Case presentation

Dr Tariq Masood TMO Radiology Department, HMC

Case
2 year old male child
Mother had noticed some white spot in the window of

his left eye since early childhood And gradual protrusion of the eye

Clinical differentials?

Leucocoria
TUMOR
Retinoblastoma (most common cause--58%) Retinal astrocytic hamartoma (3%): Medulloepithelioma (rare)

DEVELOPMENTAL
Persistent hyperplastic primary vitreous (2nd most common cause--28%) Coats disease (16%) Retrolental fibroplasia (3--5%) Coloboma of choroid / optic disc

 INFECTION Uveitis Larval granulomatosis (16%) DEGENERATIVE Posterior cataract

TRAUMA Retinopathy of prematurity (5%) Organized vitreous hemorrhage Long-standing retinal detachment

 Leukocoria in Normal-sized Eye CALCIFIED MASS Retinoblastoma Retinal astrocytoma NONCALCIFIED MASS Toxocaral endophthalmitis Coats disease Leukocoria with Microphthalmia UNILATERAL Persistent hyperplastic primary vitreous (PHPV) BILATERAL Retinopathy of prematurity Bilateral PHPV

Diagnosis?

RETINOBLASTOMA

History/Overview
In 1597 it starts with a man named Pieter Pauw and

his autopsy findings of cancerous tumor originating in a 3 year-old eye. The results of the autopsy were later found by Edwin B. Dunphy who suggested Retinoblastoma.

 In 1872 a Brazilian ophthalmologist called Hilrio de Gouva treated a boy with retinoblastoma. Later in life, the boy had two daughters that also had retinoblastoma. This proposed perhaps the disease was genetic.

 In 1986 Dr. Knudson discovered the retinoblastoma

gene and then a year later he isolated the gene making it the first ever tumor suppressor to be identified.

 In one of Knudsons cases he found that one family

had a genetic past of the disease and found that the gene causing the disorder is located in chromosome 13 that has been mutated.

Retinoblastoma
Rare malignant congenital intraocular tumor arising

from primitive photoreceptor cells of retina (included in primitive neuroectodermal tumor group) AKA neuroepithelioma of the retina

Cause of Retinoblastoma
1. Mutations Mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene, which means that it normally regulates cell growth and keeps cells from dividing too rapidly or in an uncontrolled way.

2.Chromosomal anomaly
A small percentage of retinoblastomas are caused by

deletions in the region of chromosome 13 that contains the RB1 gene. Because these chromosomal changes involve several genes in addition to RB1, affected children usually also have; microcephaly, ear changes, facial dysmorphism, mental retardation, finger + toe abnormalities, malformation of genitalia.

TYPES
A.Non-Heritable form
B.Heritable form

 A.Non-Heritable form(60%)
RB1 mutations occur only in the eye and cannot be

passed to the next generation. typically only one eye is affected and there is no family history of the disease. Affected individuals are born with two normal copies of the RB1 gene. Then, usually in early childhood, both copies of the RB1 gene in retinal cells acquire mutations or are lost Mean age at presentation--23 months

B.Heritable form(40%)
RB1 mutations occur in all of the body's cells, including reproductive cells (sperm or eggs). People with germinal retinoblastoma may have a family history of the disease, and they are at risk of passing on the mutated RB1 gene to the next generation. Mutations in the RB1 gene appear to be inherited in an autosomal dominant pattern.

 Autosomal dominant inheritance suggests that one

copy of the altered gene in each cell is sufficient to increase cancer risk. A person with germinal retinoblastoma may inherit an altered copy of the gene from one parent, or the altered gene may be the result of a new mutation that occurs in an egg or sperm cell or just after fertilization.

 For retinoblastoma to develop, a mutation involving

the other copy of the RB1 gene must occur in retinal cells during the person's lifetime. This second mutation usually occurs in childhood, typically leading to the development of retinoblastoma in both eyes.

