Oncology Flashcards
somatic mutation
mutations acquired after conception
not passed on to offspring
BWS cancer surveillance
exam and 3monthly abdo USS until 8 years
Looking for Wilms + hepatoblastoma
t(1;13) or t(2;13)
alveolar rhabdomyosarcoma
this translocation is diagnostic
worse prognosis than embryonal RMS
mets to bone marrow
t(8;14)
Burkitts lymphoma or B-ALL
t(11;22) in bone
Ewings sarcoma
22q12 EWSR1 gene associated with sarcomas
MYC amplification
MYC-N= Neuroblastoma
MYC-C (translocation)= Burkitts
RB1 gene
RetinoBlastoma
tumor suppression gene
1 gene lost= predisposition
2 genes lost= cancer
Loss of INI1/SMARCB1 gene
Rhabdoid brain (ATRT) or kidney
P52 mutation
loss of this tumor suppression gene =
Li Fraumeni syndrome
AD
osteosarcoma
soft tissue sarcoma
brain tumors
breast cancer
leukemia
Small round blue cell tumors
Neuroblastma
Medulloblastoma
Ewings sarcoma
Whilms
Rhabdomyosarcoma
Retinoblastoma
Hepatoblastoma
blue is nucleus on H+E stain - as rapidly dividing
Causes cytopenia
leukemia (blasts) or solid tumor bone marrow infiltration
why do we always use chemo instead of surgery
improves survival even in localised cancers
kills micro metastases (too small to see on imaging but we know they are almost always there)
makes surgery easier and safer, as tumor is less vascular (less bleeding) and smaller
Kills residual tumor that has to be left behind
Chemo that has highest risk second cancer
what age does renal cell carinoma present
> 10 years
Where do Whilms tumor metastasise to
lungs
lymph nodes
clots in IVC
WAGR syndrome
Wilms tumor (50%)
Aniridia (100%)
Genitourinary abnormalities
Retardation
WT1 deletion
Denys Drash syndrome
Nephropathy (proteinurea etc)
Intersex
Wilms tumor
WT1 missense mutation
Ewings sarcoma features
Embryonal - small round blue cell
Present in adolescence (but often younger than osteosarcoma)
2nd most common bone malignancy after osteosarcoma
Bone or soft tissue primary
Location: Diaphysis (“D” near “E”) + pelvic bones
Xray: Lytic (less bone, more black), onion skin (compared to osteosarcoma- scleorotic/sunburst)
Mets: lungs, bone, marrow (number of mets is a prognostic feature)
Symptoms: pain, soft tissue mass/swelling, erythema, mass, fever, anemia, unwell
Genetics: t(11;22) in 90%- diagnostic osteosarcoma doesnt have translocation*
EWSR1 rearrangement (chr 22)
Rs: surgery, chemo +/- radiation (radiosensitive unlike Osteosarcoma)
Axial tumors have worse prognosis as difficult to resect
Osteosarcoma features
Present in adolescence
Most common bone cancer in children
Location: Metaphysis (“M” near “O”)
- knee and proximal humerus most common
Xray: sunburst, sclerotic (extra bone, more white)
Mets: lung and bones
Symptoms: pain, mass, pathological #
Genetics: retinoblastoma predisposition (RB1), P53 mutation, prior RT
Rx: surgery and chemo, no radiation,
Rhabdomyosarcoma
Malignant tumor arising from mesenchymal cells arrested in myogenic differentiation, can arise anywhere in body that has muscle
Embryonal
- “resemble foetal muscle”
- more common
- better prognosis
- younger age
- central
- low-mod invasiveness
- mets to lung
- no translocation
Alveolar
- “resembling pulmunary alveoli”
- worse prognosis
- fusion protein t(1;13) t(2;13)
FOXO1-PAX5 fusion
- mets everywhere
- incurable
Neuroblastoma presentation
Localised disease
1. Asymptomatic mass in neck, thorax, abdomen, pelvis
2. Hepatomegaly
3. Symptoms due to mass effect
Spinal cord compression
Motor deficits are most common followed by radicular back pain, bladder an bowl dysfunction, and rarely sensory deficits = MEDICAL EMERGENCY, rapidly progressive
Bowel obstruction
Superior vena cava syndrome
Horner’s syndromeor just ptosis (always check if there is a neck lump with new onset ptosis)
Thorax–>respiratory distress, Horner’s, incidental
Pelvic/sacral–> mass, dysuria, constipation
Metastatic disease
1. Non-specific symptoms of marrow failure: fever, bruising, petechiae, pallor
2. “Racoon eyes” - Ptosis and periorbital ecchymoses suggests orbital metastases
3. Bone pain, limp, refusal to walk
Systemic symptoms
1. Produce catecholamines–> sweating, hypertension (NB. hypertension may also be due to renal artery compression)
2. Tumour lysis syndrome
3. DIC
4. Weight loss
5. Irritability
6. Intractable diarrhoea (VIP)
Subcutaneous nodules
3 types of neuroblastoma risk
High risk malignant
- MYCN amplification
- rx kitchen sink including stem cell transplant and immune therapy (Dinutuximab)
Intermediate risk
- chemo and surgery
- no stem cell transplant, no immune therapy, radiation rare
Low risk
- localised
- small ones in babes can resolve spontaneously (highest rate of spontenous resolution of any cancer)
- larger ones cured with resection alone
Blueberry nodules on a baby + rapidly expanding liver + resp distress –> quick death
Familial adenomatous polyposis
APC mutation
hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age.
