Retinoblastoma
-RB gene is
an antioncogene
-oncogenesis occurs with mutational inactivation of both
copies
-RB gene
product functions to inhibit DNA synthesis and cell proliferation
-gene
located on 13q14 region
-tumorogenesis requires homozygosity
of mutant allele
-inheritance
of predisposition is dominant
-tumor
formation is a recessive trait
-inheritance
of one allele imparts predisposition
-CELL OF
ORIGIN OF Rb is likely immature neural epithelial
cell (have potential to differentiate into photoreceptors or Muller cells)
-retina
matures in a wave from posterior pole to periphery
-peripheral
retina most likely to be affected by late-onset tumor
-DNA
analysis is available for detecting mutations of RB1 gene
-some
mutations have higher penetrance than others (overall
about 80%)
-40%
hereditary, 60% sporadic
-only 10
percent have familhy history
-incidence
1/18000 live births
-assoc with
advanced paternal age
-recent
evidence for inc incidence in developing countries
eval:
-correct
diagnosis can be made in >99% of cases
-presenting
signs/symptoms:
age <5
leukocoria, greater than 50
percent
abnl red reflex test by pediatrician
strabismus
red, painful eye
orbital cellulitis
DDX:
persistent fetal vasculature
coats' disease
ocular toxocariasis
congenital cataract
ROP
w/u:
to confirm the diagnosis
to stage the tumor for treatment planning
w/u:
physical exam by pediatrician
imaging study
staging EUA
CT vs. MRI
CT less
expensive and faster
CT better at
detecting calcified lesions
MRI more
sensitive for optic nerve and pineal lesions
MRI has no
radiation exposure
U/S
dependent on echographer
good sensitivity for calcification
allows for accurate measurement of size
EUA complete
routine w/u:
slit lamp for rubeosis and ant vit seeds
fundus drawing
photography
Metastatic workup:
done only when there is evidence of extraocular
disease
-bone marrow
bx, LP, bone scan
other ancillary tests:
fine needle bx - WARNING: viable tumor cells
demonstrated in needle tracks
aqueous neuron specific enolase and
lactate dehydrogenase
atypical manifestations:
presentation at older age
hyphema
vit hemorrhage
glaucoma
diffuse infiltrating rb: hypopyon, granulomatous
appearance, orbital cellulitis
RB in older
children:
34 of 400
greater than 5 years old
active RB in 26 and retinoma in 8
(benign)
misdiagnosis common: 5 of 26 had undergone prev vitrectomy
Reese-Ellsworth
developed in 50's to predict survival of eye after external beam
radiation
indirect ophthalmoscope was just being introduced
anterior lesions, even if small, classified as more advanced
any vitreous seeding places eye into worst category
Murphree:
based on likelihood of salvage based on todays
treatment modalities (chemo, laser, cryo, EBR)
Endophytic grow in vs. exophytic grow out
towards RPE:
no difference in optic nerve invasion, orbital recurrence, or
survival
diffuse infiltrating: no
calcium, no mass, just thickened retina, almost always unilateral, may have pseudohypopyon
Retinoma: benign variant, no growth or mets
Treatments:
Focal
treatments:
photocoagulation (if less than 1 DD)
hyperthermia (TTT, using diode laser for long time)
cryotherapy - for lesions up to
2.5mm in thickness (free-thaw 3x)
often require sequential treatments every 2-3 weeks
increase cellular uptake of carboplatin so
used in conjunction with chemo
Brachytherapy
-I125 plaque
-dosimetry calculated for 40 Gy to
apex if primary treatment (different from melanoma=100)
-use 20 Gy for eyes previously treated with chemo
Chemotherapy:
-sig advance in management of intraocular RB
-primary (neoadjuvant) chemotherapy: first therapeutic intervention,
can be followed by focal therapy (chemoreduction)
-adjuvant
chemotherapy: given after enuc to prevent mets, used when path specimen shows ON invasion beyond
lamina or massive choroidal invasion
agents used (CEV protocol = carboplatin,
etoposide, vincristine)
complications/side effects: bone marrow toxicity, anemia, neutropenia; renal, hepatic, ototoxicity;
nausea, vomiting, alopecia
etoposide likely inc risk of
future leukemia
periocular carboplatin
combined with focal treatment:
higher vit levels and lower serumxxx
external beam radiotherapy:
most effective still
inc chances of second malignant neoplasms
in field of treatment
mortality rate of SMNs at 40 years in
bilateral RB: 6% without EBR, 35% with EBR (these are if given before age 1)
enucleation:
indications
-tumor
filling >half to two-thirds of the eye
-no
likelihood of salvageable vision
-if giving
chemo anyway for the other eye, can wait and judge response before enucleation
technique
-leave low
stumps of LR and MR for traction
-lateral canthotomy
-goal is
>10mm of optic nerve
do not clamp nerve before dividing
medpor implant wrapped in
sclera, muscles attached
Follow-up:
-appearance
of treated tumors (regression patterns)
type I -
calcified scar, looks like cottage cheese, II - semitransparent, fish flesh
appearance, III - combination of I and II, IV- flat chorioretinal
scar (best)
these patterns originally defined with use of EBR
type I and IV are the most likely to be stable long term
screening for trilateral RB (in both eyes and pineal gland)
-3% of
patients
-question of
benefit from screening on ultimate survival
-recs vary from no screening to MRI
scanning every 3-6 months x 9 years
we currently scan everyone at diagnosis and bilateral cases yearly
thereafter
genetic counseling:
important numbers
-offspring
have 50% chance of inheriting RB1 gene
-penetrance is 80-90%, so 40-45%
chance of having RB
-10% of
heritable cases are unilateral
-risk for
sibling of new bilateral patient is 2% if parents are clear
-risk for
sibling of new unilateral patient is 1% if parents are clear