definition: inflammation of skin in area of previous radiation
agents: dactinomycin, anthracyclines
pathogenesis: epidermal dysplasia, necrotic keratinocytes, fibrosis, vasodilation
management: dose reduction, CS
Retinoblastoma
incidence: most common intraocular tumour childhood, <2yrs
etiology: sporadic and heritable
inherited: germ line mutation familial or sporadic
- familial: RB1 gene mutational inactivation of both alleles: 1st mutation at birth then 2nd mutation in development causing multifocal/bilateral tumours, 90% penetrance
- sporadic: both allele mutations arise sporadically in a single somatic cell of the retina
- increased risk with family history/13q deletion
clinical: destruction of the eye and globe, metastases after 6 months, death within yrs
- leukocoria, strabismus, decreased VA, ocular inflammation, orbital inflammation, hyphema, pupil irregulalities
diagnosis: opthalmoscopic examination, CT, MRI
management: enucleation, radiotherapy, radioactive plaques, cryotherapy, laser, photoablation, chemotherapy
prognosis: 93% survival
Secondary malignancies
AML
prevalence: most secondaries are AML
clinical: pancytopaenia with BM infiltrate
bone marrow: large cells (myeloid), heterogenous, more cytoplasm, 2-5 nucleoli
agents:
- alkylating agents (5yr latency)
- topoisomerase inhibitors: latency 2 yrs, 1% risk, 70% mortality
Secondary malignancy
etiology: secondary to chemotherapy/radiation used
risk factors:
chemo: etoposide, cyclophosphamide, carboplatin
cancers: HL (16% within 30 yrs dx), soft tissue sarcomas, breast cancer, thyroid cancer, AML, ALL (3% risk, more with cranial RTX), medulloblastoma (4% gliomas/astrocytomas), RB (40% risk at 50yrs)
Soft tissue sarcoma
3% paediatric cancers, M>F 2:1, mean age 12 yrs
liposarcoma: arise precursors adipocytes, extremities/retroperitoneum, 3 types (well-diff, myxoid/round cell, pleomorphic liposarcomas)
leiomyosarcoma: SM differentiation, retroperitoneum/vein/uterus, cutaneous more indolent
synovial sarcoma: cell of unknown origin, resembles synovial cell
malignant peripheral nerve sheath tumour: ectodermal origina, 50% in NG1
angiosarcoma: uncommon, subcutaneous tissues head/neck/breast, assoc therapeutic radiation post 8-10yrs
solitary fibrous tumour: pleura/dura/pelvis, slow growing
treatment for ALL: surgery
Spinal cord compression
(cancer)
incidence: leukaemia, lymphoma, NB, rhabdomyosarcoma, ewing’s sarcoma
management: URGENT imaging/histology, surgical decompression, dexamethasone, chemotherapy
Syndromes associated acute leukamaemias
- T21
- NF-1
- Bloom syndrome
- Ataxia telangiectasia
AML
11% paediatric leukaemias
incidence: adolescence, adults>kids
risk factors: T21, Bloom, Fanconi’s, Kostmann, Schwachmann-Diamond, Diamond-Blackfan, Li-Fraumeni, NF-1
diagnosis: >20% blasts in BM
- classified via FAB: M0-M7
clinical as for ALL PLUS:
- subcutaneous nodules, leukaemia cutis, blueberry muffin nodules, gingival infiltration, DIC, extramedullary disease (<1%), eye white plaques
prognosis:
- age/WCC not strong indicator
- good outcome if low MRD 2nd timepoint
cytogenic/molecular more prognostic
- low risk: t(8:11), inversion 16, t(5:17)
- intermediate risk: MLL rearrangement
- high risk: MLL rearrangement, monosomy 7, abnormal 11q23, 8:16
treatment:
chemo: high risk relapse (56% survival)
- used low risk group
BMT: high mortality, infertility, cardiac cx (63% survival)
- used intermediate/high risk or relapse
Teratoma
pathology: GCT can differentiate into any somatic cell type
- benign but comtain malignant elements
location:
- infants: sacrococcygeal, intracranial
- adults: anterior mediastinum, retroperitoneum, suprasellar
types:
mature cystic teratoma (dermoid cyst) >95%
- fully differentiated tissue from somatic cells (ectodermal, endodermal, mesodermal) with hair/sking/GIT
immature: partially undifferentiated/embryonal tissue
malignant: 15-30% malignant components, increased ALP/bHCG
clinical:
- in utero: caudal mass in fetus
- infancy: asymptomatic or obstruction bladder/rectum
treatment: resection, chemo
Testicular relapse
incidence: 10% all boys ALL
clinical: painless swelling of one or both testicles
risk factors: T cell ALL highest rates
