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Retinoblastoma Summary

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					Retinoblastoma
ID: 1055
Type: Monograph Standard [en-gb]

Topic Synonyms
  •   Retinoblastoma
  •   Glioma retina
  •   Glioma retinae
  •   Retinal glioblastoma
  •   Retinal glioma
  •   Retinal neuroblastoma
  •   Retinal tumor
  •   Retinal tumour
  •   RB
  •   REBL
  •   Rb
  •   RTB
  •   Rbl

Related Topics
  •   Assessment of vision loss
  •   Cataracts
  •   Tuberous sclerosis complex

Categories
  •   Oncology
  •   Ophthalmology
  •   Paediatrics and adolescent medicine

Summary
Key Highlights
  •   Most common intraocular malignancy in children.
  •   90% of all retinoblastoma cases are diagnosed by 3 years of age.
  •   Disease can be unilateral or bilateral.
  •   Most common presenting sign is leukocoria (white papillary reflex), which can often be seen in
      photographs.
  •   In 30% to 40% of cases, the disease is associated with a germline mutation in the RB1 gene, which
      carries an associated increased risk of secondary non-ocular tumours.
  •   10-year survival is 95% to 99% in resource-rich countries. Patients in resource-poor countries typically
      present with extraocular extension or metastatic disease with a dismal prognosis.
  •   Treatment typically involves systemic chemotherapy plus focal therapy with laser or cryotherapy.
      Enucleation may be required.

 History and              Tests              Treatment Options
 Exam,                     1st Tests To        Acute
                           Order




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Diagnostic                •   funduscopy     •   with vitreous seeding
                              and                  •
Factors                       examination          • with gross anterior chamber involvement or
 Key Diagnostic               under                    neovascular glaucoma or orbital inflammation
 Factors                      anaesthesia                 • enucleation
                          •   ophthalmic           • with gross anterior chamber involvement or
   •   age under 3
                              A- and                   neovascular glaucoma or orbital inflammation
       years
                              B-scan                      • postoperative systemic chemotherapy
   •   positive family
                              ultrasound           • without gross anterior chamber involvement or
       history
                                                       neovascular glaucoma or orbital inflammation
   •   leukocoria        Other Tests                      • systemic chemotherapy
       (white            to Consider               • without gross anterior chamber involvement or
       pupillary
                          •   molecular                neovascular glaucoma or orbital inflammation
       reflex)
                              testing                     • concurrent laser ablation or cryotherapy
   •   strabismus
                          •   MRI                  • without gross anterior chamber involvement or
   •   pseudo-orbital
                                                       neovascular glaucoma or orbital inflammation
       cellulitis
                                                          • external beam radiation or brachytherapy
   •   13q
                                                   • without gross anterior chamber involvement or
       syndrome
                                                       neovascular glaucoma or orbital inflammation
 Other Diagnostic                                         • periocular carboplatin therapy
 Factors                                           • without gross anterior chamber involvement or
                                                       neovascular glaucoma or orbital inflammation
   •   pinealoma
                                                          • enucleation
                                             •   without vitreous seeding
                                                   •
                                                   • tumour greater than 2 disc diameters in size
                                                          • systemic chemotherapy
                                                   • tumour greater than 2 disc diameters in size
                                                          • concurrent laser ablation or cryotherapy
                                                   • tumour greater than 2 disc diameters in size
                                                          • external beam radiation or brachytherapy
                                                   • tumour greater than 2 disc diameters in size
                                                          • periocular carboplatin therapy
                                                   • tumour greater than 2 disc diameters in size
                                                          • enucleation
                                                   • tumour 2 disc diameters or less in size
                                                          • focal laser ablation alone
                                                   • tumour 2 disc diameters or less in size
                                                          • systemic chemotherapy
                                                   • tumour 2 disc diameters or less in size
                                                          • concurrent laser ablation or cryotherapy
                                                   • tumour 2 disc diameters or less in size
                                                          • external beam radiation or brachytherapy
                                                   • tumour 2 disc diameters or less in size
                                                          • periocular carboplatin therapy
                                                   • tumour 2 disc diameters or less in size
                                                          • enucleation

                                            Ongoing
                                             •   recurrence
                                                   •
                                                   • post-globe-salvaging therapy



Page 2
                                                              • brachytherapy
                                                        •   post-enucleation
                                                              • external beam radiation or brachytherapy
                                                        •   post-enucleation
                                                              • systemic chemotherapy

Basics
Basics: Definition
Retinoblastoma is the most common malignant intraocular tumour in children. It can be unilateral or bilateral,
familial or spontaneous, and in 30% to 40% of cases is accompanied by a germinal mutation in the RB1
gene. It most commonly presents with leukocoria (white pupillary reflex), strabismus or pseudo-orbital
cellulitis. It often causes an exudative retinal detachment with vitreous seeding. Ophthalmic ultrasound
typically shows variable or high internal reflectivity with foci of calcification. The diagnosis is made without
a biopsy.

Basics: Classifications
 International classification of retinoblastoma[1]
First published in 2005, this classification was created to replace the Reese-Ellsworth's classification (see
below), which had been in place for 50 years and was geared towards treatment with external beam
radiation, a treatment that has now fallen out of favour. The goal of this classification is to reflect the
likelihood of ocular survival based on modern treatment techniques (typically chemotherapy plus focal
therapy).
Group A
  • Retinoblastoma 3 mm or less in basal dimension or thickness, located at least 3 mm from the foveola
    and 1.5 mm from the optic nerve.
Group B
  • Retinoblastoma not in Group A with 1 or more of the following:
        •   Macular location (less-than or equal to3 mm to foveola)
        •   Juxta-papillary location (less-than or equal to1.5 mm to optic nerve)
        •   Additional subretinal fluid (less-than or equal to5 mm from margin).
Group C
  • Retinoblastoma tumour with 1 of the following:
        •   Focal subretinal seeds
        •   Focal vitreous seeds
        •   Both focal subretinal and vitreous seeds.
Group D
  • Retinoblastoma tumour with 1 of the following:
        •   Diffuse subretinal seeds
        •   Diffuse vitreous seeds
        •   Both diffuse subretinal and vitreous seeds.
Group E
  • Very high-risk eyes with 1 or more of the following:




Page 3
        •   Neovascular glaucoma
        •   Massive intraocular haemorrhage
        •   Aseptic orbital cellulitis
        •   Tumour anterior to the vitreous face
        •   Tumour touching the lens
        •   Diffuse infiltrating retinoblastoma
        •   Phthisis bulbi (also known as end-stage eye, this is a non-functioning, atrophic, scarred and
            disorganised globe, frequently with dystrophic calcification).

 Reese-Ellsworth's classification[2]
This is the traditional classification designed by Algernon Reese and Robert Ellsworth in the 1960s. It
reflects the likelihood of ocular survival after lateral port external beam radiation. Most scientific literature
still utilises this classification, although it is beginning to be replaced by the International classification of
retinoblastoma.[1]
Group I
  • a. Solitary tumour, less than 4 disc diameters in size, at or posterior to the equator of the eye (an
    imaginary line in the coronal plane that marks the division between the anterior and posterior halves
    of the eye).
  • b. Multiple tumours, none greater than 4 disc diameters in size, all at or behind the equator.
Group II
  • a. Solitary tumour, 4 to 10 disc diameters in size, at or behind the equator.
  •   b. Multiple tumours, 4 to 10 disc diameters in size, behind the equator.
Group III
  • a. Any lesion anterior to the equator.
  •   b. Solitary tumours greater than 10 disc diameters behind the equator.
Group IV
  • a. Multiple tumours, some greater than 10 disc diameters in size.
  •   b. Any lesion extending anteriorly to the ora seratta (the serrated junction between the retina and the
      ciliary body).
Group V
  • a. Massive tumours involving over half the retina.
  •   b. Vitreous seeding.

