Sarcomas, ASPHO Flashcards
most imp somatic mutations in RMS?
PAX-FOX0O1 fusions in alv. RMS t(2;13)
most common PAX_FOXO1 in RMS?
PAX3-FOXO1 (2;13) =60% >PAX7-FOXO1 (t;13)=20%
PAX-FOXO1 mut is a ___ in tumorigenesis
driver
give 2 genetic changes seen in fusion neg RMS
aneuploidy
activation muts of RAS pathway (FGF4, NRAS, KRAS, etc muts)
p53 muts= unfav
myoD muts= unfav
LOH or Loss of Imprinting at 11p15.5
NCOA2, VGLL2 rearrangements= fav in infants with spindle cell RMS
Give 5 germline muts associted with RMS
Li-Fraumeni=p53 BWS=IGF2 Costello=HRAS Noonan= RAS-MAPK path NF1= NF1 Gorlin= PTCH1 PBB= Dicer 1
bimodal peak for general sarcomas adn soft tissue sarcomas?
infancy and teenage years
presentation of RMS?
mass
+/- pain
+/- distrubance in function like CN palasy or bladder dysfunction
most common site of RMS?
head and neck>GU>extrem
favourable H&N site for RMS
orbit, non-parameningeal
parameningeal site= unfavourable in rhabdo…waht does this include?
base of skull, including infratemporal fossa, paranasal sinuses, parapharyngeal area
favourable GU site for RMS?
paratsticular, vag, uterine
unfavoruable GU site for rhabdo?
bladder, prostate
lymphatic spread of RMS seen where?
paratesticular, extremity tumours
CNS ext seen where in RMS?
50% parameningeal
hematogenous mets go where in RMS?
lung, bone, BM, liver
stage RMS how?
- MRI or Ct of priamry site adn regional nodal basin
- CT chest
- PET scan or bone scan
- bilateral BMA/bx
- CSF cytomology if parameningeal/paraspinal
- LN for paratestictular at least 10 years of age or extremity
WHich RMS pts do NOT need bone scan, BMA/bx, possible chest CT?
ERMS, T1, N0 disease
what’s the name of the MRS staging system?
IRS
describe stage 1 or IRS staging for RMS
- favourable site: orbit, non-parameningieal head and neck, non-bladder/prosatate GU, biliary tract
- T1= confined to site of origin or T2= extension and/or fixation to surroundign tissue
- size: any
- any regional LN status
describe stage 2 for RMS staging
- unfav site: parameningeal, bladder/prostate, extremity, other
- T1 or T2 (same)
- size <5 cm
- regional lymph nodes not present or unknwon
describe stage 3 for RMS
- unfav site
- T1 or T2 (same)
- size: <5 cm if just regional LNs involved, vs. >5 cm for LNs not involved/regional involvement/unknown
describe stage 4 RMS
- all sites with distant mets
- T1 or T2 (same)
- any size
- regional LNs involved or not
what does RMS grouping tell you?
IRS grouping tells you extent of tumour remaining after SURGERY, before any other tx
Describe RMS group 1
completely resected lcoal disease
describe group 2 in RMS
gross total resection with evdience of regional spread…
A): microscopic residual diseae
b) reigonal nodes involved AND completely researcted
C) regional nodes invovled and grossly resected but have microscopic residual disease and histo involvement of the resected regional nodes
describe group 3 rmS
incomplete resection with gross residual disease
describe gropu 4 RMS
distant mets
what’s very prog in RMS?
staging= extent of disease
3 yr FFS in stages 1-4 RMS?
86%
80%
68%
25%
how does group impact prog?