Risk hepatoblastoma in affected kids
Risk factors hepatoblastoma
BWS
FAP
Li Fraumeni
T18
NF-1
Ataxia telangiectasia
TS
Fanconi anemia
AFP is elevated in
Hepatoblastoma
HCC
Germ cell tumors
Ataxia telangiectasia
Hepatoblastoma chemo
cisplatin
carboplatin
Sodium thiosulfate
antidote for cyanide poisoning
protects against cisplatin induced hearing loss
Germ cel tumors
begins in cells that give risk to sperm or eggs
can occur anywhere in body
benign or malignant
GCT: 1/3 gonadal, 2/3 extragonadal from aberrant migration
Most are curable but some are highly malignant
Risk increased with gonadal dysgenesis - eg Kleinfelters- mediastinal GCC
Turners - increased risk gonadoblastoma
Immature germ cell tumors (malignant) are positive for AFP or bHCG
Mature teratomas (benign) are negative for AFP and bHCG
**as AFP normal values change with age quickly in first year of life, may need to do serial measurements
Rx: platinum chemotherapy (cisplatin or carboplatin) or surgery alone (eg ovarian teratoma doesnt need chemo)
WT1 mutation associated with
Wilms tumor/Denys Drash/WAGR syndrome
AML
somatic mutations mean the cancer is there in that tissue
germline mutations are inherited and give predisposition to cancer eg WAGR, Denys Drash, Frasier syndrome
what do you do if a kid presents with lower back pain and subjective alteration in perianal sensation
urgent MRI spine
Alterations in perianal sensation/saddle parasthesia often preceed complete loss of sensation, bladder/bowel incontience and weakness
Cauda equine and cord compression may progress or complete in under 24 hours, and defects at that stage are typically irreversible
Therefore dont wait for full blown clauda equina, look for subtle signs as the longer the nerve is damaged, the lower the chance of recovery
would need high dose steroids and surgery
to decompress
is HSCT used in solid tumors?
yes
Autologous transplant to allow more/higher dose chemo to be given
**allogenic STC used in leukemias “graft versus disease”
tumor suppressor vs oncogenes
Tumour suppressor genes (inactivation)
Regulators of cellular growth and apoptosis
Inactivation of BOTH alleles required for a tumour suppressor gene
Inheritance of one germline mutation can be AD
A second mutation at somatic level still required
In inherited mutations, one inactivated allele may be inherited and the other undergoes spontaneous inactivation
Examples: P53 (usually initiates apoptosis) , APC, Rb, BRCA
Proto-oncogenes (activation)
Activating mutation in ONE gene results in an oncogene , via:
1. Amplification
2. Point mutations
3. Translocation
These gees interfere with apoptosis, continue to proliferate
Examples
Chromosome translocation
T(1;19) – pre- B ALL
T(14:18) – C Myc in Burkitt’s
T(9:22) – Philadelphia chromosome in ALL, CML
Gene amplification = N myc in neuroblastoma (poor prognosis)
Point mutation
1p in AML – NRAS signal transducer, point mutation
translocations are usually proto onco genes*
T (14:18)
C Myc
Burkitts lymphoma
T(9:22)
Philadelphia chromosome
ALL, CML
BAD PROGNOSTIC FACTOR
T (1:19)
pre B-ALL
Inactivation in DNA repair genes results in
Fanconi anaemia (AR leukaemia)
Bloom’s syndrome (AR leukemia and lymphomas)
Ataxia-telangiectasia (AR lymphoreticular cancers)
Dysplastic nevus syndrome (AD melanoma)
Dyskeratosis congenita predisposes to cancer by which mechanism
Mutations in telemere maintenance pathways
Short telemeres
Viruses and cancer predisposition
EBV: Burkitt lymphoma
Diffuse large cell B cell lymphoma
Hodgkin lymphoma
Post-transplant lymphoproliferative disorder
Nasopharyngeal carcinoma
Leiomyosarcoma
Gastric adenocarcinoma
Hepatitis B: Hepatocellular carcinoma Hepatitis C: Hepatocellular carcinoma HPV :Cervical carcinomas Anus, penis, vulva/vagina, oropharyngeal carcinomas HHV8: Kaposi’s sarcoma Primary effusion B-cell lymphoma Plasma cell variant of Castleman disease
Li Fraumeni syndrome
mutation in p53- inactivation of tumor suppression gene
Sarcomas (soft tissue and osteosarcoma), leukeminas,astrocytoma, medulloblastoma, breast cancer, bone, lung, brain