Basics: Vignette
Common Vignette
A mother takes her 3-year-old child to the paediatrician complaining that the child's right eye looks strange
and appears different from the left eye. The paediatrician notes that the right pupil has a white haze and
looks rather unusual. The paediatrician refers the child to a paediatric ophthalmologist who notes an
asymmetric red reflex and a total retinal detachment in the right eye. The paediatric ophthalmologist in turn
refers the patient to an ocular oncologist with the referring diagnosis of retinal detachment versus
retinoblastoma. On examination, the ocular oncologist discovers that the right eye is full of tumour with
vitreous and subretinal seeding and an overlying total retinal detachment. The left eye is unaffected with
no evidence of any retinoblastoma foci.



Page 4
Basics: Other Presentations
The most frequent presenting sign is leukocoria, a white pupillary reflex. Other presentations include
strabismus (crossed or deviating eyes), decreased vision (particularly in bilateral cases), appearance of
pseudo-orbital cellulitis with marked periorbital oedema, retinal detachment, glaucoma, hypopyon (tumour
cells anterior to the iris) and ocular pain. Retinoblastoma can sometimes be detected in utero using
ultrasound or may be identified shortly after birth, particularly if there is a known family history of the
condition. Occasionally, bilateral retinoblastomas occur with a concomitant pineal primitive neuroectodermal
tumour (pinealoma), a condition termed trilateral retinoblastoma. Although most retinoblastomas present
in children under 3 years of age, cases have been reported in children aged 7 years or older. Rarely, it
presents in conjunction with other paediatric ophthalmic conditions such as morning glory syndrome (a
congenital defect in which there is a cleft in the optic disc) or retinopathy of prematurity.

Basics: Epidemiology
Retinoblastoma is rare. The incidence of retinoblastoma is 1 in 18,000 to 30,000 live births.[3] In the US,
there are 250 to 350 new cases per year. The incidence in the US is relatively low at 3.58 cases per year
per million children under 15 years of age. In the UK, between 40 to 50 children are newly diagnosed each
year, and retinoblastoma accounts for only about 3 out of every 100 cancers occurring in children under
the age of 15 years.[4]
For many years, the reported median age at diagnosis has been 18 months, with the median age of
diagnosis of bilateral cases occurring at 12 months and of unilateral cases at 24 months.[5] Recently,
however, European investigators have questioned the basis on which these epidemiological assumptions
are made and have reported that the age at diagnosis of unilateral cases may be equal to that of bilateral
cases.[6]

Basics: Aetiology
Genetics
 • A mutation in both alleles of the RB1 gene is widely believed to be a prerequisite for the presence of
    disease. Other mutations are likely to be necessary for progression to clinical retinoblastoma.[7]
    However, only 10% of patients have a previously established family history of the disease. The majority
    of cases (even in the 25% to 30% of patients with the bilateral germinal form of the disease) have no
    antecedent family history and occur as a result of spontaneous mutations either early in embryogenesis
    or de novo in one set of parental germline cells.[8]
Viral exposure
  • One small clinical study performed in Mexico indicated that the presence of HPV sequences in
      retinoblastoma tumour tissue may play a role in the development of sporadic retinoblastoma.[9]
Advanced paternal age
  • There is evidence that mutations of RB1 are more common during spermatogenesis than
    oogenesis.[10] However, clinical studies examining the relative risk of patients with sporadic germinal
    disease with fathers older than 50 years have demonstrated mixed results.[11] [12]

Basics: Pathophysiology
Whether inherited in the germline or occurring spontaneously, a critical mutation occurs in the RB1 gene
of horizontal interneurons in the inner nuclear layer of the retina. This loss of heterozygosity results in a
cell that is homozygous null for this gene. The presence of other RB family proteins and unrelated proteins
(such as senescence proteins) can inhibit the progression of retinoblastoma. For reasons that are not clear,
but are likely to be related to the local retinal micro-environment, a high percentage of these lesions develop
aneuploidy and high copy number changes, resulting in genomic instability and a predictable series of




Page 5
losses of proteins critical for cell cycle control. Oncogenesis results and clinical retinoblastoma can be
detected.[13]

Basics: Risk Factors
Strong
 mutation in RB1 gene
  •   A mutation in both alleles of the RB1 gene is widely believed to be a prerequisite for the presence of
      disease. Other mutations are likely to be necessary for progression to clinical retinoblastoma.[7]
  •   However, only 10% of patients have a previously established family history of the disease. The majority
      of patients (even in the 25% to 30% of people with the bilateral germinal form of the disease) have
      no antecedent family history, and the disease occurs as a result of spontaneous mutations either
      early in embryogenesis or de novo in one set of parental germline cells.[8]

Weak
 HPV viral exposure
  •   One small clinical study performed in Mexico indicated that the presence of HPV sequences in
      retinoblastoma tumour tissue may play a role in the development of sporadic retinoblastoma.[9]
 advanced paternal age
  •   There is evidence that mutations of RB1 are more common during spermatogenesis than
      oogenesis.[10] However, clinical studies examining the relative risk of patients with sporadic germinal
      disease with fathers older than 50 years have demonstrated mixed results.[11] [12]

Basics: Prevention
There are no known measures for preventing spontaneous retinoblastoma. For families with a known
germline mutation, pre-implantation genetic diagnosis has been performed. In this procedure, embryos
are fertilised using standard IVF techniques and are then biopsied at the 8-cell stage. Embryos found to
be free of the familial mutation in the retinoblastoma gene are implanted, resulting in a live birth of a healthy
child.[14]
Secondary Prevention
Preventative measures to decrease the risk of second cancers in germinal retinoblastoma patients include
cessation of smoking, reduction in sun exposure and reduction in exposure to ionising radiation (e.g., x-rays
and CT scans).

Diagnosis
Diagnosis: Diagnosis Approach
Only in approximately 10% of cases of retinoblastoma is there an antecedent family history of the disease.
Children born to these families are normally examined for the disease shortly after birth and monitored
closely thereafter. In the remaining 90% of cases, the diagnosis may be suspected when certain features
are noted by parents or other caregivers.
Leukocoria (white pupillary reflex) is the most common sign of retinoblastoma and can be seen in
approximately 60% of cases. It is often noted in photographs of children taken with a flash. Less commonly,
strabismus (crossed or deviating eyes) or pseudo-periorbital cellulitis/oedema may be seen. Children with
13q syndrome may present with features of retinoblastoma in addition to other characteristic systemic
features, which may include mental and growth retardation; cranio-facial dysmorphisms; hand and foot
anomalies; and defects of the brain, heart and kidneys.[15]




Page 6
If a diagnosis of retinoblastoma is suspected, it is essential that a proper assessment is made by an
appropriate team of specialists, led by an ocular oncologist.

