SECTION 4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY
CH APTER
50 Retinoblastoma
Brenda L Callie, Vasudha Erraguntla, Elise Heon and H elen S L Chan
Retinobla stom a is the co m mo nest malignant ocular tumor of
child hood, but is quite rare at one in 20000 live births. I
Unt reate d, the tumor is almos t uniforml y fata l, but with m od ern
method s of tr eatment the survival rat e is over 90%. An int egrat ed
t eam approach of clinic al sp ecialist s wit h im aging spec ialists, play
th er apist s, parents and ot he rs is th e m ost effec t ive way t o
m anage thi s disease . Th e tumor arises fro m prim itive retinal ce lls
so th e m ajority of cases occ u r in child re n un der the age of
4 yea rs. U nt il recently, treatment included on ly enuclea tio n
or/a nd radiati on . Children with mutat ion s in the RBi t um or
suppresso r gene m ay develop seco nda ry tu m or s wh en exposed to
radiat ion so, since the 1990s, t he co mbination of syste mic
chemothe rapy and focal ther apy have bee n wide ly used, in order
t o avoid these very serio us side-effects .
Th e st udy of ret inob lasto ma has led t o a revolution in th e
und erstanding of cance r in gene ral: st ud ies revealed that bo th
her editary and nonhereditary t um or s are init iate d by the loss of
both alleles of the t umor suppressor gene, RB1.2 Th e existe nce
of spec ific genes that no rma lly act to suppress cancer was
pr edi ct ed from clinical st ud ies of retinobl ast oma.v" wh ich
ope ned up the knowled ge of even ts t hat led t o the pr edi sposition
of cance r in humans. Th e RBI gene was t he first tumor suppresso r
gene t o be cloned. ' and the knowled ge abo ut the fun cti on of thi s
gene revealed its crit ical role in ce ll cycle regulati on in cance r.
PATHOGENESIS OF RETINOBLASTOMA
----
Heritable and non heritable retinoblastoma
Nearly 50% of retinob lastoma cases are her itab le, du e t o a
mutati on in th e RBI gene, wh ich pr edi sposes a child t o develop
retinal tumors. The hallm ark of th e majority of hereditary cases
is th e occ urre nce of bilat er al or mu lt ifoca l tumors, but 15% of
child re n with unilater al tumor s also have a mutat ion of one allele
of th e RB 1 gene in their germ ce lls, t hat will be inh er it ed by one
half of their child ren. Less than 25 % of all cases have a fam ilv
hist ory of ret ino blasto ma, " since usua lly the affec te d child , even
t hose wit h bilat eral disease, has suffered a new ge rm line
mutati on. In familial cases , th e predispositio n to reti noblasto ma
is transmitted as an autosoma l dominant t rait.
No nher itable retinoblastoma is caused by mutations in th e same
RBI gene . In nonheritable reti noblastoma, somatic mu tations in
bot h alleles of t he RB1 gene occur in a single primitive ret inal cell,
which gives rise to a solitary, unilateral tum or. Since no germ cell
mutatio n is involved , the disease is not transmitt ed to the offspring.
Loss of both RB1 alleles induces
retinoblastoma
Th e sim ple clini cal ob ser vati on th at th e childre n with bilat eral
486
retinob lastoma t ended to be diagnosed at a younger age than
those with nonher editary ret inobla stoma was analyzed mat h-
em at ically by Knud son . H e predicted that two mutati onal event s
(M I and M2) were required to initiate reti noblast om a.' The ages
at diagnosis of children with bilatera l and un ilateral retinoblastoma
plotted in a semi -log curve against t he proportion not yet
diagnosed fitted a simple ex pone nt ial equation which suggest ed
that it was a single second mutation (M2) in one developing
retinal cell that initiated tumor deve lopment (heritable retino-
blastom a), in th e pre sen ce of a predisposing first mutation (M 1)
in th e germ line. H owever, tw o or more mutations (Ml and M2 )
had to occur in one single developing retinal ce ll in orde r t o
initi at e retinoblastom a in th e abse nce of a pr edi sposing germ line
mutat ion (nonheritable retinob lastom a) .
Thi s "two-hit " hypothesis was expanded by Co mings who
proposed that th e tw o events could be mutation s th at occurred on
th e two different alleles of the pr edi sposin g RBI gene, wh ich as
lon g as one normal allele was pre sent, would normally have
"suppressed " tumor formati on in the retina." Th e chance of two
or mor e pr imitive re tinal ce lls bearin g germ line M I und ergoing
addit ional M2 events is sufficie ntly high that multiple tumor s are
a com m on occurrence in her editary retinoblastoma (Fig. 50 .1) .
H owever, the chance th at both M I and M2 events would occur
in the same ret inal cell is so ex t remely-sm all that it is virtually
impossible for nonher editary cases to have mu ltipl e tumors.
Perhaps because time is required for two mutational events to
occ u r, or because two affe ct ed eyes com e to attention sooner
t han one affected eye, child ren wit h nonhereditar y reti nob lastom a
tend to be diagnosed at an older age than children wit h her editary
retinoblastoma.
In about ha lf of th e cases , the M2 event in t he tumor is loss and
reduplication of large chro mosom al regions sur rounding RBI ,
wh ich cou ld be det ect ed by loss of heterozygosit y, or
hom ozygosit y for the M I mutation (Fig. 50.2) . In suc h tumors,
th e two mutant alleles are identical and the normal allele is
m issing. V In the rem ainin g tumors, the seco nd RBI allele
acquires a com plete ly differ ent mutation .f
Function of the retinoblastoma protein
pRB is a 110 kDa ph osph op rot ein that inhibits ce ll prolifer ati on
by alte ring the ex pressio n of genes whi ch promot e ce ll division,
t hrough interaction wit h th e t ranscription fact or E2F famil y and
m any ot he r modifying prot ein s.l' DNA tumor viruses that induce
cance r, suc h as human papill om a virus, do so in part by binding
to pRB through the "pocket" region of pRB. Th e act ive form of
pRB is underphosphorylated, and for the cell cycle to proceed ,
pRB has to be inacti vat ed by phosphorylation m ed iated by
protein complexes of cyelins and cyclin-de pe nde nt kinases.
Wh y does mutation of a ce ll cyele regu latory gene lead
speci fically to the development of retinoblastoma? G ermline
 CHAPTER

Retinoblastoma 50

- ereditary retinoblastoma. (a) Family tree: mother was cured of bilateral retinoblastoma by enucleation of one eye and external beam radiation
'= : '- -: ' ~ye .
Both children were delivered at 36 weeks gestation to facilitate early treatment of tumors and developed bilateral tumors. Mother and
_ ::re" carry a germline RB 1 mutation (M1, deletion of ATTIC starting at bp 778, reading to a STOP, 9 codons away) that results in no pRB when
1l
2. ::JB 1 allele is lost (M2) from a developing retinal cell, initiating a tumor. RetCam images: (b) prior to treatment , right eye IIRC Group A, more
: - - rom optic disc) of the boy at 3 months , showing two tumors; stable right eye of boy age 4 years after laser, two cycles of CEV with
_~ _ - e A chemotherapy, and more laser treatments . (c) prior to treatment , left eye (IIRC Group B, tumor less than 3 mm from fovea) of the girl at
-5 aser scar and new tumor above nerve at 4 months of age; recurrence in original scar extending toward fovea, with tumor vascularization
~ ~- . uorescein angiograph y; flat scars at age 3 years after laser, two cycles of CEV with cyclosporine A chemotherapy to control recurrence
- _ - ~ ision chemotherap y and more laser. (Images by Leslie MacKeen, Cynthia Vandenhoeven and Carmelina TrimbolL)

: n of RBI leads t o a 40000-fold re lat ive risk (RR) for

to m a, a SOO-fold RR fo r sarco ma that is incr eased up to
by therapeutic radiation, but no increase in the RR for
ernia. 0 Alt hough pRB is pr esent in all cycling ce lls, it s fun c-
d evelop m e nt is hi ghl y ti ssu e -spe cifi c. Thus, m ic e
- :1,. .ted t o have no pRB die in utero of trophoblast failure, I I
- : ho u gh man y othe r tissu es have ap pa re nt ly form ed
- .... If the mi ce are rescue d by t h e provis ion of a wild-t yp e
-la , t hey st ill d ie at bi rth fro m in ad equate muscl e
pment . V Th e retina ma y b e uniquely d ependent on pRB in
-: be ab le t o differentiat e terminally into adu lt , fu nc t ioning
-_In th e absence of pRB , prolifer ati on of the suscept ible ce ll
- - ..Ie: w hen terminal differ entiati on or ce ll d eath shou ld
.. have occ ur re d . Further mutati on s in oncogenes and oth er
- su ppressor genes (M3-Mn) result in a retinal tumor. 13, J4
Spectrum of RB1 mutations
The m ajority of RB I mutations are unique to each affec t ed
individual in a famil y, and ar e distributed throu ghout the RB I
gene w it h no real hot spot s." Sensitive mutation identification
requires d etermination of the copy number of each ex on and the
gene promoter in order to reveal large d eletions and duplications,
sca nning and seque nc ing for point mutations, examining the
mRNA t o d et ect or confirm sp lice vari ants, and assay for the
m ethylation st at us of the promoter in tumor samples. Exon
sca nning and seque ncing re veal s ap p rox ima tely 70% of the RBI
mutati on s. Application of all these t echniques, com b ined with a
gene d isease- specific focu sed ex pe rt ise, id entifies over 90 % of
th e RBI mutations. When tumor or blood sam ples are subm itted 487
t o a clini cal t est laborat or y, it is critical to know that suc h a
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

Fig. 50.2 Exophyt ic retinob lastoma (IIRC Group D). (a) With retinal detachment in a unilaterally affected 3-year-old boy. (b) B-scan ultrasound showing
calcificatio n in a single tumor beside the opt ic nerve. (c) B-scan ultrasound showing subretinal hemorrhage and no tumor involvement of optic nerve.
(d) CT scan showing intraocular calcification , normal-sized optic nerve. (e) The eye was opened immediatel y after enucleation , in order to obtain live tumor
cells in order to det ermine the two RBt mutations (M1, M2) (homozygous exon 16 deletion C-1450, insertion AT). This mutant RBt allele was not detect ed
in the child's blood , eliminating risk for his siblings. His future offsp ring will be checked for this mutant allele since he could still be mosaic . (f) The child
two days after enucleation, wearing the temporary prostheti c conformer inserted at the time of surgery. The exon 16 RBt mutation of the tumor is not
detected in blood , indicating high likelihood that the retinoblastoma is not heritable, eliminating risk for siblings. Due to the remaining possibility that the
affected child is mosaic for the RB t mutat ion, his future offspring will be tested for this mutation. (Images by Cynthia Vandenhoeven and Carmelina
Trimboli.)

