Retinoblastoma

It is a common congenital malignant tumour arising
from the neurosensory retina in one or both eyes.
Incidence
1. It is the most common intraocular tumour of
childhood occurring 1 in 20,000 live births.
2. Age. Though congenital, it is not recognised at
birth, and is usually seen between 1 and 2 years
of age.
3. Sex. There is no sex predisposition.
4. Race. It is rarer in Negroes than Whites.
5. Bilaterality. In 25-30 percent cases, there is
bilateral involvement, although one eye is affected
more extensively and earlier than the other.
Genetics and heredity
Retinoblastoma (RB) gene has been identified as 14
band on the long-arm of chromosome 13 (13q 14) and
is a ‘cancer suppressor’ or ‘antioncogenic’ gene.
Deletion or inactivation of this protective gene by
two mutations (Knudson’s two hit hypothesis) results
in occurrence of retinoblastoma.
Retinoblastoma may arise as hereditary and nonherditary
forms.
1. Hereditary or familial cases. In such cases 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 nonocular
tumour). Second hit (mutation) occurs late in
postzygote phase and affects the second allele,
resulting in development of retinoblastoma. Some
facts about hereditary retinoblastoma are:
Accounts for 40% of all cases.
All bilateral cases and about 15% of the unilateral
cases are hereditary.
Most hereditary cases are multifocal.
Some hereditary cases have trilateral retinoblastoma
(i.e., have associated pinealoblastoma).
Inheritance is autosomal dominant and the risk of
transmitting the gene mutation is 50%. Because
of high peneterance 40% of offspring of a surviver
of heraditary retinoblastoma will develop the
tumour.
There are 40% chances of developing tumour in
a sibling of a child with bilateral retinoblastoma
(with unaffected parents).
2. Non-hereditary or sporadic cases. In nonhereditary
cases both hits (mutations) occur in the
embryo after fertilization and in the same retinal cell.
Some facts about non-hereditary (somatic)
retinoblastoma are:
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.
Clinical picture
It may be divided into four stages:
I. Quiescent stage. It lasts for about 6 months to one
year. During this stage, child may have any of the
following features:
1. Leukocoria or yellowish-white pupillary reflex
(also called as amaurotic cat’s eye appearance)
is the commonest feature noticed in this stage
(Fig. 11.34).
2. Squint, usually convergent, may develop in some
cases.
3. Nystagmus is a rare feature, noticed in bilateral
cases.
4. Defective vision. Very rarely, when the tumour
arises late (3-5 years of age), the child may
complain of defective vision.
5. Ophthalmoscopic features of tumour. In the early
stages, before the appearance of leukocoria,
fundus examination after full mydriasis may reveal
the growth. Ophthalmoscopic signs in two types
of retinoblastoma are as follows:
i. Endophytic retinoblastoma (Fig. 11.35A): It
grows inwards from the retina into the
vitreous cavity. On ophthalmoscopic
examination, the tumour looks like a well
circumscribed polypoidal mass of white or
pearly pink in colour. Fine blood vessels and
sometimes a haemorrhage may be present on
its surface. In the presence of calcification, it
gives the typical ‘cottage cheese’ appearance.
There may be multiple growths projecting
into the vitreous.
ii. Exophytic retinoblastoma (Fig. 11.35B). It
grows outwards and separates the retina
from the choroid. On fundus examination it
gives appearance of exudative retinal
detachment (see page 278).
II. Glaucomatous stage. It develops when
retinoblastoma is left untreated during the quiescent
stage. This stage is characterised by severe pain,
redness, and watering.
Signs. Eyeball is enlarged with apparent proptosis,
conjunctiva is congested, cornea become hazy,
intraocular pressure is raised. Occasionally, picture
simulating severe, acute uveitis usually associated
with pseudohypopyon and/or hyphaema may be the
presenting mode (retinoblastoma masquerading as
iridocyclitis).