Groups1-3 have better 5-yr FFS and 5-yr OS (73% and 84%) than group 4 (30% and 42%)…..also 3-yr FFS gets worse with higher group: 83%->86%->73%->25%
RMS histo subtypes in fusion neg?
spiondle cell, botryoid, embryonal
what if you are fusion negative but alveolar RMS?
better prog, simialr to embryonal histo
describe RMS risk gruops (COG)
low risk has a 5 yr FFS of at lesat 85%…drops to 50-75% for intermed and 20% or less for high…to be low risk, must be stage 1-2 with group I-II diseaes, embryonal OR stage 1, group III ORBIT, embryonal….high risk: stage 4, group 4, at lesat 10 yrs of age with emrbryonal or stage 4+ group 4 wtih alv. RMS (fusion pos)…everything else= intermed
primary site in RMS = prognostic. best site? worst site? order?
best= orbit/head and neck
worst= extremity
order. orbit/head and neck>GU non-bladder/prostate> then GU ballder/prostate, parameningeal>other>extremity
other than primary site, genetic mutations, staging, group, what else is prog in RMS?
- mets…mets to lung better than to bone/bone marrow.
- and # of met sites…2 or less is better than 3 or more!
- recurrence…~20-25% 3-5 yr OS
if relapsed RMS, waht are good RFs?
botryoid histology
ERMS that was stage 1 or group 1 at initial dx with local or regional recurrence adn not previously tx’ed iwth cyclophos
what are 3 main types of childhood RMS
embryonal, alveolar, spindle cell
ERMS and spindel cell RMS fall in teh category of ___ ___ tumours; what else is in this category?
spindle cell; synovial sarcoma
how can you differentiate synovial sarcoma from RMS (ERMS or spindle cell RMS)?
ERMS and spindle cell RMS: pos for MyoD, myogenin, Desmin, muscle specific actin…but synovial: cytokeratin, EMA, Bcl2
ARMS falls in teh category of what tumours?
Small round blue cell tumour
small round blue cell tumour pos for NSE, synaptophysin, TH, PHOX2b?
NBL
small round blue cell tumour + for CD99, vimentin, +/-NSE, synaptophysin?
EWS/PNET
SRBC tumour + for myoD, myogenin, desmin, muscle specific actin?
ALVEOLAR RMS
SRBCT pos for LCA< CD3, CD20, TdT?
lymphoma
most common type of RMS?
embryonal, ~2/3
ERMS has includes a ___ pattern
botryoid
ERMS associated with a ___ age, ___ site, ___ disease, ___ prog
younger; favourable; localized; favourable
spindle cell RMS: associated with ___ or ___ rearrangements in infants and a ___ prog
NCOA2; VGLL2; favourable
what % of alv RMS is fusion neg?
20%
RMS tx involves? broadly
surgery, radiotherpay, chemo
tx in RMS based on?
risk groups
RMS risk groups based on what things? 4
stage
group
histo/fusion status
age (soemtimes)
surgical approach in RMS?
excise pirmary tumour upfront whenever possible wihtout –> major functional or consmetic defs…sometimes wait to do surgery if think may spare radiation
which RMS sites reqwuire surg assessmetn of LNs?
paratesticular (retroperitoneal for boys 10 yrs+), extremity
who doesn’t need rads in RMS?
group 1 ERMS/spindle cell RMS
do radiation when in RMS?
usually begins during week 3-15 of therpay
dose of rads in RMS
36-50.4 Gy
Standard= interm risk chemo in RMS?
VAC x 45 weeks = vcr, dactinomycin, cyclophos
low risk chemo in RMS?
VA…or shorter duration with VA + lower CPM dose
high risk chemo in RMS?
no standards…can add doxo, epto, ifos, irinotecan
image how often in RMS?
q3 months
response at 12 weeks: predictive of survival in RMS?
no
aucte tox in RMS?
heme tox, infection, VOD with dactinomyicn and cyclophos
late effects of RMS?
infert due to alk agents 7.5-8 mg/m2 esp in boys (standard dose and higher)…secondary maligs due to alk agents/radiation/CPS…bone growth/arrest/muscle atrophy due to radiation
non rhabdo soft tissue: tend to occur where? spread wehre?
extremities, trunk….lungs, bone, LNs
general work up for non rhabdo soft tissue tumours?