If adrenocorticocarcinoma or choroid plexus carcinoma, LFS unless proven otherwise
If medulloblastoma + Li-Fraumeni, almost certainly Sonic Hedgehog subtype
NF1 cancers
optic glioma
neurofibroma
phaeochromocytma
meningioma
astrocytoma
soft tissue sarcoma
breast cancer >age 50
NF2 cancers
bilateral acoustic neuromas, meningiomas, epyndymomas
Von Hippel-Lindau disease
Autosomal dominant, mutation of tumour suppressor gene VHL
Cysts, benign and malignant tumours
hemangioblastoma
renal cell carcinoma
pheochromocytoma
Bloom syndrome
Short stature, photosensitive telangiectatic erythema(red rash in sun exposed areas, esp face/cheeks)
Immune deficiency
Excessive number of broken chromosomes due to DNA repair defects
Increased risk leukaemia, lymphoma, solid tumours(AML most common
Ataxia telangiectasia
AR
Mutation in ATM tumour suppressor gene (11q22-23)
Neurodegenerative; ataxia, telangiectasia, immunodeficiency with sinopulmonary infections, impaired organ maturation, X-ray hypersensitivity
Lymphoma, leukaemia
Defects in immune surveillace lead to ..
Leukaemia+ lymphoma
1. Wiskott-Aldrich
2. SCID, CVID
3. X linked lymphoproliferative syndrome
4. Kostmann syndrome
1. Congenital neutropaenia
Risk of myelodysplastic syndrome/ leukaemia
Downs syndrome cancer risk
500 fold increase in AML. 25% of kids with TAM develop AML
20 fold increase in ALL
Gorlins syndrome
medulloblastoma + BCC
MEN 2A
Medullary carcinomas of thyroid
PTH adenoma
Phaeochromocytoma
Alkylating agents examples and MoA
Add alkyl groups –> cell cycle arrest –> death
Work in all phases of cell cycle
Cyclophophamide
Ifosfamide
- both alkylate guanine and thus inhibit DNA synthesis
Cyclophosphamide side effects
N/V
Myelosuppresion
Alopecia
HAEMORRHAGIC CYSTITIS
PULMUNARY FIBROSIS
SIADH
INFERTILITY
Secondary neonplasm
**use hyperhydration + mesna to prevent haemorrhagic cystitis
Ifosfamide side effects
N/V
Myelosuppression
Haemorrhagic cystits (less common than cyclophosphamide)
SIADH
Iphosphamide encephalopathy (rx thiamine, methylene blue)
Renal tubular acidosis (proximal RTA/Fanconi)
Infertility
Antimetabolites MoA
Disrupt DNA synthesis
Cause cell death during S phase of cell cycle
Eg
Methotrexate = folate atagonist, inhibits DNA synthesis
6- mercaptopurine = inhibits purine syntheiss
Cytarabine (Ara-C)= pyrimidine analog, inhibits DNA polymerase
5-flurouracil = pyrimidine analog
Methotrexate adverse effects
N/V
Hepatitis (LFT derangement)
Photosensitive dermatitis
Myelosuppression
High dose- renal and CNS toxicity (lowers IQ)
can accumilate and cause toxicity in 3rd space fluid eg pleural/ascites
Need hyperhydration, urinary alkalinisation and folinic acid to avoid toxicity
Vinca alkaloids MoA
Inhibit microtubule assembly during MITOSIS, causing cell arrest
eg
Vincristine
Vinblastine
Vincristine side effects
constipation
abdo pain
neuropathy- peripheral, autonomic, cranial nerve
jaw pain
mucositis
phlebitis
Alopecia
VESICANT
IV only
Minimal myelosuppression
Not ematogenic
Topoisomerase MoA
Disrupts topoisomerase I and II –> inhibits DNA replication
Works in S + G 2 phase of cell cycle
eg
Etoposide
Etoposide side effects
N/V
Myelosuppression
Secondary leukemia
Type 1 hypersensitivity reactions
Anthacyclin MoA
increase oxygen free radicals–> cell apoptosis
Intercalates DNA
Not specific to any phase in cell cycle
eg
Doxorubicin
Danorubicin
Doxorubicin side effects
N/V
Cardiomyopathy
Radiation dermatitis
Myelosuppression
Arrythmia
*dexrazoxane reduces risk of cardiotoxicity**
Platinum agents MoA
Inhibit DNA synthesis by cross linking DNA
Not phase specific
eg
carboplatin
cispatin
Cisplatin side effects
HIGHLY EMATOGENIC including delayed N/V
Ototoxicity - very common
Nephrotoxicity
Hypomagnesemia
Myelosuppression, seizures, neuropathy- uncommon
THROMBOSIS
**sodium thiosulfate and amifostine otoprotective
L- asparaginase works at which phase of cell cycle
G1
L-asparaginase side effects
Anaphylaxis
Pancreatitis
Coagulopathy
Hyperglycemia
Cerebral sinus thrombosis
*give PEG asparaginase if become allergic to L-asparaginase
