dr george deogratias from TANZANIA

1. RETINOBLASTOMA
Prepared by
George deogratias MD5 student.
Archbishop James university college the constitute of st.augustine
university of Tanzania.
(biziriko1991@gmail.com)
+255656592079

2. Contents
• Introduction
• Epidemiology
• Pathogenesis
• Clinical stages
• Classification
• Diagnosis
• Differential diagnosis
• Treatment
• Prognosis
• Genetic counseling
• References

3. Introduction
• Retinoblastoma is a rapidly developing
cancer that develops from the immature
cells of a retina, the light-detecting tissue
of the eye and is the most common
malignant tumor of the eye in children .

4. Epidemiology
• Most common primary intraocular cancer of
childhood
• Third most common intraocular cancer
overall after melanoma and metastasis
• Incidence is 1/18,000-1/30,000 live births
• 90% of cases present before 3 years of age

5. • Occurs equally in males and females
• Occurs equally in right and left eyes
• No racial predilection
• 60% unilateral (mean age at diagnosis, 24
months)
• 40% bilateral (mean age at diagnosis, 12
months)

6. • A higher incidence is noted in developing
countries, this has been implicated to lower
socioeconomic status and the presence of
human papilloma virus sequences in the
retinoblastoma tissue.
• In the developed world, Rb has one of the
best cure rates of all childhood cancers (95-
98%), with more than nine out of every ten
sufferers surviving into adulthood.

7. Retinoblastoma may arise as;
• hereditary/familial
• Nonherditary/non familial/sporadic

8. hereditary/familial
• Accounts for 40% of all cases.
• All bilateral cases and about 15% of the
unilateral cases are hereditary.
• Most hereditary cases are multifocal.

9. • Inheritance is autosomal dominant and
the risk of transmitting the gene mutation
is 50%.
• Some hereditary cases have trilateral
retinoblastoma (i.e., have associated
pinealoblastoma).

10. • Accounts for 60% of all cases.
• All non-hereditary cases are unilateral and
unifocal and accounts for 85% of the all
unilateral cases of retinoblastoma.
• Patient is not predisposed to get second
nonocular cancer.
• Tumour is not transmissible.
Non herditary/non familial/Sporadic

11. Pathogenesis
• It arises as malignant proliferation of the
immature retinal neural cells called,
retinoblasts, which have lost their
antioncogenic genes RB1.
• Because these cells disappear within the
first few years of life, the tumour is seldom
seen after 3 years of age
• RB1 is a tumor suppressor gene
• Identified as 14 band on the long-arm of
chromosome 13 (13q 14)

12. • It normally regulates cell growth and
controls cell division.
• If there is gene mutation of RB1 –then
there will be no functional protein and no
effective regulation of cell division
• As a result, certain cells in the
retina(photoreceptors) can divide
uncontrollably to form cancerous tumors.

13. • In hereditary, first hit (mutation) occurs in
one of the parental germ cells before
fertilization.
• This means mutation will occur in all somatic
cells (predisposing to develop even non
ocular tumor).
• Second hit (mutation) occurs late in post
zygote phase and affects the second allele,
resulting in development of retinoblastoma.

14. • In nonhereditary cases both hits (mutations)
occur in the embryo after fertilization and in
the same retinal cell.
• Because all the retinal precursor cells contain
the initial mutation, these children develop
bilateral and multifocal tumors in hereditary
form.

15. • Heritable retinoblastoma patients also have a
predisposition to nonocular cancers, most
notably pineal or suprasellar primitive
neuroectodermal tumour (PNET; also known
as pinealoblastoma and trilateral
retinoblastoma), which occurs in about 3%..

16. • Second malignant neoplasms include
osteosarcoma, melanoma, and malignancies
of the brain and lung, each of these tumours
tending to occur in a particular age group.
• The risk of second malignancy is about 6% but
this increases five-fold if external beam
irradiation has been used to treat the original
tumour, the second tumour tending to arise
within the irradiated field.