MR/Ct of primary, Ct chest, PET scan, nodal eval for select tumorus
non rhabdo soft tissue sarcomas: prog depends on?
stage, group (extent of resection), tumouor size (< or >5 cm), grade (mitotic rate), tumour type, age
ilst 3 non-rhabdo soft tissue sarcomas that are reposneive to chemo
synovial, undifferentatied, infantile fibrosarcoma
most common non-rhabdo soft tissue sarc?
synovial
transloc in synovial sarc?
t(X;18) SYT-SSX
tranlsoc seen in infantile fibrosarcoma?
t(12;15)= ETV-NTRK3 fusion…most common STS in children <1 yrs…give VA, VAC, or larotectinib if not resected
3 non rhabdo soft tissue sarcs that are poorly responsive to chemo
MPNST, leiomyosarcoma, alveolar soft part sarcoma, epithelioid sarcoma
MPSNT asscoiated with what CPS?
NF1
sarcoma associated with immunosuppression and HIV?
leiomyosarcoma
fusion seen in alv soft part sarcoma?
t(X;17) = ASPSCR1-TFE3 fusion
non rhabdo STS: tx philopshy?
surgery + radiotherpay….+/- chemo
general tx approach in nrSTS?
based on extent of resection…group 1: observe unless grade 3 or large, then do RT (and maybe chemo= doxo + ifos)….group 2: RT alone unless grade 3 or large, then consdier chemo (Doxo + ifos)…group 3-4: RT, delayed surgery, consider chemo
what’s being investigated in NRSTS?
pazopanib= tki
give 2 cytogen changes seen in osteosarcoma
chromothripsis
supernumary ring chromosone 12q13-15
3 molecular abnoramliteis seen in osteosarcoma
Rb, p53, RECQL4 helicase mutations (germline)
peak age for osteo?
~15
3 rfs for osteo?
ionizing rad, hereditary rb, li fraumeni
presentation of oseto?
pain +/- mass invovlign metasphyses of long bone
3 most common primary sites in osteo?
distal femur> prox tibia>prox humerus
what is a skip lesion?
pattern of spread of osteo; can be several cm from primary, in the same bone…occurs in 20% of osteo
how does osteo spread?
skip lesions adn hematgenous spread
sites of osteo mets? (2)
lung>bone
what % of osteo has mets at dx?
15-20%
stage osteo how?
plain films of primary
MRI of primary
CT chest
PET scan or bone scan
stage assginemnt in osteo based on waht two things?
localized or not
resectable or not
localized osteo 3 yrs EFS?
65-70%
5 yrs EFS in met osteo?
<30%
in osteo, bettter to have unilateral pulm mets or bone mets?
unilateral pulm mets
describe role of necrosis in osteo
if at lesat 90% necrosis at 10 week of pre-op chemo, better 3-yr EFS…80% vs 60%
types of histo that are favorable in osteo?
parosteal, fibroblastic, telangiectatic
how does lcoation and size play a role in osteo prog?
extremity better than axial; 8 cm or less better
relapsed osteo don’t do well. RFs for shorter survival after realpse?
age >10
mets at dx
lung and bone recurrence
time to relapse<2 yrs
pathognomic features on histo for osteo?
osteoid-producing malig cdells
2 major histo subtypes of osteo?
central (medullary) and surface tumours
for the following types of OS, indicate if central=medullary or surface 1-small round cell 2-low grade central 3-parosteal 4-telangiectatatic 5-conventional 6-periosteal 7-high grade surface
1-central 2-central 3-surface 4-central 5-central 6-surface 7-surface
3 features of osteo on x-ray?
- mixed osteoblatsic+ oteolytic features
- cortical destruction adn expanstion into soft tissue
- periosteal reaction, eg: codman triagle, sunburst pattern
ewings is more ___ than osteo
osteolytic
5 ddx for osteosarcoma?
ewing sarcoma mets LCH oseomyelitis osteoblastoma aneurysmal bone cyst fibrous dysplasia
tx philosophy for osteo?
SURGICAL resection of all gross tumour adn chemo
timing of surgery in osteosarcoma?
after 10 weeks of neoadj chemo
advanrages of neoadj chemo in osteo?