laboratory does have t he sta te -of-the-art t est sensit ivity, and that
the turn-arou nd-ti me in that particular laborat ory is op t ima l,
since these pre requisites grea tl y im pact on care of t he entire
retinobl astoma fam ily.
Genetic counseling for retinoblastoma
Wit hout th e knowledge of wh ich RBi allele is m ut ant , t he risk for
th e re lat ives of retinob lastoma patient s can be estimated. IS
O ffspring of patients wit h a fam ily history of retinoblastoma or
bilat eral t um ors have a 50% risk of inheriting the mutant allele and
a 45% risk of dev eloping retinob lastoma . 'W hen two affected
children are born to apparently norma l parents, one paren t
must be carrying but not expressing t he m utant allele, and hence
th ere is also a 45 % risk that any subsequent child born will d evelop
retinoblastoma . The risk that other relatives have inherited the
mutant allele de pe nds on t he number of intervenin g "apparently
normal" individuals, each of whi ch have a 10% chance of carrying
but not expressing the mutant allele . The risk th erefore falls by a
factor of 0 .1 for eac h int ervening unaffected generation.
Since 15% of patie nts wit h unil at eral reti nobl ast om a have a
ger m inal mut ati on , it is evide nt that the offs pring of individuals
wit h u nilateral retinoblast om a have a 7.5% risk of carrying the
abnormal gene. Th e probability of ot he r relatives developing
reti noblast om a can be calculate d in a sim ilar way. IS
Infant s born with th e abo ve-calculate d risks for developing
retinoblastoma are exam ine d elect ively at regular int ervals to
det ect early tu m ors that can be tr eated to obtain th e best visual
result (Fig. 50. I ) . Thi s includes an awak e-exam ination of th e en tire
retina of infant s less th an 3 m onths of age, and examinat ions under
anes t hes ia subseque ntl y every 3-6 months until th ey reach th e age
of 3 years and several years of furt he r clinic ex aminations .
Impact of genetic testing
Timely and sensit ive molecul ar dia gnosis of RBi mutati on s
enables ea rlie r treat m ent, lower risk and better health outcomes
for reti no blasto ma pat ients, em po we rs fa mi lies t o make
infor m ed fam ily-planning de cision s, and costs less th an conve n-
tional su rvcillanc e.f'" New t umors occurred in 24 % of child re n
wit h retinobl ast om a, much m ore fre que ntly in the per iph eral

em phasizing t he importance of a care fu l fundosco pic
non w ith ind ent ati on t o obt ain a clear view of the
"",: ', Accurat e molecular an alysis allows definitive identifi-
;' those famil y members who carry the same mutat ion
- t he proband (Fig. 50 .1) , The un affect ed child ren
. e p reviously cons ide red t o b e at -risk) avoid further
_- 'e exam inat ions under anes t he t ic and or in the clini c.
_-:; s in direct co st s from incurred by at-risk child ren in
rni lies avoid ing su ch repeated exa m ina t ions subs ta nti ally
::'.e one-t im e cost of molecul ar testing. Moreover , h ealth
-.gs cont inu e to accrue as succeeding gene rat ions avo id
- - er essa ry examination s and usu ally d o not need molecul ar
-e . ult of th e RB1 mutations is usuall y trun cat ion of the
: ;: prot ein, which is so un stable th at no mutant pr ot ein is
e, Suc h mutat ion s show high pen etrance ( > 95 % of
-; l:Tect ed) and expressivit y (aver age of seve n tumors per
,.'ore u nc om m on RBI mutations cause much lower pen-
nd expressivit y !": "in fram e " deletion s or insertion s that
a st able but d efect ive pRB I9 ; prom ot er mutati on s
~ : in a reduced amount of ot he rw ise normal prot ein /" and
- utations that ma y be addition ally alte re d by unlinked
- - gen es".21
- -~ manifestations of RB1 mutations
. -5 of RBI also pr edi spo se t o beni gn retinal tumors,
: : ec t op ic intracr an ial retinobl ast oma (t ri lat eral
- st om a}, and second non ocul ar m alignan cies,n ,24
-'::' ~ ma
. - rna is a nonmali gnant m ani fest ation of th e RB 1
,:: Three features charact erize these nonpr ogressive
an e levat ed grey retinal ma ss, ca lcificat ion, and su rro u nd -
_ - : nal pigm ent ep it helium (RPE) pr oliferation and pigm en -
- Fig. 50 .3a , b) . Su ch features are also seen afte r radiation
:-elt fo r retinoblastoma. If do cumented at all in childhood,
- 5 very rare, retinoma is observed as a qui escent tum or th at
- : progressed to full malignancy. Ret inoma m ay d evelop
- :"e :' [2 mut at ion occurs in a nearl y d evel oped reti nal ce ll,
. .nerefore , has a reduced potential for acquiring t he M3 -Mn
._: . ns that are ne cessar y for fu ll m alignanc y, re sulting in a
;- disord ered growt h in the re t ina .' :' Th e importance of
-:: a re t inom a lies in it s significa nce for ge net ic co u nse ling
- . == ,3) , Th e pr esen ce of one retinom a puts an individual at
: car ry an RB1 mutation. With a famil y hist or y of retino-
: rna, or multiple retinomas, the individual d efinitely carries
1 m ut at ion; other family members t hat carry the same
. t ion may de velop a fu lly mali gnant retinob lastoma.
- _ ond nonocular malignancies
cren w it h the hereditary for m of ret in obla st om a are at
-eased risk of d eveloping second non ocul ar m alignan cies.r"
c:-. ma y occ ur within or outs ide the rad iati on field (Fig. 50.4) .
- arion, pa rti cu larly of infants und er one yea r of age, incr eases
nsk of sarco m as and other ca ncers w it h in th e radi ation
=- 50.3 (Facing page ) Multifocal unilateral retinorna. (a) Discovered at age 16 years, follo wed for 30 years without change. Note the apparent "seed" in
10
-~ • treous when the two images are view ed in stereo . Pat ient carries a "null " RBt germ line muta tion (deletion of one copy from the promo ter to exon 7),
---= - :ed by one of his two daughters w ho developed bilatera l retinoblastoma . (b & c) Multifocal bilatera l retinoma discovered in the grand father when his
= a- ccauc hter developed unilat eral retinob lastom a. His daughter had bilateral retinoblastoma and meningioma at age 40. (d) All affected members carry a
- _ - germline RBt mutation (heterozygous point mutation in exon 17 resulting in a STOP codon).
CHAPTER
Retinoblastoma 50
field .n Osteosarcoma is t he co m m one st second primar y tumor in
person s with RBI mutations, but a w ide variety of oth er neoplasms
have been re po rted , Since these radi ation-induced tumor s are
ve ry d ifficu lt t o treat , more child re n with RBI mutations hav e
di ed of t he ir second tumor following the cure of intraocular
retinoblast oma by radi other ap y, than those that ha ve di ed of th e
conseque nces of retinob last oma .
Ectopic intracranial retinoblastoma (trilateral
retinoblastoma)
Trilateral retinoblastoma refer s t o a midline intracranial tumor or
a primary pineal tumor associated with hereditary retinoblast oma ,
th at is not a rne tas tasis.v The tumors are neurobla sti c in origin
and resemble a poorly differentiated retinoblastoma . They arise
in the vestigial "t hird eye ". Pineal tumor s are est im ated to oc cur
in 2% of cas es of retinobla stoma.i'' but th e fr equen cy ma y hav e
d ecr eased sinc e che m ot herapy ha s repl aced rad iat ion as primary
treatment . Sin ce , in most cases, the retinobl astoma is familial or
bilater al, it is assu med that th e pineal gland , like t he developing
retina, also ha s a risk for malignant tran sformation in the
pr esen ce of an RB1 mutati on . Affected child ren usuall y pr esent
w it h sym pto ms and signs of raised intracrania l pressure and are
found t o have a pin eal or parasellar ma ss on C T sca n . Routine
sc ree ning by MRI for tumor s m ay be useful t o detect pin eal
tumors at a stag e w hen th ey can be cure d. f
Histopathology
Retinoblast omas are p oorl y differentiated malignant neuroblasti c
tumors, com posed of cells w it h lar ge hyperchromatic nuclei and
sca nty cyt oplasm. Mitotic figu res are common . In some tumors,
more di ffer entiated ce lls form th e t ypi cal Flexn er -Wintersteiner
rosettes in w hich co lum na r ce lls ar e uniformly arrange d in
sp he res arou nd a lumen co nta ining the pr imi tiv e inn er seg m ents
of ph ot oreceptor s.F
Tumor cells ofte n outg row their blood supply leading t o necrosis.
A true spo nta neous regression of retinoblastoma, whi ch is very rare ,
is probably du e t o ext ensive tumor necro sis resulting in phthisis
bulbi.22.28 Programmed cell death or apopt osis is also evide nt in t he
tumors th at gene rally lacked pRB or fun cti onal pRB, supporting the
idea that th e normal fun ction of pRB is t o promote differ entiation
over apoptosis in response t o differentiation signals. C alcificat ion is
alm ost pathognomonic of retinoblastoma, but the origin of this
calcification is not under stood.
Two ma in patterns of retinoblastoma grow t h are seen within
th e eye . Endophyti c tumors (Figs 50.5 and 50 .6) t end to pu sh
into the vit re ous with on ly a d elicate inne r limiting m embrane
se parat ing tumor from vit re ous . When th e inn er limiting
membrane of th e retina breaks, "see ds" float in the vit reou s
cav ity, where they are hypoxic and relati vely re sistant t o therapy.
When the seeds fall onto the retinal su rface, they can attac h and
grow (Fig. 50 .6) . Spread of tumor into the ante rior cha m ber ma y
lead t o hypopyon, rubeosis iridi s and glau coma, with incr ea sed
risk of m etast asis. Exophyti c tumor s (Figs 50 .2 , 50 .7) grow into
the sub retinal space leading t o retinal detach ment over the
tumor. Bru ch 's m embrane ma y b e br each ed and spre ad into th e
489
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

() Unilateral retinoblastoma • Bilateral retinoblastom a

M Meningiom a • Retinom a
o Normal * RB1 Exon 17 sto p

490 @)
 CHAPTER

Retinoblastoma 50
choroid can occur, whic h, when ex te nsive, increases the risk of
spreading ou tside the eye and system ic metast asis. Diffu sely
infiltrating ret inoblastoma is uncommon, and since ther e is no
solid, calc ified tumor mass or retinal de tac hme nt, d iagnosis m ay
be difficult .29
If retinoblastoma metastasizes, it is gene rally becomes evide nt
within 1 months of t he last active tumor in t he eve, and is rare
bevond 3 yea rs without evidence of active tumor inthe eye .' The
mosr common and da ngerous route of m etast asis of reti no -
blas toma is d irect extension into th e opt ic ne rve . T he tumor ca n
grow toward t he optic c hiasm and be yond , or into the
subarachnoid space wit h extensive leptomeningeal involvem ent
(Figs 50 .8 and 50 .9) .30 Direct extension into opt ic nerv e or via
the choroida l vesse ls, or spread along th e ciliar y vesse ls and
ne rves int o the orbit, m ay occ ur in advanc ed cases (Fig. 50 .10) .
Tru e syste m ic m et ast asis m ay occ ur via the choroidal cir cul ati on
or aqueo us drainage, parti cu larly if glauc oma is present .30•3 1 Th e
bon e m arr ow is the pr eferred site for retinoblastoma m etastasis,
and only t erm inally are bon e, lym ph node , and liver involved .
Lun g m et asta ses are rare .

