Neuroblastoma, ASPHO Flashcards
NBL originates from wehre
neural crest tissue of the sympathetic nervous system
spectrum of neuroblastic tumours?
ganglioneuroma>ganligoneuroblastoma (nodular vs. intermixed…intermixed= favourable)>NBL
2 features of NBL on path
SRBCT
homer-wright rosette pattern= tumour cells around neuropil
3 drivers of disease in NBL
NYMC amplificaiton/overexpression
ATRX inactivation
TERT rearrangements
chrom changes in NBL and outcome?
hyperdiploid= excellent outcome
segemental chrom aberrations/diploid DNA content= inferior outcome
most common somatic chrom aberrations/loss of genetic material in NBL?
chrom 1p36 (MYCNA); 11q23 (TERT, ATRX)
other somatic mutations in NBL?
aberations and activating mtuations of ALK; ch17q gain; ARID1a/1b deletions and point mutations, p53 mutations, PTPN11 (noonan), mtuations in genes of Ras/MAPK signaling pathway
msot common extracranial solid tumour in childhood?
neuroblastic tumours
sex predom in neuroblastic tumours?
male
neuroblastic tumour= most common solid tumour in kids __ __ __
under 1 year
CPSs in NBL?
familail NBL (alk germline mutation)
PHOX2B…neurocristopahty syndrome: central hypovent, hirschsprung’s, nbl
-Neurofibromatosis
-BWS
-Li Frameni
-Noonan
-germline deleation at 1p36 o 11q14 locus
prog features of NBL?
age <1 = BETTER
stage
path
presence of unfavourabe geentic changes (Mycn, alk, atrx, segmental chrom aberration/diploid)
old international NBL staging system based on what?
surgical resection
waht staging system do we use now for NBL? what does it indicate?
INRGSS=international nbl risk group staging system…based on pre-op features
what are the diff stages of INRGSS?
L1, L2, M, MS
Stage L1=?
lcoalized tumour not involving vital structures (no image defined risk factors) adn confied to one body compartmetn
stage L2=?
locoregional tumour with 1 or more IDRFs
stage M=?
distants mets (except MS)
stage MS?
mets in kids<18 months with disease confined to skin, liver, and/or BM
waht are the image defined risk factors?
- tumor encases vessels in neck/thorax/abdo
- encasing brachial plexus
- extending across compartments
- invading porta hepatis or renal pedicle
- infiltrating organs
- compressing spinal cord
what is the international neuroblastoma pathology classification?
INPC; determines if histo features are favourable or not favourable, priro to therapy
waht does the INPC look at?
amnt of Schwannian stroma
degree of tumour NBL maturation
mitosis-karyorrhexis index= MKI
INPC evaluated within context of what?
age…<18 mos best…>5 yrs worst
INPC = sep prog factor…how do neuronal diff and MKI fit in?
Bad= less diff Bad= high MKI
who qualitifes as low risk disease? (4)
- INSS stage 1, 2, 4s
- INRGSS L1, MS
- Any age for 4S; MS<18 months
- No MYCN amplification
who qualifies for HR disease?
- MYCN amplificaiton
- INSS stage 4
- INRGSS M AND ageat least 18 months, or 12-18 months iwth unfavouragle histo or genomics
intermed diseaes?
INSS stage 3, INRGSS L2
INSS stage 4, INRGSS M AND age<18 mos
No Myc N amp
NBL accounts for what % of childhood caner mort?
10%
Inernational NBL risk group is a ___ classification schema
pretreatment
features of pres in NBL?
-neck mass
-abdo dist
-horner syndrome
-GU symptoms
-paralysis for SC compression
-htn
features if mets:
-constittuional sx
-boney pain
-proptosis if mets at orbit
-racoon eyes
-resp distress
-skin nodules
paraneoplastic syndromes in NBL?
opsoclonus myoclonus ataxia syndorme (OMAS)
Kerner morriosn syndrome
features of OMAS?
- myoclonic jerking and random eye movment, with or without cerebellar ataxia
- associatd with favourable NB features
- can have longeterm neruo and cog defs
describe kerner-morrison syndrome
-tumour secretes VIP–> secretory diarrhea that rsolves after tumour resection
staging for NBL?
CT/MRI of piramry
I-123 MIBG to look for mets
FDG-PET if tumour NOT MIBG-avid (10%)
—Tc99 bone scan = outdated
work up for NBL?
tumour bx
bilateral BMA, bx
serum or urine catehcoalmines: HVA, VMA…secreted in 90%
nonspecfici markers: NSE, ferritin, LDH
immunohistochem for NBL
S100, CD56, PGP9.5, NSE, synaptophysin
EFS/OS for LR NBL?
> 90% for both
how to tx LR NBL?
- mainstay of tx= surgery…dealyed surgery for symptomatic 4S/MS…complete resesction NOT mandatory
- OR, can do observation alone without bx! if inant with small stage 1/L1 adrenal tumour; ongiong trials to assess observation for additional non-adrenal small L1 tumours
- chemo if acute life/organ threatening sx or recurrence
- rads if acute life/organ threatening sx
Intermed risk NBL: EFS and OS?
> 85% EFS
>90% OS
how to tx intermed risk NBL?
