Retinoblastoma

ophthalmology

1. RetinoblastomaRetinoblastoma
Othman Al-Abbadi, M.D

2. HISTORY
•Peter Pawius of Amsterdam provided the first
description of a tumor resembling retinoblastoma in
1597. The tumor was described as filled with a
"substance similar to brain tissue mixed with thick
blood and like crushed stone."
•In 1805… termed as fungal hematode.
•In 1809, Wardop concluded its arousal from the
retina and suggested enucleation as primary mode
of management.
•In 1926… it was termed as retinoblastoma by the
AAO.
•In 1970, Tso and colleagues established that the
tumor arises from photoreceptor precursors.

3. •Retinoblastoma tumor cells grown in culture have been
shown to express a red and a green photopigment gene, as
well as cone cell alpha subunits of transducin. These findings
further support the concept that retinoblastoma may be a
neoplasm of cone cell lineage.
•The so-called retinoblastoma gene is deceptively named, as it
does not actively cause retinoblastoma. The normal gene
suppresses the development of retinoblastoma.
•Retinoblastoma develops when both homologous loci of the
suppressor gene become nonfunctional either by a deletion
error or by mutation. Although 1 normal gene is sufficient to
suppress the development of retinoblastoma, the presence of
1 normal gene and 1 abnormal gene is apparently an
unstable situation that may lead to mutation in the normal
gene and the loss of tumor suppression, thus allowing
retinoblastoma to develop.

4. INTRODUCTION
•Retinoblastoma is the most common primary
intraocular malignant tumor of childhood
•Results from mutation of the RB1 gene located at
the long arm of chromosome 13 (13q14)

5. EPIDEMIOLOGY
•Most common primary intraocular malignancy of
childhood
•3% of all childhood cancers
•Third most common intraocular malignancy after
Uveal melanoma & Metastasis
•Incidence 1:18.000
•90% present before 3 years of age
•No racial, gender nor side predilection
•60% unilateral… diagnosed at 24 months
•40% bilateral… diagnosed at 14 months

6. GENETICS
•Retinoblastoma is caused by a mutation in the RB1 tumor
suppressor gene located on the long arm of chromosome 13
at locus 14 (13q14).
•Both copies of the RB1 gene must be mutated in order for a
tumor to form.
•If a patient has bilateral retinoblastoma, there is
approximately a 98% chance that it represents a germline
mutation. Only about 5% of retinoblastoma patients have a
family history of retinoblastoma. The children of a
retinoblastoma survivor who has the hereditary form of
retinoblastoma have a 45% chance of being affected (50%
chance of inheriting and 90% chance of penetrance). In
these cases, the child inherits an abnormal gene from the
affected parent. This abnormal gene coupled with somatic
mutations in the remaining normal RB1 allele leads to the
development of multiple tumors in 1 or both eyes.

7. •Inherited as autosomal Dominant (genetic level)
•Acts as autosomal Recessive (cellular level)
•Penetrance

9. •Heritable
•40%
•Transmissible to offspring
•One pair is mutated in all cells of the body
•Two-hit hypothesis for malignant transformation
•Risk for bilateral & multifocal
•Risk for non-ocular tumors; Pinealoblastoma,
Osteosarcoma, soft tissue sarcoma, Melanoma & small cell
lung cancer
•Risk of second malignancy is 6%
•Risk increases 5-folds if exposed to radiation

11. •Non-heritable (Somatic)
•60%
•Solitary & unilateral
•No increased risk for non-ocular cancers
•Risk in siblings is 1%

12. SCREENING
•Detection of mutations in RB1 has approached 95%
in recent years.
•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.
•Early diagnosis correlates with a higher chance of
1
preserving vision,
2
salvaging the eye and
3
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.

13. PRESENTATION

15. TYPES OF GROWTH
•Intraretinal
•Homogeneous, dome-shaped white lesion often with white
flecks of calcification
•Endophytic
•Projects into the vitreous as a white mass that may ‘seed’
into the vitreous
•Exophytic
•Multilobular subretinal white masses causing overlying
retinal detachment

16. INTRARETINAL

17. ENDOPHYTIC
•Tumor grows into vitreous cavity
•yellow white mass

•Progressively fills vitreous cavity & vitreous seeds
occur
• Retinal vessels not seen on tumor surface

18. VITREOUS SEEDING

20. PSEUDOHYPOPION

21. VITREOUS SEEDING

23. EXOPHYTIC
•Tumor grows towards sclera
•R.D usually occurs
•Retinal vessels seen on tumor surface

26. GRADES OF OPTIC NERVE
INVOLVEMENT
•Grade 1
superficial involvement of optic nerve head only
•Grade 2
Involvement upto or involving lamina cribrosa

27. •Grade 3
Involvement beyond lamina cribrosa
•Grade 4
Involvement upto surgical margin

28. EXTENSION
•Optic nerve
•Most common
•To the subarachnoid space
•Orbit … through sclera
•Conjunctival lymphatics… through TM
•Metz
•Skull & distant bones
•Brain & spinal cord
•Lymph nodes
•Abdominal viscera