III. Stage of extraocular extension. Due to
progressive enlargement, of tumour the globe bursts
through the sclera, usually near the limbus or near
the optic disc. It is followed by rapid fungation and
involvement of extraocular tissues resulting in marked
proptosis (Fig. 11.36).
IV. Stage of distant metastasis. It is characterised by
the involvement of distant structures as follows:
1. Lymphatic spread first occurs in the preauricular
and neighbouring lymph nodes.
2. Direct extension by continuity to the optic nerve
and brain is common.
3. Metastasis by blood stream involves cranial and
other bones. Metastasis in other organs, usually
the liver, is relatively rare.
Differential diagnosis
1. Differential diagnosis of leukocoria. Various
conditions other than retinoblastoma, which present
as leukocoria are collectively called as
‘pseudoglioma'. A few common conditions are
congenital cataract, inflammatory deposits in vitreous
following a plastic cyclitis or choroiditis, coloboma
of the choroid, the retrolental fibroplasia (retinopathy
of prematurity), persistent hyperplastic primary
vitreous, toxocara endophthalmitis and exudative
retinopathy of Coats.
2. Endophytic retinoblastoma discovered on fundus
examination should be differentiated from retinal
tumours in tuberous sclerosis and neurofibromatosis,
astrocytoma and a patch of exudative choroiditis.
3. Exophytic retinoblastoma should be differentiated
from other causes of exudative retinal detachment
(see page 278).
Diagnosis
1. Examination under anaesthesia: It should be
performed in all clinically suspected cases. It
should include fundus examination of both eyes
after full mydriasis with atropine (direct as well as
indirect ophthalmoscopy), measurement of
intraocular pressure and corneal diameter.
2. Plain X-rays of orbit may show calcification
which occurs in 75 percent cases of
retinoblastoma.
3. Lactic dehydrogenase (LDH) level is raised in
aqueous humour.
4. Ultrasonography and CT scanning are very
useful in the diagnosis. CT also demonstrates
extension to optic nerve, orbit and CNS, if any
(Fig. 11.37).
Treatment
1. Tumour destructive therapy. When tumour is
diagnosed at an early stage I i.e., when tumour is
involving less than half of retina and optic nerve is
not involved (usually in the second eye of bilateral
cases), it may be treated conservatively by any one
or more of the following tumour destructive methods
depending upon the size and location of the tumour:
Present recomendations are for sequential
aggressive local therapy (SALT) comprising of multimodality
therapy as below:
Chemoreduction followed by local therapy
(Cryotherapy, thermochemotherapy or brachytherapy)
is recommended for large tumours (>12
mm 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).
Cryotherapy is indicated for a small tumour (<4.5
mm indiameter and <2.5 mm in thickness) located
anterior 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.
However, if the above modalities are not available,
the eyeball should be enucleated without hesitation.
2. Enucleation. It is the treatment of choice when:
Tumour involves more than half of the retina.
Optic nerve is involved.
Glaucoma is present and anterior chamber is
involved.
The eyeball should be enucleated along with maximum
length of the optic nerve taking special care not to
perforate the eyeball.
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.
3. Palliative therapy is given in following cases
where prognosis for life is dismal in spite of aggressive
treatment:
Retinoblastoma with orbital extension,
Retinoblastoma with intracranial extension, and
Retinoblastoma with distant metastasis.
Palliative therapy should include combination of :
Chemotherapy,
Surgical debulking of the orbit or orbital
exentration, and
External beam radiotherapy (EBRT)
Note: Exentration of the orbit (a mutilating surgery
commonly performed in the past) is now not preferred
by many surgeons.
Prognosis
1. If untreated the prognosis is almost always bad
and the patient invariably dies. Rarely
spontaneous regression with resultant cure and
shrinkage of the eyeball may occur due to necrosis
followed by calcification; suggesting role of some
immunological phenomenon.
2. Prognosis is fair (survival rate 70-85%) if the
eyeball is enucleated before the occurrence of
extraocular extension.
3. Poor prognostic factors are: Optic nerve
involvement, undifferentiated tumour cells and
massive choroidal invasion.