treatment: chemotherapy and local RTX
Thymoma
definition: benign tumour arising from the thymus
incidence: adults 40-60yrs
associations: MG and other paraneoplastic sx
Trisomy 21
acute leukaemia and transient myeloproliferative disorder
incidence: 20X more common than general population
type: ALL>AML
prognosis:
- ALL: poorer outcome, very sensitive to methotrexate
- AML: better outcome >80% long term survival
neonatal conditions: 10% of neonates transient leukmaemia, myeloproliferative disorder
- increased WCC, blasts, anaemia, thrombocytopaenia, hepatosplenomegally
- may require transfusions
- 20-30% develop AML by 3 yrs
Tuberous sclerosis
genetics: 9q34 TSC1, 16q13
types:
subependymal giant cell tumours: benign, slow, periventricular
cortical glioneural hamartomas: enlarged, atypical, disorganised neuronal/glial elemetics with astrocytosis
- present in 90% TSC
diagnosis: MRI
Tufted angioma
definition: rare vascular tumour
pathology: benign, tufts of capillaries within the dermis
clinical: infiltrated, firm, dusky red to violet plaques/nodules with ill-defined border, 1-10cm
- usually over arms/legs/trunk
management: excision, laser
prognosis: can regress but never completely resolve
Tumour Lysis Syndrome
incidence: starts post chemotherapy within 24 hours and lasts 4-5 days
risk factors: high proliferation, large tumour burden, high sensitivity to chemotherapy
- common in lymphoma (Burkitt’s), ALL, AML
- rare in solid tumours
predisposing factors: dehydration, oliguria, nephrotoxins
pathology: breakdown of cells producing
- high levels phosphate (conc 4x normal in blast cells)
- uric acid (from DNA break down)
- potassium (from IC contents)
PLUS hypocalcaemia (bound to PO4), lactic acidosis, azotemia (increased protein metabolism with increased urea)
clinical: N/V/D, anorexia, lethargy, haematuria, CHF, cardiac dysrhythmias, seizures, cramps, tetany, syncope, death
diagnosis: 2 of more abnormal serum levels within 3-7 days chemo OR 1 serum marker and 1 clinical feature
management: prevention
- low risk: allopurinol, NaBicarb
- high risk: fluids, uric acid oxidase, NO NaBicarb
treatment: as above + electrolyte control, cardiac monitoring, dialysis
monitoring: urine output, urine urate/xanthine/hypothanthine/CaPO4 crystals, Ca/Mg/Ph 4-8hrly
Turcot syndrome
genetics: FAP (APC gene)
definition: associated FAP/HNPCC with brain tumours
associations:
FAP: medulloblastoma
HNPCC: gliomas
Vincristine
Vinblastine
class: vinca alkaloids
mechanism: mitotic arrest via spindle fibre inhibition
use: ALL, lymphoma, Wilm’s, Ewing’s, rhado, NB, brain tumours, histiocytosis
side effects: abdo pain, constipation/ileus, jaw pain, loss of ankle jerk, SIADH
Von Hippel Lindau disease
genetics: AD, assoc mutation tumour supressor gene VHL chromosome 3
etiology: increased erythropoeitin/grow factors causing syndrome with benign and malignant tumours
clinical:
onset of tumour at childhood/adolescence:
- cerebellar haemangioblastoma (assoc retinal angiomata)
- clear cell RCC
- pheochromocytoma
- endolymphatic sac tumour of middle ear
- serous cystadenomas
- neuroendocrine tumours of the pandreas
- papillary cystadenomas of the epididymis/broad ligament
management: early diagnosis/treatment, genetic counselling
Wilm’s tumour
definition: neuroblastoma embryonal malignancy of kidney
incidence: 6% paed malignancies, F>M, 2-5yrs, bilateral 7%
etiology: sporadic, famlial 2% (WT1 (WAGR, Deny’sDrash), WT2, WTX (30%), FWT1, FWT2, Beckwith-Wiedermann (10% chance), Periman sx, NF1, Sotos sx
associations: isolated hemihypertrophy, aniridia, GU abnormalities
clinical: incidental finding, abdominal mass, abdo pain, haematuria, HTN (25%), anaemia, coagulopathy
diagnosis: CT/MRI (claw sign: focal necrosis/haemorrhage/hydronephrosis), PET
treatment: nephrectomy, chemotherapy (doxorubicin/cyclophosphamide/etoposide/carboplatin), post op radiotherapy (>stage 2)
prognosis: survival 90%
Non-Hodgkins Lymphoma
MOST burkitts: highly aggressive B cell malignancy
three forms:
- endemic: Africa
- sporadic: developed countries
- immunodeficiency related
clinical: rapidly growing tumour mass, TLS, LN
genetics: cMYC translocations
- t(8:14), t(2:8), t(8:22)
Risk Statification
