Retinoplastoma.. malignant ocular tumour.. presented by Dr.Zeinab Medani

1. Retinoblastoma
By Dr. Zeinab Medani

2. • Retinoblastoma is rare, occurring in up to 1 : 18 000 live births
• Is the most common primary intraocular malignancy of childhood
• Accounts for about 3% of all childhood cancers.
• After uveal melanoma, it is the second most common malignant
intraocular tumor.
• Survival rates are over 95% in specialized centers, with preservation
of vision in a majority of eyes.

3. • Tumours are composed of small basophilic cells (retinoblasts) with
large hyperchromatic nuclei and scanty cytoplasm.
Many retinoblastomas are undifferentiated but varying degrees of
differentiation are characterized by the formation of structures known
as rosettes.

4. • Growth may be endophytic (into the vitreous) with seeding of tumour
cells throughout the eye, or exophytic (into the subretinal space)
leading to retinal detachment, or mixed, or the retina may be diffusely
infiltrated
• Optic nerve invasion may occur, with spread of tumour along the
subarachnoid space to the brain.
• Metastatic spread is to regional nodes, lung, brain and bone.

5. Retinoblastoma needs to be excluded in a
young child
with leukocoria.

6. Genetics
• The tumour suppressor gene in which mutations predisposing to
retinoblastoma occur is RB1; .
• The size of a gene deletion tends to correlate with aggressive retinoblastoma
behaviour.
• Mutations in RB1 or associated genes in a common pathway are also
disrupted in many sporadic tumours.
• Modifier genes for retinoblastoma have also been identified and may
constitute therapeutic targets.

7. • Heritable (hereditary, germline) retinoblastoma accountsfor 40%.
• In heritable retinoblastoma one of the pair of alleles of RB1 is mutated
in all the cells in the body. When a further mutagenic event affects the
second allele, the cell may then undergo malignant transformation.
Because of the presence of the mutation in all cells, a large majority of
these children develop bilateral and multifocal tumours.
• Heritable retinoblastoma patients also have a predisposition to non-
ocular cancers such as pinealoblastoma , osteosarcoma, soft tissue
sarcoma and . The risk of a second malignancy is about 6% but this
increases five-fold if external beam irradiation has been used to treat
the original tumour.

8. • Non-heritable (non-hereditary, somatic) retinoblastoma. The tumour is
unilateral, not transmissible and does not predispose the patient to
second non-ocular cancers. Ninety per cent of children with unilateral
retinoblastoma will have the non-hereditary form.

9. • Screening of at-risk family members. Germline mutations are
• autosomal dominant
• Detection of mutations in RB1 has approached 95%
• Once identified in a particular child, the same mutation can be sought
in siblings, its presence confirming
their high-risk status. Siblings at risk of retinoblastoma should
• be screened by prenatal ultrasonography, by ophthalmoscopy
• soon after birth and then regularly until the age of 4 or 5 years.

10. • Early diagnosis correlates with a higher chance of preserving vision, salvaging the
eye and preserving life.
• If a child has heritable retinoblastoma, the risk to siblings is 2% if the parents are
healthy and 40% if a parent is
affected.
It is important that all family members, including the parents, are examined for the
presence of retinoblastoma- associated eye lesions (retinomas, calcified retinal scars,
phthisis).

11. International classification of retinoblastoma
• Group A: Small intraretinal tumours (<3 mm) away from foveola and disc.
• • Group B: Tumours >3 mm, macular or juxtapapillary location, or with
subretinal fluid.
• • Group C: Tumour with focal subretinal or vitreous seeding within 3 mm of
tumour.
• Group D: Tumour with diffuse subretinal or vitreous seeding > 3 mm from
tumour.
• Group E: Extensive retinoblastoma occupying >50% of the globe with or
without neovascular glaucoma, haemorrhage, extension of tumour to optic
nerve or anterior chamber.

12. Clinical features
• Presentation is within the first year of life in bilateral cases
• around 2 years of age if the tumour is unilateral.
• ○ Leukocoria (white pupillary reflex) is the commonest presentation (60%)
and may first be noticed in family photographs .
• ○ Strabismus is the second most common (20%).
Fundus examination is therefore mandatory in all cases of childhood squint.
• ○ Painful red eye with secondary glaucoma, which may occasionally be
associated with buphthalmos

13. • Inflammation or pseudoinflammation
• ○ Routine examination of a patient known to be at risk.
• ○ Orbital inflammation mimicking orbital or preseptal cellulitis may
occur with necrotic tumours
○ Orbital invasion or visible extraocular growth may occur in neglected
cases
• ○ Metastatic disease involving regional lymph nodes and brain before
the detection of ocular involvement is rare.