Clinical examination and funduscopy
All children with suspected retinoblastoma should undergo a thorough bilateral eye examination. Strabismus
or pseudo-periorbital cellulitis/oedema may sometimes be noted. Leukocoria (white pupillary reflex) is often
seen, especially with advanced retinoblastoma. [image] Examination under general anaesthesia should
also be conducted. Funduscopy reveals a characteristic chalky, white-grey retinal mass. Dilated fundus
examination with 360-degree scleral depression is important to enable identification of peripheral tumours.
Often there is a total retinal detachment and the retinal vessels within the detached retina can be seen
behind the lens. Vitreous and subretinal seeding are also frequently present. [image] [image] [image]
[image]

Ophthalmic ultrasound
Standard ophthalmic A- and B-scan ultrasound should be performed to aid diagnosis. It is typically performed
during the initial clinical examination. If necessary, it may be carried out as part of the examination under
anaesthesia. With retinoblastoma, A-scan reveals variable or high internal reflectivity and B-scan typically
reveals a mass filling the globe with calcification and accompanying shadowing.

CT and MRI scans
In general, imaging studies of the head and orbit are not necessary for the diagnosis of retinoblastoma.
CT scans, in particular, are not recommended as they result in radiation exposure that increases the risk
of secondary cancers in retinoblastoma patients with a germline mutation. If scans are done, retinoblastoma
usually appears on MRI and CT as an intraocular mass containing calcium. On T2-weighted MRI,
retinoblastoma typically appears hypo-intense to vitreous.
However, patients diagnosed with bilateral retinoblastomas should have an MRI of the brain to exclude
the possible presence of a concomitant primitive neuroectodermal tumour (PNET) in the pineal gland (a
condition referred to as trilateral retinoblastoma).

Biopsy
Biopsies are never performed for this disease because of the unacceptable risk of orbital seeding and
metastasis. Consequently, diagnosis is based on funduscopic and ultrasonographic characteristics.

Molecular genetic testing
Molecular testing for a mutation in the RB1 gene is most useful when tumour tissue is available and/or if
there are multiple family members affected. In general, results of molecular testing do not guide ocular
therapy. However, the presence of a germinal mutation can be helpful for family planning and screening
for secondary cancers.

Referral
Any child with suspected retinoblastoma should be referred to a specialist ocular oncologist or other
ophthalmic specialist. The rarity of the disease, its potential for morbidity and mortality, and the opportunity
of a high survival rate with early detection and treatment means that treatment by an inexperienced clinician
is inappropriate in countries where specialist expertise is available. Referrals to a paediatric oncologist,
radiation oncologist and geneticist are almost universally handled by the ocular oncologist, who typically
has ongoing collaborations with these colleagues.

Diagnosis: History and Exam, Diagnostic Factors
Key Diagnostic Factors




Page 7
 age under 3 years (common)
  •   90% patients with retinoblastoma are under 3 years of age at time of diagnosis.
 positive family history (uncommon)
  •   There is a positive family history of retinoblastoma in 10% of patients.
 leukocoria (white pupillary reflex) (common)
  •   This is the most common clinical presentation and is usually seen in advanced disease. [image]
 strabismus (common)
  •   The second most common clinical presentation.
 pseudo-orbital cellulitis (uncommon)
  •   The third most common clinical presentation.
 13q syndrome (uncommon)
  •   Children who have a large deletion on the long arm of chromosome 13 present with retinoblastoma
      as well as other characteristic features that may include mental and growth retardation; cranio-facial
      dysmorphisms; hand and foot anomalies; and defects of the brain, heart and kidneys.[15]

Other Diagnostic Factors
 pinealoma (uncommon)
  •   Can occur in conjunction with bilateral retinoblastomas in a condition termed trilateral retinoblastoma.
      It occurs in patients with a germinal mutation.

Diagnosis: Tests
1st Tests To Order
                     Test                                                       Result
funduscopy and examination under anaesthesia              chalky, white-grey retinal mass; may show retinal
  •   Dilated fundus examination with 360-degree scleraldetachment with retinal vessels visible behind the
      depression is important to enable identification of lens; may show vitreous and/or subretinal seeding
      peripheral tumours. [image] [image] [image] [image]
ophthalmic A- and B-scan ultrasound                       A-scan reveals variable or high internal reflectivity;
  •   Typically performed during the initial clinical     B-scan typically reveals a mass filling the globe
      examination. If necessary, may be completed as      with calcification and accompanying shadowing
      part of the examination under anaesthesia.

Other Tests to Consider
                                     Test                                                  Result
molecular testing                                                                may show mutation in the RB1
  •   Molecular testing for a mutation in the RB1 gene is most useful in         gene
      patients for whom tumour tissue is available or if there are multiple
      affected family members.
  •   Generally, results of molecular testing do not guide ocular therapy.
      However, the presence of a germinal mutation can be helpful for family
      planning and screening for secondary cancers.




Page 8
MRI                                                                          may show presence of
  •   In general, imaging studies of the head and orbit are not necessary forpinealoma in patients with
      the diagnosis of retinoblastoma itself. However, patients diagnosed bilateral retinoblastoma
      with bilateral retinoblastomas should have an MRI of the brain to exclude
      the possible presence of a concomitant primitive neuroectodermal
      tumour (PNET) in the pineal gland (a condition referred to as trilateral
      retinoblastoma).

Diagnosis: Differentials
      Condition                       Sign/Symptoms                            Differentiating tests
Coats' disease            •   Around 90% of patients are male;        •   Fundus examination: lesion appears
(exudative retinitis or       95% of cases are unilateral.                more yellow-coloured (versus
retinal telangiectasis)   •   Mean age at presentation for Coats'         chalky white-grey in
                              disease (6 years) is greater than for       retinoblastoma); telangiectatic and
                              retinoblastoma (most cases                  aneurysmal retinal vessels are
                              diagnosed by 3 years).                      characteristic of Coats' disease but
                                                                          uncommon in retinoblastoma.
                                                                      •   Ophthalmic ultrasound: can be
                                                                          misleading because calcification
                                                                          can also be seen in Coats' disease.
Persistent fetal          •   Associated with a micro-ophthalmic     •    Measurement of axial length using
vasculature (formerly         eye (a small, malformed eye).               fundus examination and ultrasound
known as persistent       •   Dragging of the ciliary processes on        shows short axial length in
hyperplastic primary          examination.                                persistent fetal vasculature.
vitreous)                 •   Often associated with a cataract (rare
                              in retinoblastoma).
                          •   Congenital (retinoblastoma
                              uncommonly presents at birth).
Retinopathy of            •   Generally occurs in premature           •   Fundus examination: reveals
prematurity (ROP)             children given high-dose oxygen.            gliotic-appearing retina, which is
                          •   Can result in total retinal detachment.     different from the retinal detachment
                                                                          associated with retinoblastoma.
Ocular toxocariasis       •   Generally causes vitreoretinal traction •   Fundus examination reveals
                              and ocular inflammation not seen in         characteristic signs.
                              retinoblastoma.
Astrocytic hamartoma      •   Grey-white retinal tumour associated •      Fundus examination reveals the
                              with tuberous sclerosis.                    characteristic signs.
                          •   Associated with other neurological
                              and skin findings not characteristic of
                              retinoblastoma.
Medullo-epithelioma       •   Generally congenital and unilateral.   •    Fundus examination reveals the
                          •   Characterised by mass in iris/anterior      characteristic signs.
                              chamber/ciliary body.                  •    Ultrasound reveals cystic changes.
                          •   Can cause cataract or lens notch.
Congenital cataract       •   Presents at birth.                      •   Fundus examination reveals lens
                          •   Lens opacification rare in                  opacification.
                              retinoblastoma.                         •   Ultrasound shows increased
                                                                          echogenicity of lens.