CLINICAL MANAGEMENT OF
RETINOBLASTOMA
:- 50.4 Glioblastoma multiforme. Arising within the radiation field, 10
~ _ after enucleation of the left eye and irradiation of the right eye for
Prese ntation
: a.eral retinoblastoma. The majo rity of child ren wit h ret ino blasto ma without a fam ily
histo ry are first noti ced because of leukocori a (Tabl e 50. 1) .32
Fig. 50.5 Endophytic Worl dwi de, pare nts have glim psed an odd appearance in th e ir
retinoblastoma. (a) The ch ild's eye, whic h de pends on th e source of illuminat ion being in
tumor has invaded the
line wit h t he viewers gaze. So, unl ess t he ped iatricia n or fam ily
vitreous and seeds can
be seen on the back of phys ician is aware of th e im portance of this sympto m and refer s
the l en~(lIRC Group E). t he child appropriate ly to a specialist, the diagnosis m ay be
(b) Calotte of de layed. The pa re nt's descripti on is usually very accura te, and
enucleated eye wit h should st im ulate full invest igat ion of the eyes but it is st ill
tumor filling the eye commo n for d iagnosis t o be delayed because the pri m ary ca re
(same patient).
ph ysician is not awa re of the impl icat ion of what th e parents are
t ellin g them . Frequently snapsho ts of th e bab y show th e white
pupil , "photoleukocoria," before eve n th e parents have noti ced it
(Fig. 50 .11) .33 In nonfamilial retinoblastoma , earlier diagno sis is
dep endent on this appea rance of th e eyes on photographs . A
sim ilar appearance ca n result from various benign cond itions
including: m yelinated nerv e fibers, opt ic nerve colobom a, high
m yopi a, congenita l cata ract , or eve n normal optic ner ves if th e
ca me ra angle is direct ed at th e normal opt ic nerve .
Th e nex t mo st com mo n prese nting sign is st rabismus (esotropia
or exo tropial.V Th e st rabismus is constant and un ilateral rath er
t han alte rnating, and vision in th e st rabismic eye is poor. All young
chi ld ren wit h a consta nt unilate ral st rabismus should have a careful
fu ndus exam ination to rule out thi s diagnosis. Other presenting
symptoms and signs (Table 50. 1) include a painful red eye from
glaucoma, and orbita l cellulitis seco nda ry to exte nsive necrosis of
t he intraocular tu mor (Figs 50 .8 and 50. 1Z), 28 un ilateral mydr iasis,
heter ochromia , hyph em a, hy po pyo n uveiti s, and "sea rching"
nystagmus (du e to blindness from bilate ral macular involvernentj.F
In countries with limited medical services, man y children present
lat e ofte n with ex t raocular and systemic extension, so th at
exte nsive unilateral or bilateral proptosis with orbital ex te nsion of
th e tumo rs is a com mo n presentation (Figs 50 .8 and 50.10) .
I I I Retinobl astoma in babies and child re n that are relat ives of
pati ents with hereditable retinobl astoma should be looked for
~ s1 2 speci fically by scre ening exa m inat ions, long before any sym pt oms 491
occ u r (Fig. 50 .1) . For most famili es, it is po ssible to det ect
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

Fig. 50.6 Unilateral endoph ytic IIRC Group E retinoblastoma. (a) With massive vitreous seeding (left); and (right) extension of tumor for 1800 inferiorly,
anterior to the ora serrata (arrow s) to lie on the pars plana. (b) Ultrasound biom icroscopy of tumor on pars plana and pars plicata of ciliary body. HaE
staining of ciliary region show ing tumor anterior to ora serrata (arrow); box corresponds to area imaged in (b). (RetCam®) images by Carmelina Trimbol i.)

Fig. 50.7 Collage of RetCam® images of the whole retina. The ora serrata is visualized for 360 0 by sclera l depress ion. (a) Left eye at diagnosis of child
with bilateral multif ocal exoph ytic IIRC Group D retinob lastoma , no family history, and a "null" RB1 mutat ion (heterozygous deletion of exons 18 to 23) in
blood . (b) Excellent regression aft er 3 of 7 cycles of CEV with cyclosporine A chemotherapy, with arrow indicating residual tumor treated by laser and
492 cryotherapy. Similar appearance of residual tumor and tented retina near the macula was not treated to optimize vision and has not changed over 1 year
off treatment. (Images and colla ge by Cynth ia Vandenhoe ven.) This child had excellent response in both IIRC Group D eyes.

:- - .8 Extraocular retinoblastoma. (a) With iris invasion, glaucoma, subconjunctival and orbital extension. (b) CT scan showing optic nerve
_ e-nent. (c) CT scan showing suprasellar and cerebral extension from optic nerve invasion .
olecularly the prec ise RB1 mutati on of t he proband, che ck th e
-d at ives for that mutation, identify t hose car rying the muta nt
lele, and di agnose and initi at e t reatmen t early when th e tumors
re st ill smal l. Suc h sma ll tum ors can often be cured by laser
: era py alone , or with sho rt cycles of chemotherapy.
Dia g nos is
'h en a child is referr ed with a po ssible diagnosi s of retino-
. lastom a, a careful hist ory and thorough ocu lar and syst em ic
exam ination m ay exclude some import ant d ifferent ial diagnoses
Table 50 .2) .32 Referr al of a ch ild with possible retinoblastoma is
considered ur gent , namely, within one week.
CHAPTER
Retinoblastoma 50
Fig. 50.9 Unilateral retinoblastoma. (a) Unilateral
retinoblastoma that presented as orbital celluliti s
(IIRC Group E, suggesti ve of extrao cular tumor).
(b) Extensive intraocular necrosis and replacement
of the opt ic nerve w ith tumor. (c) Despite therap y,
the brain was covered w ith meningeal
retinoblastoma four months later and the child
died .
Initial visit
Leukocoria (Fig. 50. 11) requires t hat a carefu l history be
obtained of the pregnancy, labor and de livery of the mo ther, and
bir th we ight and neo natal period of the child. Mat ern al illnesses
in ea rly pregnancy, premature labor and oxyge n usage in the
neo natal period may be relevant . For olde r infants, t he parents
should be asked about exposure to kittens, pu pp ies, and othe r
anima ls. A careful fam ily hist ory of any eye di sorder sho uld be
obtained . The ret inas of t he parents, t he siblings, and any ot he r
fami ly members with a history of sim ilar eye disorder sho uld also
be examined . T he discovery of a ret inoma in a relative will
significantly alter the understa nding of disease and m ana gem ent 493
of the chi ld and t he family.
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

Table 50.2 Differential diagnosis of retinoblastoma. Modified

from Shields and Augsburger (1981)

Hereditary conditions Inflammatory conditions

Norrie disease Toxocariasis
Warburg syndrome Toxoplasmosis
Autosoma l recessive retinal dysplasia Metastatic endophthalmitis
Dominant exudati ve vitreoretinopathy Viral retinitis
Juvenile X-linked retinoschisis Vitritis
Orbital cellulitis
Developmental anomalies Tumors
Persistent hyperplastic primary vitreous Astroc ytic hamartoma
Cataract Medulloepithelioma
Coloboma Choroidal hemangioma
Congenital retinal fold Combined hamartoma
Myelinated nerve fibers
High myopia
Morning glory syndrome
Others
Coats disease
Retinopath y of prematur ity
Rhegmatogenous retinal detachment
Vitreous hemorrhage
Leukemic infiltration of the iris

Examination under anesthesia (EUA)