17. "Two hit model"
• if a child inherits a gene predisposing it to
get Retinoblastoma, a second event must
take place to change the other gene,
causing Retinoblastoma to occur.
 The nature of the 2nd event is unknown,
but research is trying to determine which
factors can precipitate the onset of this
disorder.

18. Well differentiated
Retinoblastoma
Flexner–
Wintersteiner
rosettes
comprise a ring
of nuclei
surrounding an
empty lumen.
Grade I

19. • Flexner-
Wintersteiner
rosettes: note
the central
lumen.

20. Moderately
differentiated
retinoblastoma
Homer - Wright
(Primitive ) rosettes are
formed by a rim of
nuclei with a center
filled by tangles of
cytoplasmic
fi lamentsThese rosettes
also occur in
neuroblastomas and
other tumors. Both
types may contain
mitotic fi gures.
Grade II

21. • Homer Wright
rosettes: note the
neurofibrillary
tangle (arrow) in
the center of
these structures.

22. Undifferentiated
retinoblastoma
Undifferentiated
tumors show
sheets of small and
medium-sized cells
with scanty
cytoplasm and
hyperchromatic
nuclei
Grade III

23. • The fleurette (arrow)
demonstrates bulbous
cellular extension of
retinoblastoma cells
that represent
differentiation along
the lines of
photoreceptor inner
segments.

24. Clinical Stages
1. Quiescent stage.
2. Glaucomatous stage.
3. Stage of extraocular extension.
4. Stage of distant metastasis.

25. 1.Quiescent stage.
(6/12-1yr)
• Leukocoria or yellowish-white pupillary reflex
(amaurotic cat’s eye appearance)
• Squint, usually convergent.
• Nystagmus
• Defective vision. Very rarely, when the tumour
• arises late (3-5 years of age)
• Ophthalmoscopic features;
(exo/endophytic,mixed)

26. Endophytic
-polypoidal mass of
white or pearly pink in
colour.
-Fine blood vessels+/-
haemorrhage on
its surface.
-If calcification
occurs,typical ‘cottage
cheese’ appearance.
-May be multiple
growths projecting
into the vitreous

27. Exophytic
It grows outwards and
separates the retina
from the choroid.
On fundus examination
it gives appearance of
exudative retinal
detachment

29. 2.Glaucomatous stage.
Symptoms;
• severe pain,redness, and watering.
Signs;
• proptosis,
• conjunctiva congestion,
• corneal haziness
• Raised intraocular pressure
• simulating severe, acute uveitis usually
associated
• Pseudohypopyon and/or hyphaema

31. 3.Stage of extraocular extension.
Tumour of the globe
can bursts through the
sclera, usually near the
limbus or near the optic
disc, followed by rapid
fungation and
involvement of
extraocular tissues
resulting in marked
proptosis

32. 4.Stage of distant metastasis.
• 1.Lymphatic spread first occurs in the
preauricular and neighbouring lymph nodes.
• 2. Direct extension by continuity to the optic
nerve and brain.
• 3. Metastasis by blood stream involves
cranial and other bones. Metastasis in other
organs, usually the liver, though is relatively
rare.

37. 1. Persistent hyperplastic
primary vitreous (PHPV):
A congenital developmental
anomaly of the eye resulting
from failure of the
embryological, primary
vitreous and hyaloid
vasculature to regress,
whereby the eye is shorter,
develops a cataract, and may
present with whitening of
the pupil.

38. 2. Toxocara canis :an
infectious disease of
the eye associated
with exposure to
infected puppies,
which causes a
retinal lesion
leading to retinal
detachment.