Page 9
Diagnosis: Diagnostic Criteria
 International classification of retinoblastoma[1]
First published in 2005, this classification was created to replace the Reese-Ellsworth's classification (see
below), which had been in place for 50 years and was geared towards treatment with external beam
radiation, a treatment that has now fallen out of favour. The goal of this classification is to reflect the
likelihood of ocular survival based on modern treatment techniques (typically chemotherapy plus focal
therapy).
Group A
  • Retinoblastoma 3 mm or less in basal dimension or thickness, located at least 3 mm from the foveola
    and 1.5 mm from the optic nerve.
Group B
  • Retinoblastoma not in Group A with 1 or more of the following:
          •   Macular location (less-than or equal to3 mm to foveola)
          •   Juxta-papillary location (less-than or equal to1.5 mm to optic nerve)
          •   Additional subretinal fluid (less-than or equal to5 mm from margin).
Group C
  • Retinoblastoma tumour with 1 of the following:
          •   Focal subretinal seeds
          •   Focal vitreous seeds
          •   Both focal subretinal and vitreous seeds.
Group D
  • Retinoblastoma tumour with 1 of the following:
          •   Diffuse subretinal seeds
          •   Diffuse vitreous seeds
          •   Both diffuse subretinal and vitreous seeds.
Group E
  • Very high-risk eyes with 1 or more of the following:
          •   Neovascular glaucoma
          •   Massive intraocular haemorrhage
          •   Aseptic orbital cellulitis
          •   Tumour anterior to the vitreous face
          •   Tumour touching the lens
          •   Diffuse infiltrating retinoblastoma
          •   Phthisis bulbi (also known as end-stage eye, this is a non-functioning, atrophic, scarred and
              disorganised globe, frequently with dystrophic calcification).

 Reese-Ellsworth's classification[2]
This is the traditional classification designed by Algernon Reese and Robert Ellsworth in the 1960s. It
reflects the likelihood of ocular survival after lateral port external beam radiation. Most scientific literature
still utilises this classification, although it is beginning to be replaced by the International classification of
retinoblastoma.[1]
Group I



Page 10
  •   a. Solitary tumour, less than 4 disc diameters in size, at or posterior to the equator of the eye (an
      imaginary line in the coronal plane that marks the division between the anterior and posterior halves
      of the eye).
  •   b. Multiple tumours, none greater than 4 disc diameters in size, all at or behind the equator.
Group II
  • a. Solitary tumour, 4 to 10 disc diameters in size, at or behind the equator.
  •   b. Multiple tumours, 4 to 10 disc diameters in size, behind the equator.
Group III
  • a. Any lesion anterior to the equator.
  •   b. Solitary tumours greater than 10 disc diameters behind the equator.
Group IV
  • a. Multiple tumours, some greater than 10 disc diameters in size.
  •   b. Any lesion extending anteriorly to the ora seratta (the serrated junction between the retina and the
      ciliary body).
Group V
  • a. Massive tumours involving over half the retina.
  •   b. Vitreous seeding.

Diagnosis: Screening
There is no widely accepted screening protocol for the general population. Dilated fundus examinations
are difficult for primary care providers to perform, and the ideal schedule and timing of such examinations
is difficult to determine given that the disease can present at any time during childhood.

Diagnosis: Diagnosis Guidelines
 Pediatric eye evaluations: screening and comprehensive opthalmic evaluation
View Guidelines
Published by: American Academy of Opthalmology
Last Published: 2007
Summary
  •   Provides updated recommendations for screening children for eye conditions and provides guidelines
      for performing comprehensive opthalmic evaluations in children.
 Referral guidelines for suspected cancer in adults and children
View Guidelines
Published by: Royal College of General Practitioners (UK)
Last Published: 2005
Summary
  •   Guidelines to help general practitioners make decisions about when to refer people to specialists
      when they present with symptoms that could be caused by cancer. This guideline is not about treating
      cancer.
 Control of pain in adults with cancer
View Guidelines
Published by: Scottish Intercollegiate Guidelines Network (SIGN)


Page 11
Last Published: 2008

Treatment
Treatment: Treatment Approach
The 3 goals of treatment, in order of priority, are to save the patient's:
  • Life
  •   Eye
  •   Vision.
These goals underpin the approach to treatment, which is typically highly individualised and planned by
an experienced ocular oncologist.

Vitreous seeding present
With gross anterior chamber involvement or neovascular glaucoma or orbital inflammation:
 • In these patients, enucleation (surgical removal of the eye without resection of the lids or extraocular
     muscles) is the recommended first-line treatment. Subsequent histopathological examination, performed
     by an experienced ocular pathologist, determines the degree of invasion of the optic nerve by the
     tumour and identifies other high-risk pathological features such as infiltration of the iris, ciliary body,
     choroid or sclera. If any of these features are noted, patients receive adjuvant chemotherapy. This
     typically involves high-dose combinations of carboplatin, etoposide and vincristine, with some centres
     adding additional agents.
 • Enucleation is now less frequently used than it was in the past due to the increase in the use of
     chemotherapy and focal therapy. However, it remains an important option for cases where there is
     no hope of saving the eye and there is a low chance of fellow-eye involvement. More than 99% of
     patients with unilateral retinoblastoma without microscopic or macroscopic extraocular disease are
     cured with this procedure.
Without gross anterior chamber involvement or neovascular glaucoma or orbital inflammation:
 • If there are no complicating factors, sight- and globe-salvaging treatments are first attempted rather
     than going directly to enucleation. First-line treatment in this situation is systemic chemotherapy plus
     focal therapy. Chemotherapy usually consists of 6 to 9 cycles of a 3- or 4-drug systemic intravenous
     regimen (i.e., carboplatin, vincristine, etoposide and possibly ciclosporin) accompanied by focal
     therapy.[16] Focal therapy usually involves cryotherapy or laser therapy and is synergistic if performed
     on the same day as chemotherapy.

No vitreous seeding present
Tumours greater than 2 disc diameters in size:
  • First-line treatment in these patients usually involves 6 to 9 cycles of a 3- or 4-drug chemotherapy
    regimen (i.e., carboplatin, etoposide, vincristine and possibly ciclosporin) accompanied by focal laser
    ablation or cryotherapy.[16] The number of drugs and number of cycles used varies widely by institution.
  • Patients undergo regular, frequent eye examinations under anaesthesia to assess the response to
    treatment. In experienced hands, this approach can avoid the need for external beam radiation and
    enucleation at 3 years in 100% of patients with Reese-Ellsworth Group I to IV disease and 83% of
    patients with Reese-Ellsworth Group V disease.[16]
Tumours 2 disc diameters or less in size:
  • Patients with a family history of retinoblastoma are normally screened from birth and so tumours are
    often detected when very small (e.g., 2 disc diameters or smaller). These tumours can often be treated
    successfully with focal laser alone, with no additional treatment.


Page 12
  •   The patients are typically followed up with an examination under anaesthesia every month for at least
      1 year, and then the interval between follow-up visits is gradually extended.