For anterior segment exa m ination, fundus exa m inat ion, anc
im aging t o be performed com pletely, gene ral anes t hes ia is
re quire d for infants and young child re n. Th e pupils must be
w idely dilat ed and scleral depression used in orde r t o visua lize
th e w ho le retina up to the ora se rrata . A wide -angle camera, t he
RetC am ® (M assie Laborat ories, Inc.) , has becom e sta nda rd
equipment in man y retinoblast oma ce nters, since it pr ovides
excellent 130° wi de -field im aging of the ret ina and anterior
Fig. 50.10 Late diagn osed retinoblastoma. (a) With destruct ion of the segment, including the anteri or cha m be r angle (Figs 50. 1
globe and orbital extension. (b) Ulceratin g malignant occipital lymph 50 .6-5 0 .7 , 50. 13- 50. 16) . Some small retinobl ast oma tum ors
nodes in the same pati ent. .
visua lized as an alte rat ion of the pattern of th e retinal pigm en
epit he lium, are act ually m ore easily see n on RetC am ® im ages
Table 50.1 Presenting symptoms and signs of than wit h indi re ct opht halm osco py (Fig. 50 .1, 50 .1 6) .
retinoblastoma (Ellsworth 1969) C hild re n pr esenting wit h sus pected retinoblast om a m ay be
di vided into three broad grou ps:
White reflex 56%
Strabismus 20% Group 1
Glaucoma 7%
Th er e is a clea r view of the tumor.
Poor vision 5%
Routine examination 3% Endo phyt ic t umor growth gives rise to a creamy white m ass
Orbital cellulitis 3% (Figs 50 .5, 50 .6) pr ojecting int o t he vitreous wit h large irr egular
Unilateral mydriasis 2% blood vesse ls running on t he sur face and penetrating the tu m or.
Heterochromia iris 1% H em orrh age m ay be pr esent on the sur face of the tumor. Clum ps
Hyphema 1%
Other 2%
of tum or ce lls in the vit reo us ("seedin g") is pathognomonic of
re tinoblasto ma (Fig. 50.6) . Som e tum ors are sur rounde d by a
halo of prolifer ating retinal pigm ent epit he lium , sugges t ing t hat
they m ay be slow -grow ing and have a retinoma com po nent .
Calcificatio n within th e tumor ma ss is com mo n and resem bles
The initia l clin ical exa m ination of the child will pr ovid e a white, "cottage cheese" (Figs 50 .3b , 50 .7 and 50. 17) . Such tumors
sho rt -list of d ifferentia l diagnoses, and an est ima tio n of t he leave no doubt as to the diagnosis of ret inoblastoma . Less com-
extent of disease involvem ent (the st aging) if t he diagnosis is m only, re ti noblasto ma may present as an avascular white m ass in
retinobl ast oma. Im aging st udies suc h as CT scan or MRI m ay be t he pe riphe ry of the retina.
ordered pr ior t o the exa mi nation und er anesthes ia (EUA) . If
chemot herapy mi ght be indicated, a sur gery cons ulta tion for t he Group 2
co ncur re nt place ment of a ce ntral ve nous line should be arra nge d Th e t um or is poorl y seen due t o vitreous opacity or ext en sive
prior t o the first EUA. Th e whole multi di scip linary team re tinal de tachment (Fig. 50 .2a) . Th e pr esen ce of calcificatio n
(ophthalm ology, oncology, nur sing, social wo rk, cyt ogenetics) co nfir me d by ultrasonography or CT scan (Figs 50 .2b ,c,d , 50 .6 ,
sho uld be awa re of t he patient and eac h will playa role from th e 50 .8, 50. 12) , may be crit ical in esta blishing the diagnos is of
494 retinoblasto ma . Other aspects of the exa mi nat ion ma y support or
beginni ng and t hroughou t t he management of each patient.
 CHAPTER

Retinoblastoma 50

: - .11 Leukoria. (a, b, c) Unilateral leukocoria . (d) Bilateral leukocoria. (e, nRight unilateralleukocoria, more obvio us in right gaze due to the anterior
- _ c-a location of tu mor. (Images by Leslie MacKeen.)

50.12 Retinoblastoma presenting as orb ital cellulitis (IIRC Group E). (a) At referral the patient was ill but not apyrexial. The globe could not be seen
_" · 0 lid swelling, which reduced after 2 days of syste mic steroid treatment. A small noncalcified tumor was present in the left eye and a calcified
-=- blastoma was present in the right eye, (b) shown on CT scan.

c p exclude the diagnosis of ret inobl astom a. For example, Group 3

-e-inoblast om a gene rally occ urs in normal-sized eyes, whe reas
""1.icropht halm os is m or e likely to be assoc iated with 'a develop-
-nen t al abnormality. Exam inat ion of the ot her eye is very
rnpo rt ant . Th e presen ce of sma ll tu mors in th e ot he r eye con firms
- e d iagnosis of retinob last om a. D ragged retinal vessels sugges ts
-e inopat hy of prematurity. Peri ph e ral vitreoretina l cha nges
zzest a do m inant ex uda tive vitreore tinopathy.
Unusua l presenta t ions: het er ochrom ia, hypopyon (Fig. 50 .8),
uveitis or orbita l ce llulit is (Fig. 50 .12) . H er e, the diagnosis ma y
be d ifficult and specialized investigati on s are helpful , particularly
CT scan or MRI.
On ce th e diagnosis of retinoblast om a is clear, bone marrow
aspirat ion and lum bar puncture to scre en for m etast at ic disease, 495
are pe rfo rmed at the initia l EUA , es pec ially if one or both of the
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

Fig. 50.13 Unilateral retinoblastoma. (a) At diagnosis. (b) The subretinal seed (arrow) inferiorly at th e 6 o'clock posit ion places this eye in IIRC Group 0
(subreti nal seeding more than 3 mm from the tumor). (c) Response to chemotherapy (four cycles of carbo platin, etoposide, vincristine with high dose
cy closporine) and laser and cryotherapy. (d) Fluorescein angiography shows active tumor vessels in the scar, w hich were successfully ablated by 532 nm
and 810 nm laser treatments. (Images by Leslie MacKeen and Cynth ia Vandenhoeven.)

Fig . 50.14 Right eye prior to enucleation for IIRC Group E retinob lastom a.
(a) Large retinoblastoma, tota l retinal detac hment, large subret inal seeds ,
neovascular glaucoma and (b) anterior chamber seeding , arrow, visualized
496 a by RetCam® anterior segment and anterior chamber angle photography
through gel. (Images by Leslie MacKeen .)
 CHAPTER

Retinoblastoma 50

- - ·5 =reeze- thaw cryotherapy. Sequential RetCam® images of the first freeze of triple freeze-thaw cryotherap y applied to a small peripheral
- 2.5, rna after placement of a 532 nm laser barrier line to limit serous effusion.

~ 50.16 New tumor in a previously treated eye. (a) Arrow indicates no tumor8 months after initiation of CEV chemotherapy with cyclosporine for IIRC
:. _~;J 0 retinoblastoma in the right of the child whose left eye is shown in Fig. 50.7. (b) New peripheral small tumor 2 months later, 10 months after
: ;;;'1o sis. (c) Triple freeze-thaw cryotherap y for the small new tumor, encasing the tumor in ice, thawing for one minute , and refreezing. (RetCam® images
: Cynthia Vandenhoeven).

Fig. 50.17 Retinoblastoma regression following

external beam radiation . (a) Calcified "cottage
cheese" appearance. (b) Mixed , suspicious
regression, but after 4 years follow -up, no
recurrence occurred.

497
SEC-\\Ol--l
4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY
opt ic nerves are not visibl e or th er e are other adve rse risk
features (Figs 50.5, 50.8-10 and 50.14) . Th ese test s are not
necessary if t he tumors are sma ll and requi re only focal ther ap y.
Differential diagnosis
C onditions which m ay simulate reti nob lastoma are detailed in
Table 50.2. In North Am eri ca, Coa ts disease, oc ular toxocariasis,
and persist ent hyp erplasti c pr ima ry vit reo us (PH PY) are th e
three co m monest co nd it ions co nfuse d with ret inob lasto ma. 3~
Coats disease
See C hapter 55.
Coats disease is almos t always unil ater al and usuall y affec ts
boys. It may present with loss of vision and the leukocori a is
ye llowis h du e to ex uda te at th e mac ula whereas in ret ino -
blast oma it is white . Int raocular calcificat ion is rar e in C oats
disease , and ultrasonography shows a diffuse uniform increase in
opacity of the vitreous with no ma ss. Later there is an exudative
detachment with te langiect at ic vesse ls, subretinal lipid and
choleste rol crystals (Fig. 50.18). Treatment of early Coats disease
with cryo t herapy or laser coag ulat ion may arrest the disease or
result in improvement of th e retinal ex uda te 35 ,36
Ocular toxocariasis
O cul ar infl ammat ion due to t oxocan asis pr esents eit he r as
ch ronic e ndo pht ha lm itis wit h an opaque vit reo us, or a solita ry
retinal gra nuloma in an ot herwise hea lt hy child .37 Seve ra l
features help t o differ entiat e t his co ndition fro m retinobl ast om a.
Toxoca riasis m ay show m ark ed vitreous inflam ma t ion, wit h
ye llow-grey st ra nds ex te nd ing int o the vitreous fr om th e
chorioret inal lesion s. Such find ings are rare ly see n in retino-
blast om a. CT scan shows calcificatio n in ret inoblasto ma but not
in t oxocariasis. Solit ar y granulomas may resemble retinobl ast om a
but ofte n show a sm all tran slucen t ce nte r (Fig. 50.19) . If th ere-is
doubt abo ut th e diagno sis, a peri od of obse rvat ion with regular
fundus ex am inat ion m ay be indi cat ed. A positive sero logical t est
fo r t oxocaria sis is su pport ive , but not diagnosti c, since ex pos ure
to th e organ ism is com mo n.
Fig. 50.18 Coats disease presenting with leukocoria. Note yellow
appearance , not white as in retinoblastoma , total retinal detachment and
498 the characteristic aneurysmal vascular malformations in the peripheral
retina,
Fig. 50.19 Solltary
granuloma in the
macula, with a
cilioretinal arteriole.
masquerading as a
retinoblastoma,
Persistent hyperplastic primary vitreous (PHPV)
See Chapter 47 .
PHPV is congenital and is almost always unilateral. Th e affect ..
eye is mi crophthalmic and th er e is a dense retrolental mas s wh i -
m ay be vascu larized . Th e ciliary processes are often pr orn ine- :
and drawn toward s th e ce nte r of the pupil. PHPV eyes m
develop pupillar y block glauco ma, vitreous hemorrhage, ret in;
det achment or phthisis bu lbi . In on e report, an infant pr esenu r :
with unilater alleu kocoria has been found to have both PHPV ar-c
a diffuse infiltrating reti nobl ast om ar'"
Retinal dysplasia
See C hapt er 49.
Retinal dyspl asia prese nts as bilateral retrolental masse ~.
birth or soon aft erward s, unrelat ed to pr em aturity or oxygen u..
Th er e may be se rious syste mic abnorm alit ies (see C ha pter -I..
Th e re ma y be a sha llow anterior cham ber, a clea r len s, and ..
relati vely avascu lar ret ro lenta l mass wit ho ut any infl amrnat or-
signs . There is no calcificat ion on ultrasonograph y or C T scan .
Retinopathy of prematurity (ROP)
See C hapt er 51.
Advanced cicatri cial ROP ma y give rise to den se uni lat er al r
bilat er al retrolenta l masses . It is seen predominantly in ver y 10\
birth weight infants who have been exposed to oxygen . It i
seldo m mi staken for retinob lastoma .
Metastatic endophthalmitis
Metast ati c endophthalmitis results from hemat ogen ou s spread 0
infecti on from a dist ant infecti ve locu s such as meningit is
endoca rditis or intra -abdom inal sepsis. Streptococcus, Staphylococcus
and M enin gococcus are th e most com mo nly involved organisms.
The co nd ition m ay cause mark ed vit re ous op acificati on but th e
prese nce of ot her inflammat or y signs and syste m ic infect ion
usually d ist inguishes thi s co ndi tio n fro m retinoblast om ar' "
Medulloepithelioma (diktyoma)
Thi s t umor arises from th e ciliary epithelium and is always
un ilateral. It gene rally occ urs at a lat er age than ret ino blastoma.
It is locat ed anterior to the ciliary body and has a cystic
st ruc t ure.I" Th e tum or is wh ite and friabl e, some t imes with a
felt-like texture (Fig. 50.20) . Th ese tumors are best tr eated by
enuc leat ion since local excision is not usua lly success ful." A
course of medullobl ast om a-t yp e che mot herapy is recommended .
Life ex pec ta ncy is good.
Other disorders
O ccasiona lly, chronic granulomatous uveitis with a hyp opyon
 CHAPTER