Bleomycin works at which phase of cell cycle
G2
Bleomycin side effects
N/V
Pneumoatosis
Mucocutaneous reactions and dermatitis
Alopecia
Pulmunary fibrosis- less common
NO MYELOSUPPRESSION
Bleomycin side effects
N/V
Pneumoatosis
Pulmunary fibrosis
Mucocutaneous reactions and dermatitis
NO MYELOSUPPRESSION
Ciclosporin MoA
Calcineurin inhibitor
Reduce IL-2 and IL-2 receptor production
Ciclosporin side effects
Hirsuitism
Gingival hyperplasia
Nephrotoicity
Tremor
Headache
Hyperglycemia
Elevated LFTs
HTN
Which drugs cause no or minimal myelosuppression
Vincristine
Asparaginase
Bleomycin
Which drugs cause alopecia
Vincristine
Cyclophosphamide
Which drugs cause mucositis
antimetabolities
doxyrubicin
bleomycin
etoposide
which chemo agent is most ematogenic
cisplatin
carboplatin
Cyclophophamide
High dose methotrexate
Cytarabine
which chemo agents are minimally ematogenic
Vincristine
Asparaginase
Bleomycin
Mercaptopurine
Low dose methotrexate
low- flurouracil, busulfan, low dose cytarabine, doxorubicin, etoposide,
which chemo agents have highest risk secondary malignancy
etoposide (AML)
Cyclophosphamide (AML)
Carboplatin/cisplatin
which chemo agents are associated with SIADH
cyclophosphamide
ifosfamide
cisplatin
which chemo drugs can be given intrathecally
methotrexate
cytarabine
at which phase of cell cycle to topoisomerase inhibitors work
S and G2/M
at which phase do vinca alkaloids work
M phase
eg vincristine (microtubule formation)
which chemo agents are cell cycle indepenant
Platinum analgues - cisplatin, carboplatin
Anthracyclines- doxorubicin
Alkylating agents - cyclophosphamide, ifosfamide
busulfan
which chemo agents work in G2
bleomycin
etoposide
Cytarabine side effects
fever and flu like symptoms
mucositis
phlebitis
diarrhoea
GI ulceration
deranged LFT
neuro and pulmunary toxicity
side effects busulfan
acute lung injury or intersitial lung fibrosis
N/V
Diarrhoea
chemo agents associated with radiation enhancement/radiation recall
bleomycn
dactinomycin
doxorubicin
hydroxyurea
methotrexate
radiation recall only - arsenic, cyclophosphamide, cytarabine, etoposide,
Tumor lysis syndrome
hyperkalemia
hyperphosphatemia
hyperuricemia
hypocalcemia (binds to phosphate)
risk TLS highest in
acute leukemias WCC> 100
Burkitts lymphoma
Large tumors eg abdominal
patients with preexisitng renal disease/hyperuricemia
timing of TLS
usually within 24-48 hours of starting treatment, up to 7 days after starting
Consequences of TLS
hyperuricemia- precipitation uric acid in tubules – inflammation – AKI
hyperphosphatemia – precipitates calcium phosphate and uric acid deposition in kidneys
–> uric acid nephropathy (in acidic urine), or calcium phosphate nephropathy (at alkaline pH)
Hyperkalemia– arrythmias
Hypocalcemia- seizures, muscle cramps, tetany
Treatment TLS
Hyperhydration
Alkalinization is usually necessary to maintain a urine pH of approximately 7.0. The urinary excretion of uric acid is reduced at an acidic pH, whereas the excretion of phosphorus is impaired by over-alkalinization (and they precipitate more at these pHs)
Allopurinol
- if low risk
BLOCKS XANTHINE OXIDASE
- blocks catabolism of hypoxanthine and xanthine (more soluable than uric acid)- but xanthine can still precipitate at high levels
-* contraindicated in combination with azathioprine or 6MP as causes severe bone marrow suppression
Rasburicase
- if high risk
- urate oxidase. Catalyses uric acid into water soluable allantoin
Treatment of electrolyte derangements in TLS
Treatment of hyperkalaemia:
1. Cardiac membrane stabilisation -> IV calcium gluconate immediately
2. Shift of K+ intracellularly -> insulin/glucose infusion, sodium bicarbonate, beta-agonists (salbutamol)
3. Reduction of K+ load -> resonium, loop diuretics, dialysis (last resort)
Treatment of hyperphosphatemia:
1. Dietary restriction of phosphate
2. Phosphate binders
3. Dialysis
Treatment of hypocalcemia:
1. IV calcium gluconate with caution as can increase precipitation of calcium phosphate (Don’t give if hyperphosphatemia. Don’t treat if asymptomatic)
Flow cytometry
- Immature cells = CD34, CD117, HLA-DR