14. • Signs
• ○ An intraretinal tumour is a homogeneous, dome-shapedwhite lesion
that becomes irregular, often with white flecks of calcification.
• ○ An endophytic tumour projects into the vitreous as a white mass that
may ‘seed’ into the gel.
• ○ An exophytic tumour forms multilobular subretinal white masses and
causes overlying retinal detachment

15. Investigation
Red reflex testing with a direct ophthalmoscope is a simple
screening test for leukocoria that is easily employed in the community

16. • Examination under anaesthesia includes the following:
• ○ General examination for congenital abnormalities of the face and
hands.
• ○ Tonometry.
• ○ Measurement of the corneal diameter.
• ○ Anterior chamber examination with a hand-held slit lamp.
• ○ Ophthalmoscopy, documenting all findings with colour
• drawings or photography.
• ○ Cycloplegic refraction.

17. • Ultrasound is used mainly to assess tumour size. It also detects
calcification.
Wide-field photography is useful for both surveying and
documentation •
CT also detects calcification but entails a significant dose of radiation
so is avoided by many practitioners.
• Plain X-rays may be used to detect calcification in resource poor
• regions.

18. • MRI does not detect calcification but is useful for optic nerve
• evaluation, detection of extraocular extension and pinealoblastoma
• and to aid differentiation from simulating conditions.
• • Systemic assessment includes physical examination and MRI
scans of the orbit and skull as a minimum in high-risk cases.
• If these indicate the presence of metastatic disease then bone
• scans, bone marrow aspiration and lumbar puncture are also
performed.
• • Genetic studies on tumour tissue and blood samples from the
• patient and relatives

19. Treatment
• A collaborative approach is required involving the ophthalmologist,
paediatric oncologist, ocular pathologist, geneticist, allied health
professionals and parents. Treatment is highly individualized.
• The prognosis has improved significantly in recent years.

20. • Chemotherapy is the mainstay of treatment in most cases
and may be used in conjunction with local treatments (focal
consolidation ).
• ○ Intravenous treatment: carboplatin, etoposide and vincristine
(CEV) are given in three–six cycles according to the grade of
retinoblastoma. Single- (carboplatin alone) or dual-agent therapy has
also given favorable results in some circumstances, such as bridging
therapy to allow deferral of more aggressive measures.

21. • Selective ophthalmic artery infusion: this is a promising new
therapeutic option with high rates of globe salvage.
The treatment offers significantly better results than intravenous
treatment in eyes classified as group D. In this procedure a small
calibre cannula is introduced via the femoral artery into the opening of
the ophthalmic artery. Melphalan or topotecan is then injected over about
30 minutes and is carried into the branches of the arteries that supply
blood to the uvea and retina. The overall safety profile is better than IV
multi-drug chemotherapy.

22. • Chemo-reduction may be followed by focal treatment with
cryotherapy or TTT to consolidate tumour control
• TTT achieves focal consolidation following chemotherapy, or
• is sometimes used as an isolated treatment. Focal techniques
• such as TTT and cryotherapy exert both a direct effect and
• probably increase susceptibility to the effects of chemotherapy

23. • .
• • Cryotherapy using a triple freeze–thaw technique is useful for
• pre-equatorial tumours without either deep invasion or vitreous
• seeding.
• Brachytherapy using a radioactive plaque can be utilized
• for an anterior tumour if there is no vitreous seeding and
• in other circumstances such as resistance to chemotherapy
• •

24. • • External beam radiotherapy should be avoided if possible,
• particularly in patients with heritable retinoblastoma because
• of the risk of inducing a second malignancy. At present this
• option is used only for eyes with residual or relapsed retinoblastoma
• following previous intravenous or ophthalmic
• artery infusion. Adverse effects include cataract, radiation
• neuropathy, radiation retinopathy and hypoplasia of the bony
• orbit.