30. INVESTIGATIONS

31. RED REFLEX TESTING

32. EUA
•General examination for congenital abnormalities
of the face and hands
•Corneal diameter
•Tonometry
•AC examination
•Fundus exam with scleral indentation
•Cycloplegic refraction

33. RB ON SCLERAL INDENTATION

34. ULTRASOUND
•Assess tumour size
•Calcification

35. 3D U S

36. WIDE-FIELD PHOTOGRAPHY
•Surveying and documentation
•advantages in the management of retinoblastoma

37. C T SCAN
•Detects calcification
•Delineates extraocular extension

39. M R I
•Does not detect calcification
•Optic nerve evaluation
•Detection of extraocular extension
•Preferred over CT

40. M R I

41. FINE NEEDLE ASPIRATION BIOPSY
•Rarely done, invasive procedure
•Approach through peripheral cornea, A/C, zonules,
vitreous is recommended

42. WHY NO TO FNA
•Taking a biopsy specimen from a tumor in the eye
can’t be done easily without harming the eye and
risking spreading cancer cells outside the eye.
•Retinoblastoma can usually be diagnosed
accurately without a biopsy

44. 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.

45. GENETIC STUDIES
•
1
Tumour tissue and
2
blood samples from the patient
and relatives

46. CLASSIFICATION

47. REESE-ELLSWORTH CLASSIFICATION

48. INTERNATIONAL CLASSIFICATION

49. TREATMENT

51. •The first and foremost important to understand that it is a
malignancy.
•When the disease is contained within the eye, survival
rates exceed 95% in the Western world. However, with
extraocular spread, survival rates decrease to under
50%.
•Therefore, when a treatment strategy is being decided,
the first goal must be
1
preservation of life, then
2
preservation of the eye, and, finally,
3
preservation of
vision.
•The modern management of intraocular retinoblastoma
currently incorporates a combination of different
treatment modalities

52. CHEMOTHERAPY
•The mainstay of treatment in most cases
•Intravenous
•Intravitreal
•Selective ophthalmic artery infusion
•Sub-Tenon
•Intravenous carboplatin, etoposide and vincristine
(CEV) are given in 3-6 cycles every 3-4 weeks
according to the grade of retinoblastoma
•Chemoreduction may be followed by focal
treatment

53. TRANSPUPILLARY THERMOTHERAPY
•Used as solitary or adjuvant therapy
•Exert both a direct effect and probably increase
susceptibility to the effects of chemotherapy
•The diode laser (810 nm) is used to provide
hyperthermia.
•Direct application to the surface increases the tumor ’s
temperature to the 45°–60° Celsius range and has a
direct cytotoxic effect, which can be augmented by
both chemotherapy and radiation

54. CRYOTHERAPY
•Applied under direct visualization with a triple
freeze–thaw technique
•Typically, laser photoablation is chosen for
posteriorly located tumors and cryoablation for
more anteriorly located tumors

55. BRACHTHERAPY
•Using a radioactive plaque
•For anterior tumour if there is no vitreous seeding,
•and in resistance to chemotherapy

56. EXTERNAL BEAM RADIOTHERAPY
•Retinoblastoma is radio-sensitive
•Globe salvage rates are excellent, with up to 85% of
eyes being retained
•Visual function is often excellent and limited only by
tumor location or secondary complications
•Complications:
•The association of germline mutations of the RB1 gene with
a lifelong increase in the risk of second, independent
primary malignancies
•Midface hypoplasia, radiation-induced cataract, and
radiation optic neuropathy and retinopathy
•Evidence suggests that combined-modality therapy
that uses lower-dose radiotherapy coupled with
chemotherapy may allow for increased globe
conservation with decreased radiation morbidity

57. ENUCLEATION
•The definitive treatment for retinoblastoma, providing, in
most cases, a complete surgical resection of the disease
•Indications:
•>50% of the globe involvement
•orbital or optic nerve involvement is suspected
•anterior segment involvement is present
•neovascular glaucoma is present
•there is limited visual potential in the affected eye
•Enucleation should be performed with minimal
manipulation
•A section of optic nerve at least 10 mm should be
obtained

58. EXTRAOCULAR EXTENSION
•External beam radiotherapy is indicated when there
is tumour extension to the cut end of the optic
nerve at enucleation, or extension through the
sclera
•Adjuvant chemotherapy consisting of a 6-month
course of CEV is given subsequent to enucleation at
some centres if there is retrolaminar or massive
choroidal spread

59. DIFFERENTIAL DIAGNOSES
•Persistent fetal vasculature
•Coats disease
•ROP
•Toxocariasis
•Uveitis
•Vitreoretinal dysplasia
•Trilateral retinoblastoma (pinealoblastoma)

60. SPONTANEOUS REGRESSION
•Retinoblastoma is one of the more common
malignant tumors to undergo complete and
spontaneous necrosis (although this is rarely
recognized with active disease)
•It’s recognized clinically after involutional changes
such as phthisis have occurred
•Incidence is unknown
•Mechanism is not understood, but its histologic
appearance is diagnostic

61. PROGNOSIS
•The most important risk factor associated with
death is extraocular extension of tumor