Vitreous seeding after chemotherapy and/or focal therapy
If patients develop vitreous seeding following chemotherapy and/or focal therapy, external beam radiation
or brachytherapy (a local radioactive source) is given. Although external beam radiation was frequently
used in the past, it is now reserved for cases that do not respond satisfactorily to chemotherapy and/or
focal therapy because it results in an increased risk of secondary cancers. Rates of eye preservation with
external beam radiation are as high as 95% for Reese-Ellsworth Group I to III eyes, and an 83% 3-year
eye preservation rate was observed in the most recent large series of Group IV and V eyes treated with a
standard lateral beam approach.[17] A study of Reese-Ellsworth Group Vb eyes demonstrated a 81%
1-year ocular survival rate and a 53% 10-year ocular survival rate.[18] Short-term side effects of external
beam radiation include periorbital redness and oedema, dry eye and cataracts. Long-term side effects
include secondary cancers and temporal bony hypoplasia, particularly in children radiated at less than 6
months of age.
For patients with non-calcified vitreous seeds, where external beam radiation has not produced a satisfactory
result, periocular carboplatin therapy may be a reasonable treatment option before enucleation; however,
periocular carboplatin therapy is not effective against subretinal seeds. Although there are no systemic
side effects from periocular carboplatin, it can cause major ocular side effects such as fibrosis of the
extraocular muscles and optic nerve atrophy.[19] [20]
When tumours do not respond satisfactorily to attempts at globe-salvaging therapies using external beam
radiation or periocular carboplatin therapy, enucleation is performed.

Recurrence: post-globe-salvaging therapy
If a patient develops a focal, non-macular, circumscribed tumour with no associated vitreous seeds following
treatment with other modalities, brachytherapy may be used to treat the lesion.
Although otherwise not often used for this disease, iodine or ruthenium brachytherapy can occasionally
be useful for these particular tumours. Iodine-125 is currently the most commonly used isotope in
brachytherapy for retinoblastoma. The main advantage of this isotope is that radioactive seeds can be
placed into a custom-built plaque designed to match the size of the lesion.
A tumour recurrence rate of 12% at 1 year post-treatment has been reported when plaques are used as
primary treatment for retinoblastoma.[21] Radioactive plaques can also be successful when used as salvage
therapy for eyes that have failed other treatment methods. One recent study found a 60% overall eye
preservation rate (15 out of 25 eyes) for salvage brachytherapy after primary chemotherapy or
radiotherapy.[22] Another study reported on 148 tumours treated with brachytherapy plaques after failure
of other methods.[21] Tumour recurrence at 1 year was detected in 8% of tumours previously treated with
chemotherapy and 25% of tumours previously treated with external beam radiation therapy.

Recurrence: post-enucleation
If recurrence occurs within the orbit post-enucleation, first-line therapy is with external beam radiation.
Alternatively, some centres may offer brachytherapy. Depending on the extent of the orbital recurrence,
some patients may also receive a course of systemic chemotherapy, in addition to radiotherapy.

Trilateral retinoblastoma
This signifies bilateral retinoblastomas and a concomitant pineal primitive neuroectodermal tumour (PNET)
or pinealoma. Patients have their retinoblastomas treated according to the principles above. In addition,
the pinealoma is treated by surgical excision followed by radiotherapy. This may be supplemented by a
second-look surgical procedure and re-excision.




Page 13
Treatment: Treatment Options
Acute
                    Treatment
Patient Group          Line                                        Treatment
with vitreous          asdf
seeding
      with gross       1st      enucleation
         anterior                 • Enucleation is surgical removal of the eye without resecting the lids or
       chamber                       extraocular muscles. There are no major side effects if surgery is done
involvement or                       correctly, the correct orbital implant is used and there is good prosthesis
   neovascular                       management.
   glaucoma or                    • More than 99% of patients with unilateral retinoblastoma without microscopic
          orbital                    or macroscopic extraocular disease are cured with this procedure.
  inflammation

                     adjunct postoperative systemic chemotherapy
                               • If postoperative histopathological examination of the enucleated specimen
                                  by an experienced ocular pathologist shows the presence of tumour
                                  extension into the cut section of the optic nerve or another high-risk feature,
                                  patients receive a course of adjuvant chemotherapy.
                               • What constitutes a high-risk feature is the subject of some debate, but can
                                  include features such as scleral invasion, post-laminar optic nerve disease
                                  with concomitant scleral or choroidal invasion, or invasion to the surgical
                                  margin.
                               • Adjuvant chemotherapy in this circumstance typically involves high-dose
                                  combinations of carboplatin, etoposide and vincristine, with some centres
                                  adding additional agents.

                                Primary Options
                                  • carboplatin : consult specialist for guidance on dose and
                                  • etoposide : consult specialist for guidance on dose and
                                  • vincristine : consult specialist for guidance on dose
  without gross        1st      systemic chemotherapy
        anterior                  • Treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or
       chamber                       4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide
involvement or                       +/- ciclosporin) accompanied by focal therapy with laser ablation or
   neovascular                       cryotherapy.[16]
   glaucoma or                    • The number of drugs and number of cycles used varies widely by institution.
         orbital                     Patients undergo regular, frequent examinations under anaesthesia to
  inflammation                       assess the response to treatment. Focal therapy, such as diode laser
                                     therapy, is synergistic if performed on the same day as chemotherapy.
                                  • In experienced hands, such an approach can result in avoidance of external
                                     beam radiation and enucleation at 3 years in 100% of patients with
                                     Reese-Ellsworth Group I to IV disease and 83% in patients with
                                     Reese-Ellsworth Group V disease.[16]

                                Primary Options
                                  • carboplatin : consult specialist for guidance on dose and
                                  • vincristine : consult specialist for guidance on dose and
                                  • etoposide : consult specialist for guidance on dose



Page 14
                             • carboplatin : consult specialist for guidance on dose and
                             • vincristine : consult specialist for guidance on dose and
                             • etoposide : consult specialist for guidance on dose and
                             • ciclosporin modified: consult specialist for guidance on dose
                    plus   concurrent laser ablation or cryotherapy
                             • Focal therapy, such as diode laser therapy, is synergistic if performed on
                                the same day as chemotherapy.
                             • In experienced hands, such an approach can result in avoidance of external
                                beam radiation and enucleation at 3 years in 100% of patients with
                                Reese-Ellsworth Group I to IV disease and 83% in patients with
                                Reese-Ellsworth Group V disease.[16]

                    2nd    external beam radiation or brachytherapy
                             • External beam radiation or brachytherapy is given to patients who have
                                persistent vitreous seeding after chemotherapy/focal therapy.
                             • Although external beam radiation was used frequently in the past, it is now
                                reserved for cases that do not respond satisfactorily to chemotherapy/focal
                                therapy, since it results in an increased risk of secondary cancers in this
                                population.
                             • Rates of eye preservation with external beam radiation are as high as 95%
                                for Reese-Ellsworth Group I to III eyes. An 83% 3-year eye preservation
                                rate was observed in the most recent large series of Group IV and V eyes
                                treated with a standard lateral beam approach.[17] A study of
                                Reese-Ellsworth Group Vb eyes demonstrated a 81% 1-year ocular survival
                                rate and a 53% 10-year ocular survival.[18]

                    3rd    periocular carboplatin therapy
                             • Patients with non-calcified vitreous seeds despite treatment with
                                chemotherapy, focal laser therapy and external beam
                                radiation/brachytherapy may be given periocular carboplatin therapy as a
                                last option before enucleation.
                             • The treatment has the potential for major ocular side effects such as fibrosis
                                of the extraocular muscles and optic nerve atrophy.[19] [20] However, there
                                is no systemic toxicity.
                             • This treatment is not effective for subretinal seeds.