25. • Enucleation is generally indicated if there is neovascular glaucoma,
anterior chamber infiltration, optic nerve invasion or if a tumor occupies
more than half the vitreous volume (group E). It is also considered if
chemo-reduction fails and is useful for diffuse retinoblastoma because of
a poor visual prognosis and a high risk of recurrence with other
modalities.
• Enucleation should be performed with minimal manipulation and it is
imperative to excise a section of optic nerve to at least 10 mm.

26. • Extraocular extension
○ Adjuvant chemotherapy consisting of a 6-month course of CEV is
given subsequent to enucleation at some centers if there is
retrolaminar or massive choroidal spread.
○ External beam radiotherapy is indicated when there is tumor
extension to the cut end of the optic nerve at enucleation, or extension
through the sclera.
○ Systemic spread, especially CNS involvement, involves aggressive
treatment with high dose chemotherapy and autologous stem cell
rescue.

27. • Review. Careful review at frequent intervals is generally required
following treatment, in order to detect recurrence or the development of
a new tumour, particularly in heritable disease.

28. External beam radiotherapy should be avoided if possible in children
with heritable retinoblastoma, because of the risk of inducing a late
second malignancy in the radiation field.

29. Differential diagnosis
Persistent anterior fetal vasculature (persistent hyperplastic primary
vitreous is confined to the anterior segment and often involves the lens.
○ Presentation is with a lens opacity or leukocoria involving a retrolental
mass into which elongated ciliary processes are inserted
○ The size and density of the retrolental fibrovascular tissue
is variable.
○ Complications include cataract and angle closure glaucoma.
○ Early lens and vitreoretinal surgery may preserve useful vision in some
cases.

30. • Persistent posterior fetal vasculature is confined to the posterior
segment and the lens is usually clear.
• ○ Presentation is with leukocoria, strabismus or nystagmus.
• ○ A dense fold of condensed vitreous and retina extends from the optic
disc to the ora serrata .
• ○ Treatment is not effective.
• • Coats disease is almost always unilateral, more common in boys
and tends to present later than retinoblastoma

31. • Retinopathy of prematurity, if advanced, may cause retinal
detachment and leukocoria. Diagnosis is usually straightforward
because of the history of prematurity and low birthweight
• • Toxocariasis. Chronic Toxocara endophthalmitis may cause a
cyclitic membrane and a white pupil. A granuloma at the posterior pole
may resemble an endophytic retinoblastoma.

32. • Uveitis may mimic the diffuse infiltrating type of retinoblastoma
seen in older children. Conversely, retinoblastoma may be mistaken for
uveitis, endophthalmitis or orbital cellulitis.

33. • Vitreoretinal dysplasia is caused by faulty differentiation of
the retina and vitreous that results in a detached dysplastic retina
forming a retrolental mass with leukocoria .
• Other features include microphthalmos, shallow anterior chamber and
elongated ciliary processes. Dysplasia may occur in isolation or in
association with systemic abnormalities:

34. • Norrie disease is an X-linked recessive disorder in which affected males are
blind at birth or early infancy. It is caused by mutations in the NDP gene.
Systemic features include cochlear deafness and mental retardation.
○ Incontinentia pigmenti is an X-linked dominant condition that is lethal in
utero for boys. Mutations have been found in the NEMO gene. It is
characterized by a vesiculobullous rash on the trunk and extremities that with
time is replaced by linear pigmentation.
Other features include malformation of teeth, hair, nails, bones and CNS.

35. • Walker–Warburg syndrome is an autosomal recessive condition
characterized by absence of cortical gyri and cerebellar malformations
that may be associated with hydrocephalus and encephalocele.
Neonatal death is common and survivors suffer severe developmental
delay.
• Apart from vitreoretinal dysplasia other ocular features include Peters
anomaly, cataract, uveal coloboma, microphthalmos and optic nerve
hypoplasia.

36. • Other tumours
• ○ Retinoma (retinocytoma) is a variant of retinoblastoma that generally
exhibits benign behaviour but has a genetic profile indicating
premalignancy – rarely, a retinoma can undergo late transformation into
a rapidly growing retinoblastoma.
• It manifests as a smooth whitish dome-shaped lesion, which typically
involutes spontaneously to a calcified mass associated with RPE
alteration and chorioretinal atrophy.
• Retinal astrocytoma, which may be multifocal and bilateral

37. Thank you