Retinoblastoma 50
Fig. 50.20 visua lized on C T scan (Figs 50 .2d and 50 .Sb), but th e opt ic
Medulloepithelioma nerves can be assessed, and the pineal region ima ged . Since
(diktyoma) presenting avo idance of rad iat ion, even th e sm al1 doses incurred on C T
as a felt-like structure
arising in the ciliary sca nning, is d esirab le for child re n with RB 1 mutations, m agnetic
body and involving the re sonance im aging (MRI) m ay be p re fe rred since it provid es
iris. sim ilar informati on, and is particul arl y good for d elineating th e
ana tomy of the optic ner ve and pineal gland. However, MRI is
no t effect ive for delin eatin g calcificat ion, if the dia gnosis is in
qu esti on .V
Flu or escein angiogra phy (FA) ma y be he lpful in di stinguishin g
som e ret inobl ast om a tumors from Coats dis ea se or dominant
ex uda t ive vit reo ret ino pa t hy. Tiny early retinoblastoma tumors
are not vascu lari zed and are be st see n on color imag es. However,
flu or escei n angiograp hy ca n play an important rol e in the
man agement of retinoblast oma . The FA attachment of the
sim ulat e retinoblastoma, es pec ially if t he post eri or segm ent Ret C am g faci litat es th e follo w-up of retinoblastoma after focal
r ot be visualized . ther ap y, by help ing to detect vascularity and residua l activity
with in tumor s, and re currences within laser scars (Figs 50 .1c,
stigations 50 .13d an d 50 .2 1b) .
scan is he lpful in co nfirm ing t he diagnos is, bu t also for Two-dimen sional u ltrasound (B-scan) ma y be useful in diag-
_d ing intracra nial involvement and pi neal tum or. No t on ly is nosis of som e retinoblastoma tumors (Fig. 50 .2b, c) and in monitor-
.nt raocular ma ss and it s pathognom on ic calcificat ion well ing th e height of the tumor, but its major rol e ma y be in fo llowing
regression aft er ther ap y, particularl y wh en the tumor cannot
be dir ectl y visualized due to radiation keratopathy or cat arac t.
The 3D ultrasound can also play a role by monitoring tumor
volume.43
Ultrasou nd biomicro scop y (UBM) is the on ly wa y to detect
anterior disea se beyond the ora and in the region of the ciliary
bod y, whi ch cannot be viewed by indirect op hthalmoscopy, nor
by Ret C am® and co nvent ional ultrasonography (Fig. SO.6b) . It is
critica l to d et ect the pre sence of anterior disease. Anterior
disease is an indi cation for immediate enucleation because the
chance of salvaging the eye is sm all, but risk for syste mic
metasta sis is increased.
Sin ce th e su rvival of patients is normal if retinobla stoma
remains intraocular (96 % of cas es), but th e di sea se is ver y diffi-
cult to cu re on ce it becomes m etastatic, the biopsy of reti no-
bla stoma is strictly cont raindicate d du e to it s incurring an
increased risk for tumor sp read outside the eye . In cases of
sus pec te d retinob lastoma with anterior segment invo lvement,
when the diagno sis remains unclear d espite all investigations, an

Fig. 50.21 Bilateral retinoblastoma treatment. Bilateral retinoblastoma was treated with enucleation of the left eye and CEV chemotherapy without
cyclosporine for the right eye with II RC Group D disease . (a) Extensive recurrence with vitreous seeding. (b) No detec table active tumor 3 months after 499
our cycles of CEV chemotherapy with cyclosporine A with prechemo cryotherapy and sub-Tenon's carboplatin; fluorescein angiogram showing no tumor
vessels in the location of recurrent tumor. (RetCam®images by CynthiaVandenhoeven).
SECTION
4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY
aqueous ta p through clear cornea ma y be cautiously performe d
for a cyto logical dia gnosis. H owever, a vit reo us biop sy sho uld be
avoide d unl ess the likelihood of retinoblastoma is extreme ly
sm all because biop sy of re tinoblastoma risks extraocular spread
of tumor ."
Treatment
Th e treatment of ret inobl ast om a is bes t delivered in specialized
ce nte rs where multidi sciplinary team s have been develop ed,
special ex pe rt ise and eq uipment are available, and specific tr eat-
m ent protocols are used . Thi s cancer is m uch t oo rare for
ind ividual ophthalmologists and onco logists t o remain up -t o-d ate
and m anage eac h pati ent in an ad hoc ma nner, or to have required
the ex pe rt ise nece ssary fo r op t im izing outcomes for t he child ren
and their fam ilies. In additio n, overall outcomes will only im prove
if each affecte d child is tr eated syste matically on de fined prot ocols,
suc h that t he kn owl ed ge gained from ana lyzing t reat m ent results
can be built on for designing mo re effective future t rea tment
prot ocols.
Classification
Optimi zed care and outcome for int raoc ular reti noblastoma
dep en d on use of the th er ap y with the least mo rbidity t hat is
m ost likely t o cure the tum or. The informed selection of t he rapy
depe nds on class ification of t he d isease seve rity in a way t hat is
m eaningful for pred icting outcomes from current ther apies. Th e
Reese- Ellsworth (R~E) C lassification of the 1960s was devised
for pr edi cting prognosis when int raoc ular retin obl ast om a was
treat ed with ex te rna l beam radiotherap y. T he Int ernat ion al
Intraocul ar Retinobl ast oma C lass ification (lI RC) ha s' b een
devel op ed for p re d icting outcomes from current the rap y
(p red ominantl y che mot he rapy and foca l t he rapy, with rad iat ion
as a salvage m od alit y for rec ur rence) (Figs 50 .1, 50 .2, 50.5 - 50 .7,
50.9, 50 .12- 50 .14 , 50 .1 6 and 50. 21) .45 T he IIR C has been
validate d by correlat ing disease severity at presentati on wit h
outcomes from prima ry ther apy, and eve ntual ou tcomes after
salvage therap y, t hrou gh a two-step Inte rn et Survey that
collec ted informat ion on m or e than 100 0 affected eyes t reat ed
wo rld-wide in re t inoblastoma ce nte rs .46,47 At diag nosis, it is
valua ble t o record both the R-E and IIRC classifica tion stages for
com pa riso n wit h pr eviou s data. Current t reatment protocols m ay
also be recommended based on IIRC stag ing (Table 50 .3).
IIR C gene ral prin cipl es:
Group A: eyes wit h sma ll tum ors away from t he m acul a and
the op tic nerve are primarily treat ed wit h focal th erap y only
(Fig. 50.1).
Group B: eyes wit h med ium -sized tumor s or t umo rs at th e
m acul a and the op t ic nerve may be first shru nk wit h a sma ll
number of che mothe rapy cycles before applying foca l thera py
to op t imize the visua l potent ial (Fig. 50. 1).
Gro up C: eyes with large tu m ors wit h limited vit reo us and/or
subret inal see d ing are pr im arily tr eat ed wit h chemot he rapy
followed by foca l therap y.
Group 0: eyes wit h large tumors with ex tensive vit reous and/or
subretinal seeding are also prima rily treated with chemot herapy
and foca l th erapy (Figs 50 .2, 50 .7, 50. 13 , 50 .16 and 50. 2 1).
M ost ce nte rs, but not all, now use ex ternal beam irrad iati on only
as a salvage m od alit y for G rou ps B, C and D eyes that have failed
chemot he rapy and focal th er ap y, rather than as init ial elect ive
ther apy.
500 Group E: eyes (Figs 50 .5,50.6,50.9,50.12,50.14) wit h high-
risk features suc h as t um or to uc hing the lens, neovascular
Table 50.3 International Intraocular Retinoblastoma
Classification
Group A
Small intraretinal tumors away from foveola and disc
All tumors 3 mm or smaller in greatest dimension , confined to the retina and
All tumors located further than 3 mm from the foveola and 1.5 mm from the
optic disc
Group B
All remaining discrete tumors confined to the retina
All tumors confined to the retina not in Group A
Any tumor-associated subretina l fluid less than 3 mm from the tumor with
no subretinal seeding
Group C
Discrete local disease with minimal subretinal or vitreous seeding
Tumor(s) discrete
Subretinal fluid , present or past, without seeding, involving up to 1/4 retina
Local subretinal seeding, present or past, less than 3 mm (2 DO) from the
tumo r
Local fine vitreous seeding close to discrete tumor
Group 0
Diffuse disease with significant vitreous or subretinal seeding
Tumor(s) may be massive or diffuse
Subretinal fluid, present or past, without seeding, involving up to total retinal
detachment
Diffuse subretinal seeding, present or past, may include subretinal plaques
or tumor nodules
Diffuse or massive vitreous disease may include "greasy" seeds or
avascular tumor masses
Group E
Presence of anyone or more of these poor prognosis features
Tumor touching the lens
Neovascular glaucoma
Tumor anterior to anterior vitreous face involving ciliary body or anterior
segment
Diffuse infiltrating retinoblastoma
Opaque media from hemorrhage
Tumor necrosis with aseptic orbital cellulitis
Phthisis bulbi
glauco ma, orbita l ce llulit is (Figs. 50.9 and 50 .12), ant er ior
segme nt , anterior cham be r (Fig. 50 .14), iris or ciliary invol ve-
m ent (Fig. 50 .6) , tot al hyph em a, sus pec te d cho roid, optic
ne rve or orbita l involvem ent (Fig. 50 .8) on ult rasonography,
MRI and CT scans, are enucleated.
Enucleetion
Initi al enucleat ion is indicat ed fo r all Group E eyes since a tri al
of che mothe rapy pri or t o enucleat ion ma y cre ate a se nse of false
security by obsc uring those adve rse fact or s that puts th e child 's
life at risk. Suc h adve rse risk fact ors may be indi cati on s for
fur t he r int en sive t he rapy suc h as bon e m arr ow or peripher al stem
cel l t ransplanta t ion. Enucle at ion is an excellent way to cure
ret ino blasto ma that is confine d t o the eye, such as in the case of
unilat er al retinobl ast oma at diagno sis, or whe n th e ot he r eye is
Group A fo r which che mo t he rapy is not ne cessary. Th en the
G rou p C or D fellow eye m ay be enucle ate d to avoid eve r giving
t he child chemot hera py. Enucleation is also indicated for
recur rent tumor that has failed all ot he r tr eatment m od aliti es.
It is rar e now for both eyes t o be primaril y enuclea te d, except
if bo t h eyes are Group E, since at tem pts t o save suc h severely
invo lved Group E eyes ma y put the child's life in jeopardy from
possible d evel opment of d iffi cult-t o-tre at , po or -pr ogn osis
syste mic m etast asis. H owever, some G rou p E eyes can be cure d,
but very little vision is usua lly retain ed in suc h a seve re ly
dam aged eye . Addit io na lly, chemot he rapy h as short -term