                           Primary Options
                             • carboplatin : consult specialist for guidance on dose
                    4th    enucleation
                             • Enucleation is performed when tumours are not responding to attempts at
                                globe-salvaging therapy using radiotherapy and periocular carboplatin
                                therapy.

without             asdf
vitreous
seeding
         tumour     1st    systemic chemotherapy
greater than 2               • Treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or
disc diameters                  4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide
          in size


Page 15
                       +/- ciclosporin) accompanied by focal therapy with laser ablation or
                       cryotherapy.[16]
                   •   The number of drugs and number of cycles used varies widely by institution.
                       Patients undergo regular, frequent examinations under anaesthesia to
                       assess the response to treatment. Focal therapy, such as diode laser
                       therapy, is synergistic if performed on the same day as chemotherapy.
                   •   In experienced hands, such an approach can result in avoidance of external
                       beam radiation and enucleation at 3 years in 100% of patients with
                       Reese-Ellsworth Group I to IV disease and 83% in patients with
                       Reese-Ellsworth Group V disease.[16]

                 Primary Options
                   • carboplatin : consult specialist for guidance on dose and
                   • vincristine : consult specialist for guidance on dose and
                   • etoposide : consult specialist for guidance on dose
                   • carboplatin : consult specialist for guidance on dose and
                   • vincristine : consult specialist for guidance on dose and
                   • etoposide : consult specialist for guidance on dose and
                   • ciclosporin modified: consult specialist for guidance on dose
          plus   concurrent laser ablation or cryotherapy
                   • Focal therapy, such as diode laser therapy, is synergistic if performed on
                      the same day as chemotherapy.
                   • In experienced hands, such an approach can result in avoidance of external
                      beam radiation and enucleation at 3 years in 100% of patients with
                      Reese-Ellsworth Group I to IV disease and 83% in patients with
                      Reese-Ellsworth Group V disease.[16]

          2nd    external beam radiation or brachytherapy
                   • External beam radiation or brachytherapy is given to patients who develop
                      vitreous seeding after chemotherapy and focal therapy.
                   • Although external beam radiation was used frequently in the past, it is now
                      reserved for cases that do not respond satisfactorily to chemotherapy/focal
                      therapy, since it results in an increased risk of secondary cancers in this
                      population.
                   • Rates of eye preservation with external beam radiation are as high as 95%
                      for Reese-Ellsworth Group I to III eyes. An 83% 3-year eye preservation
                      rate was observed in the most recent large series of Group IV and V eyes
                      treated with a standard lateral beam approach.[17] A study of
                      Reese-Ellsworth Group Vb eyes demonstrated a 81% 1-year ocular survival
                      rate and a 53% 10-year ocular survival.[18]

          3rd    periocular carboplatin therapy
                   • Patients with non-calcified vitreous seeds despite treatment with
                      chemotherapy, focal laser therapy and external beam
                      radiation/brachytherapy may be given periocular carboplatin therapy as a
                      last option before enucleation.
                   • The treatment has the potential for major ocular side effects such as fibrosis
                      of the extraocular muscles and optic nerve atrophy.[19] [20] There is no
                      systemic toxicity.
                   • This treatment is not effective for subretinal seeds.



Page 16
                           Primary Options
                             • carboplatin : consult specialist for guidance on dose
                    4th    enucleation
                             • Enucleation is performed when tumours are not responding to attempts at
                                globe-salvaging therapy using radiation therapy and periocular carboplatin
                                therapy.

  tumour 2 disc     1st    focal laser ablation alone
   diameters or              • Patients with a family history of retinoblastoma who are screened from birth,
     less in size                and whose tumours are detected when they are very small (2 disc diameters
                                 or smaller), can often be treated successfully with focal laser alone.

                    2nd    systemic chemotherapy
                             • Treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or
                                4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide
                                +/- ciclosporin) accompanied by focal therapy with laser ablation or
                                cryotherapy.[16]
                             • The number of drugs and number of cycles used varies widely by institution.
                                Patients undergo regular, frequent examinations under anaesthesia to
                                assess the response to treatment. Focal therapy, such as diode laser
                                therapy, is synergistic if performed on the same day as chemotherapy.
                             • In experienced hands, such an approach can result in avoidance of external
                                beam radiation and enucleation at 3 years in 100% of patients with
                                Reese-Ellsworth Group I to IV disease and 83% in patients with
                                Reese-Ellsworth Group V disease.[16]

                           Primary Options
                             • carboplatin : consult specialist for guidance on dose and
                             • vincristine : consult specialist for guidance on dose and
                             • etoposide : consult specialist for guidance on dose
                             • carboplatin : consult specialist for guidance on dose and
                             • vincristine : consult specialist for guidance on dose and
                             • etoposide : consult specialist for guidance on dose and
                             • ciclosporin modified: consult specialist for guidance on dose
                    plus   concurrent laser ablation or cryotherapy
                             • Focal therapy, such as diode laser therapy, is synergistic if performed on
                                the same day as chemotherapy.
                             • In experienced hands, such an approach can result in avoidance of external
                                beam radiation and enucleation at 3 years in 100% of patients with
                                Reese-Ellsworth Group I to IV disease and 83% in patients with
                                Reese-Ellsworth Group V disease.[16]

                    3rd    external beam radiation or brachytherapy
                             • External beam radiation or brachytherapy is given to patients who develop
                                vitreous seeding after chemotherapy/focal therapy.
                             • Although external beam radiation was used frequently in the past, it is now
                                reserved for cases that do not respond satisfactorily to chemotherapy/focal




Page 17
                                 therapy, since it results in an increased risk of secondary cancers in this
                                 population.
                             •   Rates of eye preservation with external beam radiation are as high as 95%
                                 for Reese-Ellsworth Group I to III eyes. An 83% 3-year eye preservation
                                 rate was observed in the most recent large series of Group IV and V eyes
                                 treated with a standard lateral beam approach.[17] A study of
                                 Reese-Ellsworth Group Vb eyes demonstrated a 81% 1-year ocular survival
                                 rate and a 53% 10-year ocular survival.[18]

                 4th       periocular carboplatin therapy
                             • Patients with vitreous seeds despite treatment with chemotherapy, focal
                                laser therapy and external beam radiation/brachytherapy may be given
                                periocular carboplatin therapy as a last option before enucleation.
                             • The treatment has the potential for major ocular side effects such as fibrosis
                                of the extraocular muscles and optic nerve atrophy.[19] [20] However, there
                                is no systemic toxicity.
                             • Can be effective for non-calcified vitreous seeds, but is not effective for
                                subretinal seeds.

                           Primary Options
                             • carboplatin : consult specialist for guidance on dose
                 5th       enucleation
                             • Enucleation is performed when tumours are not responding to attempts at
                                globe-salvaging therapy using radiotherapy and periocular carboplatin
                                therapy.


Ongoing
                         Treatment
    Patient Group           Line                                   Treatment
recurrence                  asdf
  post-globe-salvaging       1st   brachytherapy
               therapy                •   Used for focal, non-macular, circumscribed tumours with no
                                          associated vitreous seeds appearing after treatment with other
                                          modalities.
                                      •   Although not often used for this disease, iodine or ruthenium
                                          brachytherapy can occasionally be useful for these particular
                                          tumours. Iodine-125 is currently the most commonly used isotope
                                          in brachytherapy for retinoblastoma. The main advantage of this
                                          isotope is that radioactive seeds can be placed into a custom-built
                                          plaque designed to match the size of the lesion.
                                      •   There are minimal side effects of brachytherapy with almost no
                                          radiation exposure to the surrounding tissues or contralateral orbit.
                                          Generally an inpatient admission of several days is required due
                                          to radiation safety laws, which can be difficult for a young child.




Page 18
        post-enucleation     1st     external beam radiation or brachytherapy
                                       • If recurrence occurs post-enucleation, first-line therapy is external
                                          beam radiation. Alternatively, some centres may offer
                                          brachytherapy.