- T cells = CD2, CD3, CD4, CD8
- B cells = CD10, CD19, CD20, CD22
- Myeloid = CD15, CD33
Risk factors for ALL
T21
NF1
Bloom syndrome
Ataxia telangectasia
Signs of extramedullary disease in ALL
i. Lymphadenopathy + hepatosplenomegaly
ii. Bone pain +++ – particularly lower extremities, can be severe and wake patient at night
iii. T cell disease: mediastinal adenopathy causing major airway compression with stridor and/or superior vena cava obstruction
iv. Signs of CNS involvement are INFREQUENT at diagnosis:
1. Headache, nausea and vomiting
2. Irritability, nuchal rigidity and papilledema
3. Cranial nerve involvement – most frequently involving CNVII, CNIII, CNIV, CNVI
v. Testicular involvement at diagnosis is rare – appears as painless testicular enlargement and is usually unilateral
vi. Fever- inflammatory cascade from tumor cells
Risk stratification in ALL
i. Age (1-10 years favourable, <1 yr, >10 yrs unfavourable)
ii. WCC at presentation (<50 favourable)
iii. Cytogenetic/molecular eg Ph+ = risk factor
iv. Response to induction (= MRD) – biggest prognostic factor
v. Testicular disease, CNS disease poorer prognosis
b. Low risk
i. High risk features not present
ii. Favourable cytogenetics
1. Hyperdiploidy (>50)
2. Trisomies 4, 10
3. ETV-RUNX protein (t12;21)
c. Standard risk
i. High risk features not present
ii. No favourable genetics
d. High risk/ very high risk
i. Age = <1 or >10 years
ii. Presentation
1. WCC > 50 at diagnosis
2. CSF involvement
3. Testicular involvement
iii. Additional cytogenetic + molecular features
1. Hypodiploidy (<44)
2. KMT2A/MLL genetic rearrangements - translocations of 11q23 (eg. t4;11)
3. iAMP21 amplification
4. Philadelphia chromosome t(9;22) BCR-ABL fusion protein –> very poor prognosis
Which feature on blood film is characteristic of AML
Aurer rod
Immunohistochemistry in AML
CD15 or CD33 positive
Negative for CD3 or CD 19 (as not B or T cells)
Myeloblasts will stain positive with myeloperoxidase
which cytogenetic factors give a favourable prognosis in AML
t (8,21), t (8,17), inv (16)
NPM1
which cytogenetic factors give a favourable prognosis in AML
t (8,21), t (8,17), inv (16)
NPM1
Acute promyeloocytic leukemia (APML)
t(15;17)= PML- RARA
Chemo= all trans retnoic acid + anthrayclines + cytarabine
risk differentiation syndrome and DIC
T21 and leukemia
500 x more likely to develop AML (but better survival than other kids)
30 x more likely to develop ALL
GATA1 mutations
Chronic myeloid leukemia
Most due to Philadephia chromosome t(9,22) BCR-ABL fusion protein
encodes oncogenic protein
Philadelphia chromsome on FISH
Rx: tyrosine kinase inhibitors (imatinib, dasatinib)
- inhibits BSR-ABL tyrosine kinase
Hydroxyurea
Allogenic SCT
Juvenile Myelomonocytic Leukaemia (JMML)
rare cancer of infancy
Associated with mutations in RAS/MAP kinase pathway
Only curative rx is stem cell transplant
Risk factors:
- NF1
-Noonan syndrome (mutations in PTPN11, NRAS, KRAS)
Ix: monocytosis, thrombocytopenia, anemia, BM= hypercellular myeloid cells, <20% myeloblasts, molecular analysis
Staging non hodgkins lymphoma
Murphy
I: Tumor at one site (nodal or extranodal – “E”)
II: Two or more sites; same side of body (or resectable GI primary)
III: Both sides of body
IV: CNS or marrow involvement
Staging hodgkins lymphoma
Ann Arbor
I: Tumor at one site (nodal or extranodal – “E”)
II: Two or more sites; same side of body (or resectable GI primary)
III: Both sides of body
IV: Lung, liver, or bone mets
A- asymptomatic
B- B symptoms present
Hodgkins lymphoma key points
a. A malignancy of the germinal centre B-Cells that affects the reticuloendothelial and lymphatic systems
b. Characterised by the presence of Reed-Sternberg cells (histopathologically)
c. Spread: slow, predictable, with extension to contiguous lymph nodes
Haematogenous spread also occurs (LESS COMMON) liver, spleen, bone, bone marrow or brain
d. Associated with B symptoms (which are a poor prognostic factor)
e. usually presents with painless, firm rubbery cervical /supraclavicular lymphadenopathy. Mediastinal mass of HSM.