 B.Heritable form
1.Heritable sporadic form

2.Familial retinoblastoma

1.Heritable sporadic form (20-25%)-- sporadic germinal

mutation (50% chance to occur in subsequent generations)
Mean age at presentation:

12 months--bilateral retinoblastomas in 66%

2.Familial retinoblastoma (5-10%) autosomal dominant with abnormality in chromosome 13 Mean age at presentation: 8 months usually 3 to 5 ocular tumors per eye bilateral tumors in 66% Risk of secondary nonocular malignancy: Osteo, chondro, fibrosarcoma, malignant fibrous histiocytoma

Trilateral retinoblastoma (rare variant)

bilateral retinoblastomas + neuroectodermal pineal tumor (pineoblastoma) trilateral retinoblastoma + 4th focus in suprasellar cistern

Quadrilateral retinoblastoma

Incidence
1:15,000 to 30,000 livebirths
Most common intraocular neoplasm in

childhood 1% of all pediatric malignancies

 Mean age at presentation is 18 months

98% in children <5 years of age M:F = 1:1

Patterns of growth
Endophytic
Growth occurs inwards into the vitreous anterior

chamber Cell clusters may detach and float in the vitreous (vitreous seeding)

 Exophytic
Growth occurs outwards Proliferation into subretinal space with non-

rhegmatogeneous retinal detachment + invasion of vascular choroid (hematogenous spread)

 Combined
Endophytic and Exophytic

Location
Posterolateral wall of globe (most commonly)
60% unilateral 40% bilateral + frequently

synchronous (90% bilateral in inherited forms) Normal ocular size/Enlarged

Presentations of retinoblastoma

Leukocoria - 60%

Strabismus - 20% Secondary glaucoma

Anterior segment invasion Orbital inflammation

Orbital invasion

PROPTOSIS

Imaging of RB
Ultrasound
CT scan MRI

 Imaging is crucial for timely management and survival

of patients with retinoblastoma. Cross-sectional imaging are done to exclude ; Other retrobulbar tumours with globe invasion, Optic nerve invasion by the retinoblastoma Intracranial metastases

US
Heterogeneous hyperechoic solid intraocular mass
Cystic appearance upon tumor necrosis Secondary retinal detachment in all cases Acoustic shadowing (in 75%) Vitreous hemorrhage frequent

Figure 7e. Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye.

Figure 7d. Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye.

Chung E M et al. Radiographics 2007;27:1159-1186

CT Scan
CT is sensitive to calcification.
Clumped or punctate calcification (in 95 per cent of

cases) in the posterior part of the globe extending into the vitreous Minimal enhancement.

CT Scan
Calcification in an intra-ocular mass in a child (3 yrs,

retinoblastoma until proven otherwise. Absence of calcification means this diagnosis is unlikely, since it is rare in other causes of leukocoria. Retinoblastoma is the most common cause of orbital calcifications!

CT Scan
Solid smoothly marginated lobulated retrolental

hyperdense mass in endophytic type Exophytic type grows subretinally causing retinal detachment Partial punctate / nodular calcification

 Dense vitreous (common)

Extraocular extension (in 25%): optic nerve

enlargement, abnormal soft tissue in orbit, intracranial extension Macrophthalmia

CT diagnosis of retinoblastoma
Calcification

Figure 8a. Trilateral retinoblastoma in a child of unknown age.

MRI
MRI is the modality of choice for pre-treatment

staging on retinoblastoma T1 : Intermediate signal intensity, hyperintense c.f. vitreous T2 : Hypointense c.f. vitreous subretinal exudate usually hyperintense on T1WI + T2WI (proteinaceous fluid)

 T1 C+ (Gd)
The mass usually enhances relatively homogeneously

when small Larger tumours often have areas of necrosis, rendering it heterogeneous

 Linear enhancement of the choroid beyond the

margins of the tumour should raise the possibility of choroidal involvement, although inflammation may lead to similar appearance

 Enhancement of the anterior chamber need not

represent tumour involvement, with hyperaemia, uveitis and iris neovascularisation all leading to asymmetric enhancement

 Careful assessment of the optic disc and optic nerve

should be carried out to assess for involvement

 Extra-ocular extension through the sclera will be

visible as interruption of the otherwise hypointense non-enhancing sclera by enhancing tumour

PROGNOSIS
Spontaneous regression in 1%;