- can be surgery alone, chemo alone, or both
- SURGERY upfront biopsy for genetic and histo..deleayed resection to achieve at least 50% reduction in primary tumour…complete resection NOT mandatory
- response-directed chemo (2-8 cycles) of Vcr, carboplatin, cyclophos, doxorubicin, with goal of reducing primary tumour by at least 50% and resolving mets…longer chemo duration if unfavorable histo, tumour SCA or tumour diploid (at lesat 4, up to 8 cycldes if combined with stage 4/INRGSS M disease)
- radiation only for acute life/organ threatneing disease
Main parts of HR NBL tx?
INduction
Consolidation
Post-consolidatoin
What happens during indcution for HR NBL?
-multi-agent chemo x 5 cycles
-stem cell collection (after cycle #2)
-surgery (usually between cycles 4-5)
in some cases, no surg
what happens during HR NBL consoldiation?
tandem HD chemo adn auto transplant; external beam radiotherapy
what happens during post-consolidation NBL tx?
Isotretinoin, anti-GD2 immunotherpay
what is isotretinoin?
Retinoic acid, biologic response modifier
CCG 3891 showed?
1) pts randomized to receiving RA had improved EFS to those not receiving it
2) also randomized continuation chemo after induction vs. 1 round of MA chemo adn SCT…3 yr EFS: 33% for MA chemo vs. 22% for continuation chemo–> standard of care MA chemo
ANBL0032 showed?
randomized to anti-GD2 with (dinutuxuimab) IL2, GMCSF with cis-RA, or JUST cis-RA alone after consolidation: 2 yr EFS better with anti-GD2 of 66% vs. 46%….since then, found IL2 doesn’t improve outcomes but does increase toxicity..don’t give IL2 anymore
ANBL 0532 did what?
randomized single round of MA chemo and transplant vs tandem…3 yrs EFS 73% for tandem vs 54% for single, most evident for kids who got immunotherapy
goal for LR/IR NBL?
goal to reduce pirmary tumour by 50%…via chemo alone or surg alone or both
goal for HR NBL?
compelte resection of primary tumour while preserving critical organs and structures
do we think of neg margins in NBL?
not really
role of rads in NBL and timing?
LR/IR: only for life/organ threatening symptoms
HR: 2160 cGy to primary tumour to pre-surgical tumour and margin..boost to residual gross tumour NOT found to increase local control…can irrad met soft tissue and bone sites…timing is after tandem ASCT
revised international nbl rsponse criteria: based on what 3 components? does it include VMA/HVA levels?
-response of primary
-response of met sites (soft tissue and bone)
-bone marrow response
uses MIGB, PET
….no
responses options for INRC overall resposne?
Complete response, partial, minor, stable disease, progressive disease…pretty much base overall rating on worst response for any given component…but minor response = at least 1 PR or CR and at least 1 SD (with no progressive disease)
list 5 complciations /late effects of NBL treatment
- renal damage from surgery
- neural damage from surgery
- altered msk growth from rads
- infert from rads
- secondary malig from rads
- organ dysfunction from rads (renal, heart, lungs, pituitary, neurocog, etc)
- otoxicity from platinum
- cardio tox from athracyclin
- infert from alkylator
- secondary malig from alkylator, etoposide
- decreased bone density from isotretinoin
pheochromocytoma and paraganglioma: describe origin
neuroendocrine tumours arising from chromaffin cells of either sympathetic tissue of adrenal or extraadrenal abdo locations or parasympathetic tissue in the thorax or head and neck
% of pheochromocytomas that are malig?
10%
% of paragangliomas that are malig?
25%
subtypes of pheochromocytoma and paraganglioma?
- pseudohypoxia
- wnt-signaling
- kinase-signaling pathway (PI3kinase/AKT, RAS/RAF/ERK, mTOR)
pseudohypoxia phenotype of PPGL–> what subtype? associated with what germline mut?
noradrenergic subtype; von Hippel-Lindau…get elevated norepi/normetanephrine
kinase singaling tumour associated with which phenotype? germine mut?
adrenergic, secrete metaneprhine…germline mut in FET, NF1, TMEM127
dopaminergic phenotype related to germline muts where? tumours are were?
SDHB and SDHD, secrete dopamine, head and neck tumours
PPGLs: if you have a patient with this, should do what?
refer to cancer genetics!
RFs for met disease in PPGLs?
- SDHB germline mut
- extra-adrenal location
- primary>5 cm (or >3.5 cm in tumours related to SDHB)
- young age of initial dx
- elevated 3-methoxytyramine (MT) levels
PPGLs: dx how?
- excessive catecholamines
- lcoalization of tumour by CT or MRI
- measure metaneprhines (normetanephrine and metaneprhine separately measured) in urine or plasma
- F-FDOPA or Ga-DOTATE PET (somatstatin analog)…or FDG-PET
PPGLs met where?
lungs, liver, bones, LN
role of MIGB-SPECT in PPGLs?
if considering MIBG therapy for met diseaes
PPGLs pres?
pain nerve palsies headache (90%) diaphoresis tachycarida htn hypotension/postural hypotension/alternating periods of high and low BP anxiety, panic attacks
tx localized PPGL how?
surgical resection]
-alpha blockade BEFORE beta blockage prior to surgery
tx metastatic PPGL how?
- poor prog if not resectable or mets
- chemo: cyclophos, vcr, dacarbazine
- sunitinib= TKI and everolimus= mTOR inhibitor
radioistope therapy for NBL and PPGLs?
- 131I-MIBG for relapsed and refractory NBL and PPGLs
- Lu 177 Dotatate = oral, no admission needed, radiolabeled somatostatin analog