Most commonly affects teens, rare <5 years
Less common than non Hodgkins lymphoma
Non Hodgkins lymphoma key points
a. Accounts for 60% of lymphomas in children
b. 2nd most commonly malignancy in those 15-35 years old
c. Burkitt lymphoma most common in children 0-14 years
d. DLBCL most common in adolescents/young adults
2. Key points
a. Malignant solid tumour characterised by undifferentiated lymphoid cells
b. Spread: aggressive, diffuse, unpredictable
c. Involves lymphoid tissue and can infiltrate the BM and CNS
d. Characterised by a high growth fraction and doubling time
e. Early diagnosis and treatment is critical
Rapid chemotherapy response can occur, therefore there is a higher risk for tumour lysis3. Risk factors
a. Inherited or acquired immunodeficiency (eg. SCID, Wiskott-Aldrich, HIV)
b. Viruses (eg. HIV, EBV)
c. Part of genetic syndrome (eg. ataxia-telangiectasia, Bloom syndrome)
d. Radiation therapy/ exposure
e. Post T cell depleted HSCT
Post solid organ transplan
Non Hodgkins lymphoma staging
a. Stage I: Involvement of single tumour or single anatomic area excluding the mediastinum or abdomen
b. Stage II: Two or more lymph node regions on the same side of the diaphragm or resectable primary abdominal
c. Stage III: Involvement of lymph node regions on both sides of the diaphragm; all primary mediastinal, paraspinal or extensive intra-abdominal disease
Stage IV: Any of the above and initial involvement of the CNS, BM or both
Infratentorial brain tumors
aka cerebella
present as truncal and gait ataxia, CN palsy
Usually CN 6 first (abducens)- LR affected, unable to move gaze laterally
CN4 (trochlear, SO affected)- double vision
CN3- oculomotor- down and out position, dilated pupil, ptosis
Nystagmus
Brainstem tumors
CN palsies
Nystagmus
Gait and coordination difficulties
UMN signs- hemiparesis, hyperreflexia, clonus
Supra tentorial tumors
Lateralized deficits (focal motor weakness, focal sensory changes, language disorders, focal seizures, reflex asymmetry
Supra-sellar tumors
most common= craniopharyngioma, astrocytoma
Visual field defects
neuroendocrine defects = obesity, abnormal linear growth velocity, diabetes insipidus, galactorrhoea, precious puberty, delayed puberty and hypothyroidism
1. Di-encephalic syndrome = failure to thrive + emaciation despite normal caloric intake + inappropriately normal or happy affect(tumor in diencephalon (hypothalamus, optic chiasm), most commonly pilocytic astrocytoma)
Diencephalon
structures that are on either side of the third ventricle, including the thalamus, the hypothalamus, the epithalamus and the subthalamus
Arises from the prosencephalon
Perinaud syndrome
Pineal gland tumor/midbrain infarction or haemorrhage/obstructive hydrocephalus
Paralysis of upward gaze
Pupils not reactive to light (pseudo Argyll RObertson pupil)
Nystagmus to convergence
eyelid retraction
What brain tumors come from supporting cells?
Gliomas- further divided into:
astrocytomas
ependmoma
oligodendrocytomas
mixed glial/neuronal
what brain tumors come from primitive tissue
medulloblastoma
neuroblastoma
pNET
Atypical teratoid/ rhabdoid tumors (ATRT)
Ependymoma
arise from lining of ventricles/spinal cord (most in posterior fossa)
bimodal- in kids <5 years
NF2 have increased risk
MRI: calcifications common, arise at ventricles, can look very nasty and heterogenous
Histology: pseudorosettes/ependymal rosettes
Rx: surgery + radiation, not usualy chemosensitive
Worse prognosis if cant do GTR, posterior fossa disease, diseemniated disease
Astrocytoma
Subset of glioma
Can be low grade (eg pilocytic) or high grade (DIPG/GBM)
optic pathway gliomas are low grade astrocytomas
Pilocytic astrocytoma typically in cerebellum
NF1= better prognosis
MRI: contrast enhanging nodule within wall of cystic mass
Histology: Rosenthal fibres (corkscrew pink bundles)
Pilocytic astrocytoma
Most common type of low grade astrocytoma
Typically in cerebellum, optic pathway, or tectal
Commonly in NF1
Locally aggressive but rarely invasive
May stabilise or even regress without intervention
MRI: contrast enhanging nodule within wall of cystic mass, in posterior fossa or optic tract, often associated with hydrocephalus
Histology: Rosenthal fibres (corkscrew pink bundles)
Molecular: change in BRAF (RAS/MAPK) pathway (can use BRAF/MEK/mTORinhibitors)
Rx: slow growing so dont respond well to chemo.