                           adjunct   systemic chemotherapy
                                       • Depending on the extent of the orbital recurrence, some patients
                                          may receive a course of systemic chemotherapy, in addition to
                                          radiotherapy.

                                     Primary Options
                                       • carboplatin : consult specialist for guidance on dose and
                                       • vincristine : consult specialist for guidance on dose and
                                       • etoposide : consult specialist for guidance on dose
                                       • carboplatin : consult specialist for guidance on dose and
                                       • vincristine : consult specialist for guidance on dose and
                                       • etoposide : consult specialist for guidance on dose and
                                       • ciclosporin modified: consult specialist for guidance on dose

Treatment: Emerging Treatments
 Intra-arterial chemotherapy
This is a controversial new treatment in which the ophthalmic artery of patients with advanced retinoblastoma
is selectively cannulated in order to perform a local injection of melphalan or other chemotherapeutic
agents. A number of small studies have shown promising results.[e1]However, further studies are ongoing.
If effective and safe, it is likely to be used for children with advanced intraocular disease. Alternate treatment
in the case of failure is enucleation.
 Proton beam radiotherapy
The goal of this therapy is to minimise exposure of the surrounding tissues, theoretically decreasing the
risk of secondary malignancies.[23] It is unlikely to be widely available due to the expense of proton beam
technology.

Treatment: Treatment Guidelines
 National retinoblastoma strategy Canadian guidelines for care
View Guidelines
Published by: Canadian Retinoblastoma Society
Last Published: 2009
Summary
  •    Provides evidence-based patient- and family-centred guidelines for managing retinoblastoma in
       Canada with the aim of standardising good quality of care.
 Ophthalmic services for children
View Guidelines
Published by: Royal College of Ophthalmologists
Last Published: 2005




Page 19
Summary
  •   This document summarises the views of the Paediatric Subcommittee of the Royal College of
      Ophthalmologists regarding best practice and minimum standards in relation to health services for
      children with ophthalmic disorders and/or visual impairment.
 National guideline on management and control of eye conditions at primary level
View Guidelines
Published by: South African Department of Health
Last Published: 2005
Summary
  •   Guidelines on management of eye conditions for patients, parents, health professionals, employers
      and school personnel.
 Long term follow up of survivors of childhood cancer
View Guidelines
Published by: Scottish Intercollegiate Guidelines Network (SIGN)
Last Published: 2004
 Control of pain in adults with cancer
View Guidelines
Published by: Scottish Intercollegiate Guidelines Network (SIGN)
Last Published: 2008

Followup
Followup: Outlook
Enucleation
  • Patient survival is 99%, but there is obviously no ocular salvage.
Systemic intravenous chemotherapy plus focal therapy
  • In specialist centres, systemic intravenous chemotherapy plus focal therapy results in an ocular
     salvage rate of 100% of patients with Reese-Ellsworth Group I to IV disease and 83% of patients with
     Reese-Ellsworth Group V disease.[16] Patient survival typically approaches 95%.
Focal therapy alone
  • In properly selected patients (i.e., tumours 2 disc diameters or smaller) ocular salvage rates of 100%
     can be achieved by focal therapy alone. When ocular salvage is successful there is no effect on
     patient survival.
External beam radiation
  • A standard lateral beam approach has an ocular salvage rate of 95% for Reese-Ellsworth Group I to
     III eyes, and an 83% 3-year ocular salvage rate in Reese-Ellsworth Group IV and V eyes.[17] For
     Reese-Ellsworth Group Vb tumours, it has a 81% 1-year ocular salvage rate and a 53% 10-year
     ocular salvage rate.[18]
  • This treatment causes increased patient mortality due to secondary cancers occurring at a rate of
     0.5% to 1% per year.
Periocular chemotherapy
  • This technique has an ocular salvage rate of approximately 50%, but it is generally used in advanced,
     refractory cases only. When successful in ocular salvage, there is no effect on patient survival.



Page 20
Brachytherapy
  • When used after primary chemotherapy or external beam radiation therapy, brachytherapy has a
     60% ocular salvage rate.[22] When successful in ocular salvage, there is no effect on patient survival.

Followup: Complications
                                   Complication                                        LikelihoodTimeframe
metastatic retinoblastoma                                                              low       variable
  •   Generally occurs with late presentations. Usually requires systemic
      chemotherapy +/- bone marrow transplant.
orbital recurrence                                                                     low       variable
  •  This can occur even when the surgical margin of the enucleation appears
     clear. Generally treated with orbital external beam radiation or brachytherapy,
     and additional chemotherapy.
secondary malignancy                                                                low          variable
  •   Chemotherapy and radiotherapy for retinoblastoma has the potential to induce
      secondary malignancies (e.g., lymphoma, leukaemia). The epipodophyllotoxin
      etoposide is known to induce secondary leukaemias characterised by
      site-specific DNA re-arrangements in paediatric cancer patients.[24]
fibrosis of extraocular muscles after carboplatin therapy                         high           variable
  •   Periocular carboplatin therapy has the potential for major ocular side effects
      such as fibrosis of the extraocular muscles and optic nerve atrophy.[19] [20]
      There is no systemic toxicity.
optic nerve atrophy after carboplatin therapy                                          medium    variable
  •   Periocular carboplatin therapy can cause optic nerve atrophy in some
      cases.[19] [20]
cataract formation after external beam radiation                                       medium    short term
  •   External beam radiation can cause cataract formation, as well as periorbital
      redness, oedema and dry eyes.
temporal bone hypoplasia after external beam radiation                                 high      long term
  •   Likelihood increases in children receiving radiotherapy before 6 months of
      age.

Followup: Recommendations
Monitoring
Infants with an antecedent family history of retinoblastoma are examined within 24 to 48 hours after birth
and again at 3, 6 and 12 weeks of age. All of these initial examinations are performed without anaesthesia.
Serial examinations are then typically performed at 16, 24, 34, 44 and 54 weeks of age under general
anaesthesia. Following the 54-week examination, patients are then examined approximately every 12
weeks.
For all other patients with suspected retinoblastoma, no agreed examination schedule has been developed.
This is because the rate of formation of new retinoblastoma foci, the rate of recurrence of previously treated
tumours, and the rate of formation of tumours in the fellow eye vary widely from patient to patient. The
examination and treatment schedule is highly individualised and catered toward the patient's specific risk
factors.




Page 21
Patient Instructions
Patients and their parents should be advised that treatment for retinoblastoma requires a specialised team
approach incorporating the patient, family, ocular oncologist, paediatrician, and opthalmologist. Once
treatment commences for retinoblastoma, periodic examination under anaesthesia is necessary for
surveillance and detection of disease activity. Online patient information from recommended sources may
be helpful for patient education. [w1]

Evidence Scores
e1.      Improvement in outcome: there is poor-quality evidence in the form of an observational study involving
         28 eyes of 23 newly diagnosed retinoblastoma patients that demonstrated an improvement in outcome
         when using superselective chemotherapy delivered through the opthalmic artery as initial therapy.[25]
         The need for enucleation, primary radiation or the use of systemic chemotherapy was prevented in
         27 out of the 28 eyes. Another observational study using supraselective intra-arterial chemotherapy
         in 12 eyes with advanced retinoblastoma showed a lack of progression in 9 of 12 eyes (75%) with 3
         requiring enucleation and showing viable tumours on histopathologic examinations.[26] Adverse
         effects were mild.Score: C