id ity, and radiation , significant long-t er m complications , and
~- t herapy ma y not in the best int er est of a child wit h bilateral
p E eyes.
z. te ral retinoblast om a m ost commonly present s with one eye
,~ tu m or, wit h sma ller tumors in th e fe llow eye . If bot h eyes
re chem ot herapy for Groups B, C or D d isease, t he n ne ither
needs to be enucle ated pr imarily (Figs 50 .7 and 50. 16).
=- cleat ion sho uld b e perfor m ed wit h a m inimum of
- pu lat ion of the globe, wit h grea t care not to sp ill tumor
• ert entl y. A long optic ner ve (8- 12 mm) sho uld be obtaine d
rder to ensure th at the surgical ma rgin is t umor-free . For
_..eat ion in unilaterally affec te d children, t he t umo r is very
- rt ant for RB1 mutat ion st udies, in order to de ter mi ne
: ~ er t he child has her it able or nonhe rita ble ret inobl ast om a
7 ,, _ ~ 0.2e and 50 .22) . An orbita l implant is placed within t he
cle cone, with th e mu scles su tured onto t he implant to
em its subseq uent m igrati on out of t he muscle cone .
- ants of porou s m at eri al such as hydroxyapatite or ceramic
- allow vascularizat ion will give a better long-t er m cosmetic
- -::: . The attachment of the muscles onto t he implant will
co nsensual m ovem ent of t he artificial eye with t he re ta ined
'\- eye. A confo rme r is placed under t he eye lids . 'vVe use a
ole pr ost het ic eye, so t hat when the patch is removed 48
rs lat er, th e child will look good and d oes not nee d t o
-:inue to wea r an eye -patc h'" (Fig. 50 .2f) . Th is prelim inary
- ~cia l eye may not fit pe rfec tly, but will allow healing t o be
let ed over seve ral mont hs be fore a final artificial eye is
de.
:: riemotherep v
ste rnic che mo t he rapy has becom e t he sta ndard pr ima ry
--- ~: :ne n t for IIRC Groups B, C and D . Following an initi al
_ nse to the first few cycle s of chemot hera py, foca l t herapy
tn cry ot herapy or laser ther apy is initiate d to d estr oy res id ual
- ec urr ent t umor" (Figs 50. 1, 50 .15 and 50 .16). C hemo-
- er apy is be st given on a rigorou s protocol, id eally pa rt of a
arch st udy. Th e m ost commo nly use d chemot herapy drugs
- .. de carboplatin, eto poside and vincr ist ine (CEV) given every
= -eeks through a centra l venous access line.50 H owever, different
-e-ino blast om a cent ers have admi nistered the che mo t he ra py
__ing a variat ion of th e CE V protocol.
Th e Toronto pr ot ocol sugges t s th at t he add ition of short 3-hour
-:usions of high-dose cyclosporine A enhances the effect ivene ss
: t he chemo t hera py by bl ocking t he P-glycop ro t ein that
ediates mu lt idrug res istance by act ing as a plasm a me m brane
rug -efflu x pump , w hic h is co mmonly ove r-expressed in
re ti noblast om a tumors.I ' Cyc lospo rine may also act through th e
- rc u mvent ion of ot her non -P-glycopr ot e in d rug resista nce
mec hanism s. such as by the reducti on of carboplat in inducti on of
expression of c-fos or c-myc oncoge ne, 52,53 or genes required for
repair of dr ug-induced DNA d am age .54 Furtherm ore, in vitro
'::.1: 2 suggest that cyclosporine might augment the efficacy of
eto poside even in nonresista nt tu m or cells, by mo du lating another
und efined non- mult idrug resistance rne chan isrn .P Laboratory
stu dies suggest t hat cyclosporine levels up to 5000 ng/ml do not
t lock t he function of ano t her prot ein t hat me diate s mu ltid rug
resist ance, MRp, w hich we have identi fied in relapsed
ret inoblastom a tu m ors.56,57 H owever, it is not known if the really
high cyclosporine pe ak levels of > 20 000 ng/ m l t hat we have
achieved in our pro tocol m ight be capa ble of inh ibiting MRP.
O n the Toron to prot ocol, G roups C and D eyes are treate d
wit h seven cycles of CEV chemotherapy modulated with high-
dos e cyclosporine, and Group B eye s with four cycles . Since
CHAPTER
Retinoblastoma 50
1991 , even wit h standard-dose C EV/ high-d ose cyc los po rine,
fo llowed by foca l cryot he rapy and laser therapy, our 6-yea r cure
rates (avoi dance of bo t h e nuclea t io n and ex te rna l b eam
rad iation) are excellent for Groups B and C eyes, and we have
not see n a significant increase in the t oxicit y of che mo t he ra py
given with high-dose cyclos po rine. With the ad dit ion of high-
dose cyclosporine , long-t erm results are better th an pr eviou s
published resul ts with che mo t he rapy, rad iot herapy, and eve n
chemotherapy plus radi otherapy. Furthermor e, the Tor onto
protocol has successfully salvaged eyes that have already failed
previous che mo thera py and/o r radi otherapy. The current Tor onto
prot ocol uses higher ca rbo plat in and eto pos ide dosages with
st and ard d ose vincrist ine, wit h high-dose cyclosporine, and
cyto kine granulocyte- st imulat ing fact or (N eupogen) sup port of
th e m yeloid b on e m arr ow. Preliminar y results show goo d
avoida nce of both enuclea t ion and ex te rna l beam radiation for
many G roup D eyes (Figs 50 .2, 50 .7 , 50. 13, 50. 16, 50 .2 1) 58,59
Local rec ur re nce is ex pected approxima te ly 2- 6 m onths aft er
finishing t he chemo t he rapy, w hich ca n often be cont rolled by
foca l therap y given whe n recurren ce first appe ars (Fig. 50 .16).
T his re quires vigilant EUAs wit h appropriat e focal therapy eve ry
4- 6 weeks for at least one yea r afte r any sign of active tumor.
Short -term side effec ts of che mot he rapy that are eas ily
ma naged wit h pr esent da y onco logical sup po rt ive th er ap y include
mye losup press ion (am eliorated by ad m inist rat ion of the cyto kine
gra nu locy te -st im ulat ing fact or, Ne upogen) wit h requirem ent for
hospital ad m issions for fever-and-neutrop en ia or infecti on s, low
platelet cou nt s requiring platelet transfu sion s, ane mi a requiring
blood t ransfu sion s, nausea and vomit ing pr evented by pot ent
an t ie metic dru gs, and hair loss w hic h gro ws ba ck afte r
completion of chemot hera py. We have found that th e addition of
high-d ose cyclosporine does not significantly increase the t oxicit y
du e to che mo t hera py. Unlike radi ati on , no long-t erm cosmetic
deform it y of the -orbit and upper face res ults fro m che mo t herapy,
and no rad iat ion-induced cata racts and ocular complicat ions .
Although che mo t he rapy was undertaken in order to avoid t he
known and large risk of inducti on of seco nd primary t umor by
rad iat ion, (esti ma ted to be as high a 5 1% risk at 50-year follow -
u p60) , we recom m end t he caut ious use of che m ot he ra py,
part icularly etoposide, w hich carries a sm all risk of induction of
a specific typ e of acute m yelogen ou s leu kemia with 11 q23 or
2 1q22 translocat io ns or m yel odysplast ic sy nd ro me . Th e
cumulative d osage of eto pos ide used for treat ing retinoblast om a
is less t ha n the higher dosages that have been esti mate d t o carry
a 2-3% risk of ind uci ng leu kemi a, generally in the 1-2 yea rs aft er
co mplet ion of etopos ide chemot herapy.'" Ad equat e follow -u p on
ret inoblasto ma child re n is not yet available t o pr ovide evidence
of t he precise risk . Furthermore, the leukemi a-inducti on risk m ay
be increased by the co ncur re nt usage of carbo plat in chemo-
t he rapy, and in the case of relap sed patients, t he subse que nt u se
of salvage radiat ion or ant h racy cline (d oxorubicin) and alky lat ing
agen ts [ifosphamide, cyclo phos phamide ) salvage che mo t he rapy.
We have also sho wn t hat increased intraocul ar concent rat ions
of the chemo t he rapy dr ugs (e.g. car boplatin) m ay be induced in
eyes wit h vit reo us see d ing by the applicat ion of a single-freeze
cryothe rapy ("prec he mo cryo t herapy") at the peripher al ret ina in
t he vicinity of the see ds 6 2 Th e co ncurre nt usage of high-d ose
cyclosporine appa re ntly can furt he r increase the intraocul ar
concentrations of che mo t he rapyf ' possibly by inhibiting t he P-
glycoprotein expressed in the blood- eye bar rier. Local chemo-
the rapy wit h instillati on of carboplat in into Ten on 's space m ay be
use d to achieve incr eased vit reo us co nce nt rat ion of carboplatin .v' 501
to accentuate the levels attaine d by syste mic car bo plati n therap y.
SECTION

4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY

Fig. 50.22 Harvest of fresh tumor for determinat ion of the RBt mutant alleles in unilateral tumor. (a) Optic nerve (8-12 mm) is excised from the globe and
the distal end marked with a suture. The nerve is subm itted as a separate specimen in a separate formalin container so that it is not contaminated by
tumor from the opened eye. (b) Optic nerve just beyond the cribriform plate appears normal on gross inspection , to be confirmed microscopically.
(c) Globe is opened with a razor incision in a pup illary-opti c nerve plane, superior or inferior, at the limbus , in order to access intraocu lar live tumor.
(d) Superior or inferior callott e allows harvest of large amount of intraocular tumor for adequate molecular studies. Optic nerve and choroid are not
interfered with, since these are imp ortant for patholo gical assessment for risk of extraocular spread . Tumor for molecular studies is sent to the lab in
sterile tissue culture medium . The RBt mutations (M1 and M2) in this unilateral tumor were a heterozygous exon 14 CGA to TGA (R445X) and a
heterozygous intron 16 G to A (cDNA 1498+5) causing a splice mutation. Neither M1 or M2 were detected in blood of the child. (Images by Cynthia
Vandenhoeven.)