Can do nothing, just watch if normal visual acuity
Surgery is first line
If progression- small amount of chemo (carboplatin, vincristine, vinblastine)
Survival 90%
High grade astrcytomas include:
Anaplastic astrocytoma
Glioblastoma multiforme
DIPG (midline GBM)- very agressive, 90% mortality within years
Primitive neuroectodermal tumors (PNET)
Embryonal tumors
Include medulloblastoma and ATRT
Medulloblastoma
most common childhod malignant brain tumor
Arise from cerebellum- usually vermis
1/3 have mets at presentation - usually to CNS
M>F
Peak age 3-9 years
Prognostic factors:
Good= WNT1, age >3 years, localised disease
Bad= MYC amplification (Group 3) , p53
Intermediate = Sonic hedgehog (better prognosis in infants; but SHH +p53 are very bad), group 4, >1.5 cm2 residual tumor, large cell anaplastic
Babies <3 years automatically high risk - cant do radiation
Rx: surgery, chemotherapy, radiation
Craniospinal irradiation with a boost to the posterior fossa followed by intensive adjuvant chemotherapy
MRI of spine + lumbar CSF obtained at least 10 days after surgery
Atypical teratoid/rhabdoid tumors (ATRT)
highly malignnat, fast growing
can appear anywhere in brain or spine
usually in kids <3 years
short clinical hx
mets in 20% at presentation
small round blue cells + rhabdoid tumor cells deletion/inactivation of INI1/SMARCB1
Poor prognosis, median survival 12 months
Increased risk for renal and soft tissue tumors as well
Craniopharyngioma
A craniopharyngioma develops from remnant of Rathke’s pouch in sella turcica.
Clinically often presents with headache/vomiting, visual disturbances due to the compression of the optic nerves or the optic chiasm (bitemporal hemianopia, optic atrophy, visual loss)
About 50% of childhood craniopharyngiomas extend upward into the third ventricle and result in hydrocephalus.
Bimodal, age 10-14 yo
Endocrine: growth hormone deficiency (75%); thyroid-stimulating hormone deficiency (25-64%); adrenocorticotropic hormone deficiency (25-56%); luteinising hormone or follicle-stimulating hormone deficiency (40-44%); diabetes insipidus (9-17%, but almost 100% post-op).
MRI: cystic. most calcified. suprasellar location
cytarabine syndrome
fever
malaise
myalgia/arthralgia
after cytarabine
Subependymal giant cell astrocytomas (SEGA) are associated with …
tuberus sclerosis
bengin, slow growing, arise in wall of lateral ventricles
Treated with mTOR inhibitors (eg everolimus) if unresectable
Klinefelter syndrome associated with which tumor
Extragonadal germ cell tumors (esp mediastinal)
Breast cancer
Turners syndrome associated with which tumor
Gonadoblastoma
NF1 asssociated with which tumors
Neurofibromas (cutaneous, plexiform)
Optic pathway gliomas low-grade Other brain tumors- astrocytomas, brainstem gliomas, and high-grade gliomas
Malignant peripheral nerve sheath tumors
Rhabdomyosarcoma
NF2 associated with which tumors
Vestibular schwannomas
Meningiomas
Spinal ependymomas
Posterior fossa syndrome
neurological changes 1-5 days after PF tumor resection
difficulty verbalising
irritability
nystagmus
mutism
emotional lability
mutism usually resolves but can take a year
Diffuse midline glioma (DIPG)
most common high grade glioma in kids
usually pons/brainstem
Presentation: multiple CN palsies, raised ICP, cerebellar signs, long tract signs (hyperreflexia, increased tone, clonus, Babinski +, motor deficit)
Often have basilar artery encasement
Clinical + radiological disgnosis as cant biopsy a brainstem
Most have histone H3.3 mutation
Rx: palliative radiation
Prognosis: most survive <1 year. bad
Intracranial germ cell tumors
Arise in suprasellar (pituitary, infundibulum) or pineal region
More common in Japanse
Presentation: pituitary:hormone deficiencies, DI
Pineal: usually malignant, short hx, raised ICP, diplopia, parinaud syndrome, hydrocephalus
Ix: AFP/bHCG (serum + CSF), MRI brain + spine
High AFP= non germinomatous germ cell tumor
Rx: chemo + radiation. germinomas are very radiosensitive. NGGCT- chemo + CS radiation.
Germinomas + teratomas: AFP + HCG neg
Yolk sac- AFP +
Choriocarcinoma: HCG +
Bladder masses in children
- Rhabromyosarcoma
- Other bladder cancers very rare
- Associated with haematuria, obstruction, urinary symptoms
- Usually embryonal subtype which is a small round blue cell tumor
what do you need to avoid in germline RB1 mutations
radiation/Xrays
due to high risk of other cancers
osteochondroma
most common benign bone cyst
metaphysis of long bone/tendon insertion site
Bony, non painful mass
XRay- stalk or projection of bone
osteoid osteoma
most commonly on legs
unremitting pain often worse at night and relieved by aspirin/NSAIDS
exam: limp, atrophy, weakness
xray: lucency surrounded by sclerotic bone
osteoblastoma
benign, aggressive osteogenic bone lesions commonly found in the posterior elements of the spine. Patients typically present between ages 10 and 30 with regional pain with only partial response from NSAIDs.