- allows starting therapy more rapidly
- may faciliate limb salvage surgery
- provides histo response
chemo in osteo?
HD-Mtx, doxo, cisplatin= MAP
what type of osteo doesn’t need chemo?
PAROSTEAL
what’s teh diff between parosteal and periosteal osteosarcom?
parosteal: tends to occur in distal femur, is low grade, reqwuires resection only!
periosteal: tends to occur at prox tibia, is intemdiate grade, tx with resection +/-chemo
3 things you may see on imaging that indicate osteo improving?
- increased ossification
- sclerosis or calcification or border
- reduction in soft tissue mass
late effects in osteo?
cardiomyopathy (athracyclin)…in >20%
cisplatin-indcued ototox
most common fusion in EWS?
EWSR-FLI1 fusion = t(11;22), 85%!
2nd most common EWS fusion?and another?
21;22…2;22
detect EWS transloc how?
RT PCR or FISH
EWS: more common in black or white pts?
white
presenation of EWS?
pain +/- palp mass
EWS: what part of bone involved?
diaphyses and central axis
most common site in EWS (3)
pelvis>femur>rib
top 3 met sites in EWS?
lung>bone>BM
what % of EWS have mets?
20%…same as osteo
EWS staging how?
plain films MRI or CT of primary CT chest PET or bone scan bilateral BMA/bx
assign stage how in EWS?
local vs mets
most imp prog featuers in EWS?
stage
in terms of prog, worst primary site in EWS?
pelvis
describe how tumour size and age are import in EWS prog
better if younger
better if <8 cm
2 stains used in EWS?
CD99, vimentin
EWS can have differentaition or not…if does have diff, see what? (3)
rosettes
NSE
synaptophysin
what features of EWS are seen on x-ray?
lytic lesion with a wide zone of transition and periosteal reaction…see aggressive periosteal reactions like codman triangle, sunburst pattern or onion skin pattern
ddx for EWS on x-ray?
osteosarcoma, mets, LCH, osteomyelitis
tx philosophy for EWS?
surg, radiation, neoadj chemo, (SCT)…use surg when possible
tx in EWS based on what 2 things?
stage, site
rad dose in EWS?
36-50.4 Gy
chemo in EWS?
VDC IE= vcr, doxo, cyclo, ifos, etop
other htan VDC IE, what are other active agents in EWS?
topotecan, iriontecan, temozolomide
role of SCT in EWS?
possibly for high risk localized EWS
late effects in EWS?
Radiation: –> SMNs (carcinomas, sarcomas, 10%); path fractures/limb length discrepancy/femoral head necrosis..
Chemo: leukemias, cardiomyopathy from athracyclin, ifosfamide-induced nephrotoxicity = dose-dep proximal tubular damage
BRIEFLY describe bio of RMS vs NRSTS vs OS vs EWS
ERMS: aneuploidy, point mutations ARMS: PAX-FOXO1 fusions NRSTS: many tumour types OS: chrom instability EWS: TET-ETS fusion: EWSR1-FL1
most common sites for RMS/NRSTS/OS/EWS?
RMS: head, GU tract
NRSTS: extrems, trunk
OS: metaphyseal, distal femur adn prox tibia
EWS: diaphyseal or soft tissue, pelvis and central axis most common
risk based on what for RMS/NRSTS/OS/EWS?
RMS: stage, group, fusion status, histo
NRSTS: stage, group, tumour size, grade, histo
OS: stage, resectability
EWS: stage, site
histo of RMS/OS/EWS?
ERMS: spindle cell tumour ARMS: SRBCT RMS in general: myogenin, desmin + OS: osteoid-producing malig cells EWS: SRBCT, CD99+, may show neural diff
tx in RMS?
upfront surgery +/- delayed RT/surgery…systemic= VAC +/- VI
tx in NRSTS?
local: surgery (may be dleayed) +/- RT (may be pre-op)…systemic= +/- Doxo, ifos depending on chemo sens
tx in OS?
local= delaeyd surgery syst= MAP
EWS tx?
local= delayed surgery adn/or RT syst= VDC/IE