However, sub -Tenon's carboplatin instillat ion sho uld be used only
for certain we ll-defined indications because of t he local toxicity,
including orbi tal fat necrosis t hat ma y limi t ocular m otil ity and
ca use enophthalmos, and fibrosis that may com plicate any
su bsequent eye enucleation.?"
recur rent tumors. Wh en su periorly placed , moderatel y sized tumors
must be t reat ed wit h cryot he rapy, a laser barri er placed po st erior
to t he tumor m ay protect the ret ina from detachment by the
serous ex udate of the acute freeze (Fig. 50 .18) .

Cryotherapy
Cryotherapy is used for sma ll anteriorly placed tumors (lIR C
Groups A and B eyes), or mo re posterior tu mors when visual dam age
will not result. i" Since the tumor cells are killed when t hey t haw, a
tr iple freeze -thaw technique is used, wit h care to allow a full minute
for t haw ing bet ween the successive freeze s (Figs 50 .15 and 50. 16) .
C ryotherapy almost always has to be repeated at several EUAs 4-6
502 weeks apart, until no residua l active tumor remains. Cryot herapy
may be use d eit her as a prima ry proc edure or to t reat residua l or
Laser
Laser coagulat ion is used for sm all tumor s (G roups A and B eyes)
(Fig. 50 .1) , for tumors that have been initially sh ru nk by che m o-
t herapy, or for rec urre nces follow ing che mo t herapy. Traditionall y
sma ll tumors (Grou p A eyes ) behind the equat or are tr eated by
enc ircl ing the tumor wit h a d ouble row of co ntiguous laser burns.
Th e sma ll avascular tumor can th en be dir ectly coagulate d,
sta rting with pow er/durati on settings th at barely blanch or
opacify th e tumor, and gradua lly increasing t he po wer t o m ake
the t u mor turn opaque white . Larger or visua lly threatening