Diagnosis is made radiographically by a characteristic lesion that is > 2 cm in diameter with a sclerotic margin and radiolucent nidus.
Features of aspergillus infection
Can occur any time when severely immunosuppressed
Mostly LUNGS
- halo sign and air crescent sign on CT
Can also occur in sinuses, brain
Rx: voriconazole, caspofungin second line
Inherently resistant to fluconazole
Features of candida infection
Mostly in neutropenic phase, or with prolonged antibiotics in leukemia/lymphoma
Mostly LIVER
Promyelocytic leukaemia
T15,17 RaRa gene
Complications- differentiation syndrome from all trans retinoic acid
DIC
presentation of Wilms tumor
Abdominal mass
Hematuria
HTN
fever
Syndromes associated with Wilms tumor
Denys Drasha
WAGR
Fanconi anemia
BWS
where does Wilms metastsise to ?
Lungs
IVC tumor thrombus via renal vein
anti GD2 monoclonal antibody = DINUTUXIMAB
used for high risk neuroblastoma
Kills neuroblasts
Antibodies bind to antigens on neuroblastoma cells –> active killing of antibody bound tumor cells by NK cells and macrophages
GD2 also found on peripheral + central nerves and skin
Severe pain when giving this drug- need concurrent morphine infusionAcute toxicity can present with neuropathic pain, hypotension, hypoxia, fever, capillary leak syndrome and hypersensitivity reactions.
Which of the following is the most common long-term complication of cranial irradiation?
GH deficiency
acute Graft versus Host
Present within 100 days post HSCT and with classic features of skin involvement (maculopapular rash), gastrointestinal involvement (diarrhoea and abdominal pain) and/or liver involvement (rising serum transaminases and bilirubin).
can do a skin biopsy if diagnosis unclear
Etoposide
Topoisomerase inhibitor
inhibits the enzyme topoisomerase II, which unwinds DNA, and by doing so causes DNA strands to break.
Work in S and G2 phase
which tumor is associated with coagulopathy and thrombosis
Wilms tumor
posterior reversible encephalopathy syndrome (PRES)
hemotherapeutic agents and hypertension are both risk factors for PRES. Vision loss suggests the occipital lobes are involved. The lack of diffusion restriction indicates vasogenic oedema rather than cytotoxic oedema that is seen in watershed infarcts.
most common cause of fungal meningitis in immunocompramised patients
cryptococcus neoformans
india ink stain - cells w surrounding halo
Blinutumomab
anti-CD19+ and CD-3+ monoclonal antibody with bi-specific T-Cell engagers (BITE) that is used to treat B-cell acute lymphoblastic leukaemia
Brentuximab
anti-CD30+ monoclonal antibody indicated for treatment of CD30+ lymphomas.
Which genetic marker is the strongest prognostic factor in predicting overall survival in patients with neuroblastoma
MYCN amplification
cytokine release syndrome
systemic response caused by the release of cytokines as a response to some form of immunotherapy. The exact pathophysiology is unknown, but symptoms can range from mild (fever, arthralgia, nausea) to severe (acute renal failure, seizures and disseminated intravascular coagulopathy). There is a risk of Cytokine Release Syndrome in any form of immunotherapy, but it occurs most commonly in CAR-T cell therapy (for B-ALL). The current theory is that CAR-T cells produce interleukin-1 and interleukin-6 perpetuating a pro-inflammatory response. Monoclonal antibodies and immune checkpoint inhibitors are all forms of immunotherapy and therefore have the same risks.
Tocilizumab (interleukin-6 antagonist) is used to treat cytokine release syndrome.
Auer rods seen in which cancer type
AML
Immunohistochemistry is negative for CD3 and CD19 in AML. Myeloblasts will most commonly stain positive with myeloperoxidase
B-ALL
B-lineage lymphoblasts are positive for cell marker CD19 and cytoplasmic markers CD79a and CD22. Although these markers on their own is not specific for B-ALL, high intensity positivity strongly supports the diagnosis. B-ALL must be negative for CD3 and negative on myeloperoxidase staining.
Differentiation syndrome
Diagnosis of Differentiation Syndrome is by the presence of three of more of the following features in the absence of another explanation:
Fever ≥38° C
Weight gain >5 kg
Hypotension
Dyspnoea
Radiographic opacities
Pleural or pericardial effusion
Acute renal failure
Drugs that cause minimal/no myelosuppression
○ vinca alkaloids
○ enzymes (asparaginase)
○ bleomycin
steroids
which chemo agents are given intrathecally
MTX
cytarabine