39. 3.Coats disease:
a typically unilateral disease
characterised by abnormal
development of blood
vessels behind the retina,
leading to blood vessel
abnormalities in the retina
and retinal detachment to
mimic retinoblastoma

40. 4. Retinopathy of
prematurity (ROP):
associated with low
birth weight infants
who receive
supplemental oxygen
in the period
immediately after
birth, it involves
damage to the retinal
tissue and may lead to
retinal detachment

41. Diagnosis
1.Examination under anaesthesia:
-Fundus examination.
-intraocular pressure.
-corneal diameter.
2.Plain X-rays of orbit
-Calcificatio which occurs in 75 percent cases
of retinoblastoma.

42. 3.Lactic dehydrogenase (LDH) level is raised in
aqueous humour.
4. Fine-needle aspiration biopsy (Fl AB) should
be undertaken only with extreme caution and
only by an experienced ocular oncologist,
because of the risk of systemic dissemination
of tumor.
5.Gene analysis

43. Further testing may include imaging studies.
• CT and MRI,can help define the structural
abnormalities and reveal any calcium
depositions.
• Ultrasound can help define the height and
thickness of the tumor.
• Bone marrow examination or lumbar
puncture may also be done to determine
any metastases to bones or the brain.

44. CT Scan with Retinoblastoma

45. Treatment
1. Tumour destructive therapy.
2. Enucleation.
3. Palliative therapy

46. Tumour destructive therapy.
When the tumour is;
• diagnosed at an early stage (I) i.e. when
tumour involves less than half of retina
• optic nerve is not involved,
It may be treated conservatively by any or more
of the following tumour destructive methods
depending upon;
• the size
• the location of the tumour:

47. • Chemoreduction followed by local therapy
(Cryotherapy, thermochemotherapy or
brachytherapy) is recommended for large
tumours (>12mm in diameter)
• Radiotherapy (external beam radiotherapy
i.e. EBRT or brachytherapy) combined with
chemotherapy is recommended for medium
size tumour <12 mm in diameter and <8mm in
thickness)

48. • Cryotherapy is indicated for a small tumour
(<4.5mm indiameter and <2.5 mm in
thickness) locatedanterior to equator.
• Laser photocoagulation is used for a small
tumour located posterior to equator <3 mm
from fovea.
• Thermotherapy with diode laser is used for a
small tumour located posterior to equator
away from macula.

49. A, Before trea tment. B, Same eye 6 months
later, after treatment with chemoreduction and
laser therapy

50. Enucleation.
• Excision of the eyeball.
Indications;
• Tumour involves more than half of the retina.
• Optic nerve is involved.
• Glaucoma is present and anterior chamber is
involved.

51. Postoperative
If optic nerve shows invasion, postoperative
treatment should include:
• Radiotherapy (5000 rads) should be applied to
the orbital apex.
• Chemotherapy, consisting of vincristine,
carboplatin, and etoposide which may be
combined with cyclosporin should be
supplemented.

52. Palliative therapy
When prognosis for life is dismal in spite of
aggressive treatment:orbital extension,
intracranial extension,distant metastasis.
It includes;
• Chemotherapy,
• Surgical debulking of the orbit
• External beam radiotherapy (EBRT)
• Orbital exentration

53. • If retinoblastoma has been treated
conservatively; EUA is necessary every 2 to 8
weeks until the age of 3 years, after which
time examination without anaesthesia is
performed every 6 months until the age of
about 5 years, then annually until the age of
about 10 years.

54. • Spontaneous regression is recognized
clinically after involutional changes
such as phthisis have occurred.
• The incidence of spontaneous
regression is unknown, as no child
with active retinoblastoma is observed
with the hope of spontaneous
involution.

55. • Mechanism-not understood but histological
appearance is diagnostic.
• The vitreous cavities of these phthisical eyes
are filled with islands of calcified cells
embedded in a mass of fibroconnective tissue.
• Close inspection of the peripheral portion of
these calcified islands reveals the ghosted
contours of fossilized tumor cells
accompanied by exuberant proliferation of
retinal pigment and ciliary epithelia.