Key Articles
     •   Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin
         N Am. 2005;18:41-53.[Abstract]
     •   Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24:828-848.[Abstract]
     •   Mastrangelo D, De Francesco S, Di Leonardo A, et al. Does the evidence matter in medicine? The
         retinoblastoma paradigm. Int J Cancer. 2007;121:2501-2505.[Abstract]
     •   Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative retinoma; increasing
         genomic instability correlates with progression to retinoblastoma. Hum Mol Genet.
         2008;17:1363-1372.[Abstract]
     •   Leiderman YI, Kiss S, Mukai S. Molecular genetics of RB1--the retinoblastoma gene. Semin
         Ophthalmol. 2007;22:247-254.[Abstract]
     •   Ajioka I, Dyer MA. A new model of tumor susceptibility following tumor suppressor gene activation.
         Cell Cycle. 2008;7:735-740.[Abstract]
     •   Schefler AC, Cicciarelli N, Feuer W, et al. Macular retinoblastoma: evaluation of tumor control, local
         complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser
         ablation. Ophthalmology. 2007;114:162-169.[Abstract]

Other Online Resources
w1. Retinoblastoma International

Referenced Articles
1.       Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin
         N Am. 2005;18:41-53.[Abstract]
2.       Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24:828-848.[Abstract]
3.       Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through
         1985. Arch Ophthalmol. 1990;108:128-132.[Abstract]
4.       The Childhood Eye Cancer Trust (CHECT). http://www.chect.org.uk/ (last accessed 21 October
         2010).[Full Text ]
5.       Augsburger JJ, Oehlschlager U, Manzitti JE. Multinational clinical and pathologic registry of
         retinoblastoma. Retinoblastoma International Collaborative Study report 2. Graefes Arch Clin Exp
         Ophthalmol. 1995;233:469-475.[Abstract]
6.       Mastrangelo D, De Francesco S, Di Leonardo A, et al. Does the evidence matter in medicine? The
         retinoblastoma paradigm. Int J Cancer. 2007;121:2501-2505.[Abstract] [Full Text ]




Page 22
7.    Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative retinoma; increasing
      genomic instability correlates with progression to retinoblastoma. Hum Mol Genet.
      2008;17:1363-1372.[Abstract]
8.    Leiderman YI, Kiss S, Mukai S. Molecular genetics of RB1--the retinoblastoma gene. Semin
      Ophthalmol. 2007;22:247-254.[Abstract]
9.    Orjuela M, Castaneda VP, Ridaura C, et al. Presence of human papilloma virus in tumor tissue from
      children with retinoblastoma: an alternative mechanism for tumor development. Clin Cancer Res.
      2000;6:4010-4016.[Abstract] [Full Text ]
10.   Dryja TP, Mukai S, Petersen R, et al. Parental origin of mutations of the retinoblastoma gene. Nature.
      1989;339:556-558.[Abstract]
11.   DerKinderen DJ, Koten JW, Tan KE, et al. Parental age in sporadic hereditary retinoblastoma. Am J
      Ophthalmol. 1990;110:605-609.[Abstract]
12.   Matsunaga E, Minoda K, Sasaki MS. Parental age and seasonal variation in the births of children
      with sporadic retinoblastom: a mutation-epidemiologic study. Hum Genet. 1990;84:155-158.[Abstract]
13.   Ajioka I, Dyer MA. A new model of tumor susceptibility following tumor suppressor gene activation.
      Cell Cycle. 2008;7:735-740.[Abstract]
14.   Xu K, Rosenwaks Z, Beaverson K, et al. Preimplantation genetic diagnosis for retinoblastoma: the
      first reported liveborn. Am J Ophthalmol. 2004;137:18-23.[Abstract]
15.   Ballarati L, Elena Rossi E, Bonati, MT, et al. 13q Deletion and central nervous system anomalies:
      further insights from karyotype--phenotype analyses of 14 patients. J Med Genet.
      2007;44:e60.[Abstract] [Full Text ]
16.   Schefler AC, Cicciarelli N, Feuer W, et al. Macular retinoblastoma: evaluation of tumor control, local
      complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser
      ablation. Ophthalmology. 2007;114:162-169.[Abstract]
17.   Scott IU, Murray TG, Feuer WJ, et al. External beam radiotherapy in retinoblastoma: tumor control
      and comparison of 2 techniques. Arch Ophthalmol. 1999;117:766-770.[Abstract]
18.   Abramson DH, Beaverson KL, Chang ST, et al. Outcome following initial external beam radiotherapy
      in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol.
      2004;122:1316-1323.[Abstract]
19.   Mulvihill A, Budning A, Jay V, et al. Ocular motility changes after subtenon carboplatin chemotherapy
      for retinoblastoma. Arch Ophthalmol. 2003;12:1120-1124.[Abstract]
20.   Schmack I, Hubbard GB, Kang SJ, et al. Ischemic necrosis and atrophy of the optic nerve after
      periocular carboplatin injection for retinoblastoma. Am J Ophthalmol. 2006;142:310-315. [Abstract]
21.   Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: long-term tumor control
      and treatment complications in 208 tumors. Ophthalmology. 2001;108:2116-2121.[Abstract]
22.   Merchant TE, Gould CJ, Wilson MW, et al. Episcleral plaque brachytherapy for retinoblastoma. Pediatr
      Blood Cancer. 2004;43:134-139.[Abstract]
23.   Munier FL, Verwey J, Pica A, et al. New developments in external beam radiotherapy for
      retinoblastoma: from lens to normal tissue-sparing techniques. Clin Experiment Ophthalmol.
      2008;36:78-89.[Abstract] [Full Text ]
24.   Rivera GK, Pui CH, Santana VM, et al. Epipodophyllotoxins in the treatment of childhood cancer.
      Cancer Chemother Pharmacol. 1994;34:S89-S95.[Abstract]
25.   Abramson DH, Dunkel IJ, Brodie SE, et al. Superselective ophthalmic artery chemotherapy as primary
      treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117:1623-1629. Epub 2010 Apr
      9.[Abstract]
26.   Mutapcic L, Murray TG, Aziz-Sultan MA, et al. Supraselective intra-arterial chemotherapy: evaluation
      of treatment related complications in advanced refractory retinoblastoma. Arch Ophthalmol. 2010.
      article in press




Page 23
Image Library




   Leukocoria (white pupillary light reflex) in the left eye of a patient with unilateral retinoblastoma.
                         Source: Personal collection of Dr Timothy Murray




Page 24
             Large retinoblastoma focus in the left eye.
          Source: Personal collection of Dr Timothy Murray




              Macular retinoblastoma in the right eye.
          Source: Personal collection of Dr Timothy Murray




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          Two large retinoblastoma foci in the left eye. Note the associated subretinal seeding.
                           Source: Personal collection of Dr Timothy Murray




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                           Vitreous seeding associated with retinoblastoma.
                           Source: Personal collection of Dr Timothy Murray

Credits
Authors
Amy C. Schefler
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Miami
FL
Timothy G. Murray
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Miami
FL
ACS is an author of a number of references cited in this monograph.
TGM is an author of a number of references cited in this monograph. TGM has received funds greater than
6 figures USD: NEI ROI (National Eye Institute--Return on investment).

Peer Reviewers
Susan Schneider
Director
Pharmaceutical Clinical & Scientific Affairs
Bausch & Lomb
Rochester
NY
Francis Munier
Professor and Head of Pediatric Ocular Oncology Unit
Jules Gonin Eye Hospital
Lausanne
Switzerland
SS declares that she has no competing interests.
FM declares that he has no competing interests.




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