- r (G rou ps B and C eyes) are treated first with chemo-
y while re sidual d isease and recurrent t um ors after
- -;-ing che mo t hera py are treat ed with laser coagulatio n. For
p 0 eyes, laser is used only after a good response has occurred
- - hemot herapy, t o elimi nate any residual or recurrent t umor
- re it has a chanc e t o regrow (Fig. 50 .7). The diod e 810 nm
is mos t Widely available and is th e cheapest. 'Therm ot herapy'
- ~ t he 8 10 nm laser has been promoted, us ing t he laser to
: y hea t tumor over a long period of ti me. H owever, this
-nique offe rs no special ben efit for t umor ce ll-kill, and resu lts
. igh fre quency of ed ge recurren ce and produces scars th at
te d gradually over time. 66 ,67 For sma ll G rou p A tumors, gree n
(argon or frequ en cy-d oubled YAG at 532 nm ) are used
tively without drifting of the scars . Infrared laser s (d iod e
nm or 1064 nm YAG) can be ap plied afte r chem ot he ra py to
zer, thic ke r tumors . With all laser s, it is important to NOT use
much power at anyone treatment, and to expect to re-treat
- -re quent intervals until only flat sca rs remain . Fluorescein
graphy is useful for catc hing pot ential sp ots of recurren ces
_ aser scar early (Figs 50 .1c, 50.13d and 50.21 b).
al irradiation
ta ry tumor s less than 15 mm in d iame ter which are not
ent t o the disc or m acul a may be tr eat ed with an episcleral
- act ive piaque, I25 iodine or rutheni um .P'' Plaqu es are also use-
- .or treat ing single re curren ces after chemot he ra py or ex terna l
m irra d iat ion where a seco nd course of radia tion t o t he wh ole
would be prohibited because it will lead to severe rad iat ion
--: nopat hy or optic neurop athy. U nder general anes t hes ia, th e
. or is localized and the plaque is sut ured t o the scle ra and left
- l tll u nt il the pr escribed d ose of rad iation has been d elivered
: . e apex of the tumor.
= ernal beam irradiation
to rically radiation was the first ap proac h to curing intraocul ar
- :inoblastoma, re sulting in saving m an y eyes with useful vision ,
- t wit h severe side-effects. Mo st co m mo nly, there is significant
ificat ion ("cottage cheese-like" ) or a com binat ion of calcifi-
' ion and translucent residual tumor afte r radiation (Fig. 50.17) .
' ost im port antl y, the risk of sec ond primary tumors within the
iat ion field in children with a germ line RB1 mutati on is ver y
"ni ficant , and most children died of th ese second tumors 24,69
Fig. 50 .4). The risk ma y be grea test with infants that are
rra d iated under one yea r of age .23 Addition al com plicat ions of
xternal irradiation, whi ch are not a pr oblem with che mot he rapy,
lud e cosme tic deformity du e to growt h reta rdat ion of the orbit
verse th e younger the child is at th e ti me of irradiat ion) , cataract
red uced by len s-sparin g rad iation portals), reduced tear ing
e r r ect iveness, and d ry-eye synd romes. In add itio n, recurren ces
~ llowing irradiation was co mmonly seen with large tumors and
.it reous seeding (R-E Group IV, Va and b, IIRC Grou ps C and D) .
External beam radiother ap y is now mos tly used fo r treatment
f pos tc he mo t hera py recurren ces that are t oo large or ex tensive
for foca l ther ap y, or unresp on sive t o foca l therapy. Focu sed
rad iat ion suc h as stereotac tic rad iat ion may avoid rad iation of
adjacent ti ssues for treatment of localized disease. H ow ever,
whole eye radiation ma y be the on ly choice in che mo res ista nt
ret inoblastoma with ex te nsive vitreous or subretinal se eding.
A t ot al d ose of 3500-4000 cGy has been tradition ally given for
pri m ary or seco ndary irr adi ati on of eyes wit h retinoblast om a, in
d ivide d fra ctions over a 3-4 week peri od .i" A temporal portal
exclud ing the len s is used wh en ever possible to avoid a radiation-
CHAPTER
Retinoblastoma 50
induced ca taract. i! but wh en it is import ant t o irradi at e the ora
serrata , or when vitreous seeds are pr esent, an anterior approac h
must be used de spit e th e certainty of cata rac t induct ion. Cornea l
damage ca n be reduced by irradiati ng with the eye lid ope ne d
wit h a speculum, to move th e increased ent ry d ose 5 mm below
surface, dee per into t he eye .
Extraocular retinoblastoma
Ext raocular retinoblast om a result s in a precrpitous d rop in th e
prognosis for life. U ntil recently, meta stat ic retinoblast om a was
co nsidered fata l. Local orbita l recu rrence is generally tr eated with
4000-5000 cGy orbita l radiation and systemic che mo t herapy.
Met astat ic retinoblasto ma to bone marrow or other sites may be
t reated with int ensive chemo t herapy with cyclosporine to counte r
multidrug resistan ce, and if remis sion is attained, aut ologous or
allogeneic bone marrow or peripheral stem cell transplantat ion is
performed . Meningeal spread of retinoblastoma is treated with
the addition of intrathecal and intraventricular chemotherapy via an
Omma ya re servoir. Lon g-t erm follow-up in these patients
suggests that su ch approac hes may be curat ive. 72
Prophylactic radiation is co nside re d when histopathological
exa m inat ion of the enuclea te d globe with optic ner ve sho ws
invo lveme nt of the cut end of the opt ic nerve. When mark ed
choroida l invasion and involvem ent of the optic ner ve past t he
cribriform plat e are not ed on hist op athology, ex tra ther ap y m ay
be advised to treat sprea d of tumor beyond th e eye. H ow ever,
lesser involveme nt of the o ptic nerve m ay be m an aged
adequately by close follow-up w ith regular MRI , bon e marrow
and ce re bros pinal flu id exa mi natio ns, applying treatment only
whe n disease is d ocumented . Otherwise, m an y child re n may be
treat ed u nnecessa rily. Eviden ce t o su pport these treatment
recommendations is pending a multicenter trial of pr ophylact ic
treatment for adve rse hist ology.
LONG-TERM FOLLOW-UP
Following the initial m anagem ent and resolution of act ive tumor,
assess me nt of the response to tr eatment will require frequent
gene ral anest hesia, especially in the first year following diagnosis
with com plet ion of chemot he ra py, when recurrence or new
tumors are mo st likel y to occur. Regular EUAs will be nec essary
until the child is old enough t o co-operate for a full -dil at ed eye
exa m inat ion in the clini c, variably at about 3 years of age . Follow,
up can th en be continue d on an out patient basis. However, children
with Groups C and 0 eyes may need a much longer follow -up
wit h EUA in orde r t o assess ade quate ly peripheral tumor s fo r
rec ur re nce. Like wise, pati ents who have be en treat ed with
chemot herapy and/or radi ati on will require onco logical follow-up
for ea rly detecti on and appropriate ma nage m ent of possible lon g-
term co m plicat ions of thei r prev ious ther ap y. It is part icul arly
im po rtant for ret inoblasto ma pati ents t o retain co ntac t wit h th eir
onco logist becau se of the risk of seconda ry mal ignancies, w he t he r
spo radic or induced by rad iati on or che m ot hera py. In long-t erm
follow-up, it is also important t o e nsur e that acc ura te gene tic
co unse ling is availabl e t o the parents, and to the child whe n he or
she reach es maturity.
PROGNOSIS
With modern m ethods of dia gno sis and treatment th e pro gno sis 503
for retinoblastoma is exce lle nt. Th e 3-year surv ival for both
SECTION
4 SYSTEMATIC PEDIATRIC OPHTHALMOLOGY
unilateral and bilateral retinoblast o m a ap p roac hes 96%. I In fact,
more patients with ge rm line RB1 m utat io ns d ie of the ir secon d
tum or than fro m uncontroll ed retinobl ast orn a.i''
The prognosis for vis io n is excelle nt in unilate ral r etino-
bl astoma, but depends o n the size and locati on o f the tumors in
bilat er al case s. Overall treatment w it h chemot hera py an d focal
the r ap y h as improved re sults such th at bil ateral e nu cleat io n is
now rare . Extra-foveal tumors h ave a goo d visual progn o sis but
w hen the m acular region is directly invo lved, the visual re sult
REFERENCES
I . Sande rs BM, Draper G J, Kingst on JE. Retinob lasto ma in G reat
Britain 1969- 80: incide nce, t reatment, and su rvival. Br J O pht halmo l
1988; 72: 576-83.
2. Ca venee WK, Dr yja Tp, Phillips RA, et al. Expression of recess ive
alleles by chromoso ma l mechanisms in ret inoblast om a. Nature 1983;
305 : 779-8 4.
3. Knud son AG. Mu tation and cancer: statis tica l study of retin o-
blastoma. Proc Nat! Acad Sci USA 1971; 68: 820-23.
4 . Co mings DE . A general th eory of carc inogenesis. Proc Natl Acad Sci
USA 1973; 70: 33 24-8.
5. Friend SH , Bern ard s R, Rogelj S, et al. A hum an D NA segme nt wit h
pr operties of the gene that predisposes to reti noblast om a and
osteo sarcom a. Na ture 1986; 323 : 643-6.
b. Jay M, Cowell J , Hungerford J . Regist er of re t inob lasto ma :
prel iminary result s. Eye 1988; 2: 102- 5.
7. Godbout R, Dr yja Tp, Squi re J, et al. Somatic inact ivat ion of genes
on chromoso me 13 is a com mon eve nt in retin oblast om a. Nat ure
1983; 304: 451-3 .
8. Richter S, Vandeza nde K, Che n N, et al. Sensitive and efficient
det ection of RBI Gene mutat ions en hances care for families wit h
retinoblastoma . Am J Hum Genet 2003 ; 72 : 253-69 .
9. DiCiommo D , G allie BL, Bremner R. Retin oblast om a: th e disease,
gene and prot ein pr ovide critica l leads to und erstand cancer. Semin
Ca ncer BioI 2000; 10: 255- 69 .
10 . Phillip s RA, Gill RM, Zackse nhaus E, et al. Wh y don 't germ line
mutation s in RBI predispose to leuk emi a) [Review] . C urr Top
Microbi ol Imm un ol 1992; 182: 485- 91.
II. Wu L, de Bruin A, Saaved ra HI , et al. Extr a-emb ryonic function of
Rb is esse nt ial for embryonic deve lopme nt and viability. Nature
2003 ; 421 : 942-7.
12. Zac ksenhaus E, Jiang Z, C hung D, et al. p Rb cont rols pr oliferati on,
different iat ion, and dea t h of skele ta l mu scle cells and ot her lineages
dur ing'embryogenesis. G enes D ev 1996; 10 : 305 1-64.
13. Ga llie BL, Ca m pbe ll C, Devlin H , et al. Development al basis of
ret inal-spec ific indu ct ion of cancer by RB mu tat ion . Cancer Res
1999; 59: 173I s- 35s.
14. Chen D, Pajovic S, Du cket t A, et aJ. Genomic amp lification in
retinoblasto ma narrowed to 0.6 megabase on chro moso me 6p
containing a kinesin-like gene, RBKIN. Ca nce r Res 2002; 62 :
96 7-71.
15. Mu sare lla MA, Ga llie BL. A simplified scheme for genetic counse ling
in retinoblastoma. J Pedi atr O pht halrnol Stra bismus 198 7; 24 :
124- 5.
16. Noorani H Z, Khan H N , Ga llie BL, et al. Cost com par ison of mol-
ec ular versus co nvent iona l screening of relat ives at risk for
retin ~blastoma [see com me nts ]. Am J Hum Genet 1996; 59 : 301-7 .
17. Abram son DH, G reenfield DS, Ellswort h RM. Bilateral retinoblasto ma.
Co rre lations betwee n age at diagnosis and tim e course for new
intraocular tumors. Opht halm ic Paediatr Genet 1992; 13: ] -7 .
18. Lohmann D, Ga llie BL. Ret inoblast om a: revisiting the mo del proto -
t ype of inh erited cancer. Am J Med Genet (in press) .
19 . Bremner R, Du D C , Co nnolly-Wilson MJ, et aJ. Delet ion of RB exo ns
24 and 25 causes low-penet rance retino blastoma . Am J Hu m Genet
1997; 61: 556-70.
20. Sakai T, O hta ni N, McG ee T L, et al. Oncogenic germ-line mu tations
in SpI and ATF sites in th e hu m an retinoblasto ma gene. Nature
1991 ; 353: 83-86.
504 2 I. Klutz M, Brockma nn D , Loh mann DR. A paren t-of-origin effect in
two families wit h ret inoblastoma is associated with a distinct splice
m ay b e p oor, despite tumor co nt rol. The mo st important im p ac:
o n fu rther improvin g visual outcome for r etinoblastoma child rer
lie s in the e ar lier re cognition of the pre senting sign s b y t he
primar y ca re give rs. This requires e nha nc ed awareness and u nd er-
stand ing that retinoblast oma does exi st , and enhanced recept ive-
nes s t o parental com p laints, w it h a solid op h t h alm ological an.:
o ncolog ica l network for urgent referral to fa cilitate diagnosis an.:
ap p ropriate tre atm ent as earl y as possibl e .
muta t ion in th e RBI gene. Am J Hum Genet 2002; 71: 174- 9.
22 . Ga llie BL, Ellswort h RM, Abra mso n DH, et al. Retin om a: spon-
taneous regression of ret inoblasto ma or beni gn manife station of t he
muta t ion) Br J Ca ncer 1982; 45: 513-2 1.
23. Abramso n DH , Frank C M. Second nonocular tumo rs in survivors 0 -
b ilateral ret inoblastoma: a possible age effect on rad iat ion-relatec
risk [see com me nts ] . O phthalm ology 1998; 105: 573-9; discussion
579-80 .
24 . Eng C, Li FP, Abramson DH , et al. Mortality from seco nd tu mor
amo ng long-t erm survivors of retinoblastom a. J Na t! Ca ncer Ins:
1993; 85: 1121 - 8.
25. Kivela T. Trilateral ret inoblasto ma: a met a-analysis of her ed itar-
ret inobl ast om a associat ed wit h pr ima ry ec to pic intracranial
ret inoblasto ma. J C lin On col 1999; 17: 182 9- 37.
26 . Kingst on JE, Plowman PN, Hungerford JL. Ectopic intr acranial
retino blasto ma in child hood. Br J Ophthalmol 1985; 69: 742-8.
27. Tso MO . C lues t o th e cells of origin in retin oblastoma . In:
O phthalrnol C lin 1980; 20 : 191- 21 I.
28 . Valverde K, Pand ya J, Heon E, et al. Retin oblastom a wit h centra:
reti nal artery thromb osis th at mimi cs ex t raocu lar disease . Med
Pedi atr On col 2002; 38 : 277-9 .
29 . Bhatnagar R, Vine AK. D iffu se infiltratin g retinobl ast oma.
Ophthalmology 1991; 98: 16 57- 6l.
30 . Messm er Ep, H einrich 1; Ho ppin g W, et al. Risk factor s for
m et asta ses in pat ients wit h retin oblast om a. Ophthalmology 1991;
98 : 136-4 I.
3 1. Shield s C L, Shields JA, Baez KA, et al. C horoidal invasion of
ret inoblast om a: met ast at ic potenti al and clinical risk fact ors [see
comme nts ]. Br J Ophthalrnol 1993; 77: 544-8.
32. Ellswort h RM. T he pr act ical m anagement of reti noblast om a. Trans
Am O phthalm ol Soc 1969; 67: 462- 534 .
33. MacKeen LD , Pant on RL, H eon E, et al. In: Th e 14th Internat ional
Sym pos ium for Genetic Eye Diseases (l SG ED) and II th Th e
Intern ational Sympos ium on Retin oblastoma (ISR), Paris, France,
2003.
34. Shield s JA, Parsons HM, Shields C L, et al. Lesions simulat ing
retin oblast om a. J Pediatr Ophthalm ol St rabismus 199 1; 28: 338-40 .
35 . Budning AS, H eon E, G allie BL. Visual prognosis of Co ats ' disease. J
AAPO S 1998; 2: 356 -9.
36. Ridley ME , Shields JA, Brown GC, et al. Coa ts' disease: evaluat ion
of man ageme nt. O pht halmo logy 1982; 89 : 1381- 7.
37. Zyg u lska- Mac h H, Kru kar-Bast er K, Z iobrows ki S. O cul ar
toxocar iasis in child ren and yout h . Doc Ophthalrnol 1993; 84:
14 5- 54.
38. Liang Jc, Augsburger JJ, Shields JA. Diffu se Infiltrating retino-
blastoma associate d with persist ent primary vitreo us. J Pedi at r
O phthalm ol St rabismus 1985; 22 : 3 1-3.
39 . Shie lds JA, Shield s C L, Parsons HM . Differential diagnosis of
ret inoblastom a. Ret ina 1991; II: 232-43 .
40. Brought on WL, Zimmerma n LE. A clinicopathologic study of 56
Cases of int raocu lar me dulloep it heliomas . Am J Ophth alm ol 1978;
85: 40 7-1 8.
41 . Can ning C R, McC artn ey AC, Hungerford J . Medull oepithelioma
(diktyom a) . Br J O phth alm ol1 988; 72: 764-7 .
42. Schueler AO, H osten N, Bechrakis NE, et al. High resolut ion magnet ic
reso nance imaging of ret inoblasto ma. Br J Opht halmo l 200 3; 87 :
330 -5.
43. Finger PT, Khoobehi A, Ponce-Contreras MR, et al. Three dimen-
siona l ultrasound of retin obl ast om a: initial ex pe rience . Br J
O pht halmo l 20 02; 86 : 1136- 8.