56. Genetic Counselling
Child with retinoblastoma
Family genetic counseling
retinoblastoma genetic mutation can be inherited.
Note;If the child carries the mutated RB1 gene,
then other children in the family might have
inherited the same abnormal gene as well
assuming that they have the hereditary form of
the disease (even if there is no family history of
the disease) till proved otherwise.

57. What to remember;
The genetic counselor will:
• Review the child’s medical records and ask
questions about other relatives to estimate the
likelihood of an inherited gene affecting some
family members.
• Provide information and answer questions about
Rb, genetic testing, and schedule tests for other
children in your family (if needed) so that their
risk of developing retinoblastoma can be
determined.

58. If tests show your children are at risk of
developing retinoblastoma;
• Close follow up
• Early diagnosis
• Proper management

59. • Molecular genetic test is an important tool in
genetic counselling.
• Mutation analysis of RB1 gene is done in
white blood cell DNA and tumor cells.
• If molecular genetic testing is not available or
is uninformative, empiric risks based on
tumor presentation (i.e. unifocal or
multifocal, laterality) and family history can
be used.

61. Parents of a proband
– Detectable cytogenetically chromosome 13
deletion or rearrangement do parental
cytogenetic studies to determine if either parent
carries a balanced chromosome translocation or
rearrangement
– Positive family history (i.e., the parent had
retinoblastoma or a close relative of one parent
had retinoblastoma). Conclusion: The parent has
an RB1 cancer-predisposing germline mutation.

62.  Negative family history.
DO;
– Examination of apparently unaffected
parents by an ophthalmologist
knowledgeable about retinoblastoma,
retinoma, and retinoblastoma-associated
eye lesions.
–If such a lesion is detected, the parent has
an RB1 cancer-predisposing germline
mutation

63. • Presence of a germline RB1 cancer-
predisposing mutation. Recommendation:
Molecular genetic testing of a blood sample
of both parents.
• If a germline mutation is identified in either
parent, the parent is at risk of developing
non-ocular second primary tumors and is
at-risk to transmit the mutation to other
offspring.

64. • If a germline RB1 mutation is not identified
in either parent, two possibilities exist:
1)the index case has a de novo RB1 germline
mutation (90-94% chance)
2)one parent has mosaicism (which includes
the germline) for the RB1 cancer-
predisposing mutation (6-10% chance).
• Mosaicism for an RB1 cancer-predisposing
mutation THEN Molecular genetic testing
of the parents is not necessary.

65. Sibs of a proband
depends on the genetic status of the parents of the
index case.
• If a parent is determined to have a germline RB1
cancer-predisposing mutation -the risk to each
sib of the index case is 50%
• If neither parent has the cancer-predisposing RB1
mutation -germline mosaicism in one parent is
possible and the risk to each sib of having
retinoblastoma is 3-5%

66. • If index case has mosaicism for an RB1
cancer-predisposing mutation-it is assumed
that the mutation arose as a post-zygotic
event and that neither parent has an RB1
germline mutation.
• The risk to the sibs is not increased.

67. Offspring of a proband
– If the index case has sporadic bilateral RB, a germline
RB1 cancer-predisposing mutation has to be assumed
and the risk to each offspring is close to 50%.
– If the index case has had sporadic unilateral multifocal
RB, recurrence risk for offspring is lower. (Note: In rare
families with "familial-low penetrance retinoblastoma,"
the risk of tumor development is less than 40%).
– The low (~1%), but not negligible, risk to the offspring of
index cases with unifocal disease and a negative family
history reflects the possibility of a germline RB1
mutation with low penetrance or mutational mosaicism.

68. Refferences
• wiki.ggc.edu
• http://en.wikibooks.org/wiki/Handbook_of_G
enetic_Counseling/Retinoblastoma
• American Series 4,chapter 11&19
• Wikipedia
• James. Y retinoblastoma pathology
notes(Resident – Pathology dpt)
• http://emedicine.medscape.com/article/1222
849-overview#a0104