Poor prognostic signs

Contrast enhancement
Optic nerve involvement Choroidal invasion

Anterior locations
Poor cellular

Large tumor

differentiation Older children

COMPLICATIONS
(1) Metastases to: meninges (via

space), bone marrow, lung,

subarachnoid liver, lymph nodes

(2) Radiation-induced sarcomas develop in

15-20%

Mortality
Choroidal invasion:

65% if significant, 24% if slight Optic nerve invasion:

<10% if not invaded 15% if through lamina cribrosa 44% if significantly posterior to lamina cribrosa

Margin of resection not free of tumor: >65%

Differential diagnosis
Retinal Astrocytic hamartoma
Retrolental fibroplasia Coats disease Peristent hypertrophic primary vitreous Toxocaral infestation Norries disease

DDx
Retinal astrocytic hamartoma.
May occur in association with TS or NF or an isolated

abnormality. May be bilateral multiple small retinal masses. calcification may occur in the older child

 Coats disease
Coats disease is a primary congenital, non-familial

idiopathic vascular anomaly of the retina. It is characterised by telangiectatic, leaky retinal vessels that lead to progressive retinal exudates. It usually occurs in young males (70%) with an incidence peak at age 68 years. It is mostly unilateral (90%). Patients present with leukocoria, strabismus or painful glaucoma..

 Calcification is rare,allowing differentiation from RB.

CT shows homogeneous increased density within the vitreous chamber,retinal detachment and lack of enhancement after contrast administration. The MRI findings are retinal detachment without intraocular mass and high signal subretinal effusion on both T1W and T2W MRI

 Retrolental fibroplasia

Retinopathy of prematurity causes retro-lental fibroplasia with the development of retrolental membranes. Present usually with bilateral leucocorea at the age of 7-10weeks with a history of prematurity and oxygen therapy. No Calcification. Microphthalmia.

 Persistent hyperplastic primary vitreous is caused by the failure of the embryonic hyaloid

vascular system to regress normally and extensive proliferation of embryonic connective tissue It is characterised by a leukocoria in a microphthalmic eye. Small irregular lens with shallow anterior chamber. If bilateral,PHPV may be part of the diagnosis of Norries disease.

 On CT
No calcification. Increased attenuation of vitreous with enhancement of

abnormal intravitreal tissue. Triangular retrolental density with its apex on the posterior lens and base on the posterior globe.

 Toxocara canis infection

Sclerosing endophthalmitis is a granulomatous

chorioretinitis uveitis that develops secondary to a Toxocara canis infestation, in more than 5 yrs age Present with leucocorea----often bilateral. It differs from RB by its central position, the fact that it is hyperintense to vitreous on T2 weighted images, the patient age and a positive serologic enzyme-linked immunosorbent assay (ELISA).

 CT demonstrate a hyperdense vitreous

cavity,sometimes with retinal detachment.No enhancement is seen.

 Norrie disease
Rare X-linked recessive syndrome consisting of retinal

malformation, deafness and mental retardation. Female carriers are completely healthy. The ocular changes in male patients include retinal detachments and vitreo-retinal haemorrhage

Treatment
Depends on tumour size and the stage of disease and

involves one or more modalities: Conservative external-beam radiation therapy cryotherapy laser photocoagulation radioactive plaque therapy thermochemotherapy tumour reduction chemotherapy Surgical enucleation en bloc resection

Treatment
Advantages Photocoagulation (Laser Therapy) The laser beam focuses on the cancerous tumor, cuts off blood supply to the tumor and shrinks it. Disadvantages Depending on the size of the tumor, chemotherapy may be needed for larger tumors that cannot be shrunk by just laser. The tumor will leave a pigmented scar and the eye lid will swell for a couple of days.

Cryotherapy (Freezing Treatment)

The tumor is frozen and thawed a several times by a cold gas and it deflates the tumor with no signs of a tumor at all. After the extensive cycles of chemo, the cancer cells are reduced, therefore, shrinking of the tumor.

Chemotherapy

There are several cycles, and there is a port necessary to draw blood, and insert the drugs.

Enucleation

This is removal of the eyeball and the tumor is extracted when no other option is possible due to the size of the tumor.

The whole eyeball is removed and it causes permanent eye damage because there is no way of an eye transplant.

WE HATE RETINOBLASTOMA

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