What Is Retinoblastoma?
Retinoblastoma is a common malignant tumour which usually arises from the neurosensory retina in one or both of human eyes. Retinoblastoma is a proliferation of neural cells that have failed to evolve normally.
Retinoblastoma is the second most commonest malignant intraocular tumor after uveal melanoma.
James Wardrop, an ophthalmologist in edinburg,first recognised the tumor in 1809.
Variations In Retinoblastoma
Prevalence
Retinoblastoma is a most common intraocular tumor in children, occurring 1 in 15,000 to 20,000 live births and Retinoblastoma accounts for 2% of childhood cancers as neural cells fail to proliferate.
Age
Retinoblastoma is usually seen in infants and very young children, although it may remain quiescent, passing unnoticed until the fifth or sixth year of life but sometimes it may appear in later stages.
Sex
There is no sex predisposition for retinoblastoma to occur.
Race
Retinoblastoma occurs more prevalent in white people compared to colored people.
Laterality
Retinoblastoma is unilateral in 70-75% of cases. In 25-30% of the cases bilateral involvement is seen, although one of the eyes is affected more than others, in about one fourth of cases the fellow eye is affected independently, not by metastasis.
Genetics & Heredity
Retinoblastoma gene (RB) has been identified as 14 band on the long arm of chromosome 13 (13q 14) and is “cancer suppressor” or “anti oncogenic gene”.
Deletion or inactivation of both the normal alleles of this protective gene by two mutations (Knudsons’s two hit hypothesis) results in occurence of retinoblastoma.
Types of Retinoblastoma
Types Of Retinoblastoma
Heritable Retinoblastoma
According to Knudson’s two hit hypothesis Retinoblastoma is heritable it explains that, first hit (mutation) occurs in one of the two alleles of retinoblastoma gene on the germ cells (Gametes) before fertilization.
In about 40% of the cases Retinoblastoma, 10% occur due to inheritance from the affected parent or 30% of the cases, sporadically in one of the gametes.
The second hit (mutation) occurs late in the post zygotic phase and affects the second allele of one or more retinal cells, resulting in multifocal and usually bilateral tumor formation.
As a result of this Retinoblastoma is Genotypically autosomal dominant but it is Phenotypically autosomal recessive.
Non-Heritable Retinoblastoma
About 60% of retinoblastoma cases occur sporadically by both hits (mutation) occuring in the same retinal cell in the embryo after fertilization.These mutations generally result in unifocal and unilateral tumors which cannot be passed to the offspring.
Grading of Retinoblastoma
| Group | Quick Reference | Specific Features | Risk |
| A | Small Tumor | Rb < 3 mm in basal dimension or thickness | Very Low Risk |
| B | Larger Tumor | Rb > 3mm Macular Rb location (< 3mm from foveola)Juxtapapilary Rb location (<1.5mm to disc)Subretinal fluid <3mm from margin | Low Risk |
| C | Focal Seeds | Rb with Subretinal seeds<3 mm from RbVitreous seeds<3 mm from Rb | Moderate Risk |
| D | Diffuse Seeds | Rb withSubretinal seeds>3mm from RbVitreous seeds>3mm from Rb | High Risk |
| E | Extensive Rb | Massive Rb withAnatomic or functional destruction of the eyeNeovascular glaucomaOpaque media from hemorrhage in anterior chamber,vitreous or subretinal spaceInvasion of post laminar optic nerve,choroid (>2mm),sclera,orbit,anterior chamber Tumor touching lens Diffuse infiltrating tumorPhthisis or pre phthisis | Very High Risk |
Table Showing Grading Of Retinoblastoma
Histopathology Of Retinoblastoma
Retinoblastoma arises as a malignant proliferation of the immature retinal neural cells which are small round cells with large nuclei. It is a tumour of a group of cells, called small round blue cell tumours.
Tumor chiefly consists of small round cells with large nuclei, resembling the cells of the nuclear layer of the retina, these cells may be presented as highly undifferentiated or well differentiated tumors.
Microscopic features of a well-differentiated tumour include flexner-wintersteiner rosettes (highly specific of retinoblastoma), homer-wright rosettes/pseudorosettes and fleurettes formation.
Flexner Wintersteiner Rosettes
Source- Research Gate
Other histological features of Retinoblastoma include the presence of areas of necrosis and calcification.
Clinical Features Of Retinoblastoma (Symptoms and Signs)
Common presenting features of Retinoblastoma are listed in the following table according to their incidences,
| Presenting symptoms | Percentages |
| leucocoria | 60% |
| strabismus | 20% |
| Painful red eye | 7% |
| Poor vision | 5% |
| asymptomatic | 3% |
| Orbital cellulitis | 3% |
| Unilateral mydriasis | 2% |
| Heterochromia iridis | 1% |
| Hyphema | 1% |
Leucocoria-white pupil is the most commonest and noticeable symptom of Retinoblastoma. Pupil is not white instead it’s an empty gap.
Routes of spread
- Direct extension by continuity to the optic nerve and brain is one of the most common route of Retinoblastoma spread,
- Spreading of Retinoblastoma through the lymphatic system
- Hematogenous spread, where Retinoblastoma spread through blood.
Investigations For Retinoblastoma
- Examination of fundus is done using ophthalmoscope and parameters such as intraocular pressure and corneal diameter are measured and recorded.
- X-rays can demonstrate calcification within the tumor that occurs in 75% of cases and is pathognomonic of retinoblastoma
- Computerised tomography scan is more sensitive as it demonstrates any extension of retinoblastoma to optic nerve, orbit and cns. However CT Scan should be used sparingly because of potential risk of radiation sarcomas.
- Ultrasonography(USG-B) is extremely helpful in the diagnosis of retinoblastoma.
- Biopsy is done when the entire eyeball is removed and a sample is taken from the optic nerve.
Differential Diagnosis
Various conditions other than retinoblastoma, which present as leucocoria are collectively called as pseudoglioma. A few common conditions are
- congenital cataract,
- inflammatory deposits in vitreous following a plastic cyclitis or choroiditis,
- coloboma of choroid,
- the retinopathy of prematurity,
- persistent hyperplastic primary vitreous,
- toxocara endophthalmitis and
- exudative retinopathy.
In all cases both eyes should be dilated and thoroughly examined opthalmoscopically, under general anaesthesia if necessary. The intraocular pressure should be recorded as it is raised more often in retinoblastoma,whereas lowered intraocular pressure is common in pseudoglioma.
Endophytic retinoblastoma discovered on fundus should be differentiated from retinal tumors in tuberous sclerosis and neurofibromatosis,astrocytoma and a patch of exudative choroiditis.
Exophytic retinoblastoma should be differentiated from other causes of exudative retinal detachment in children such as coat’s disease.
Treatment
Treatment of group A to D tumors include multimodal therapy comprising primary systemic chemotherapy for chemoreduction followed by focal therapy for consolidation.
Chemotherapy- CVE REGIMEN
| A to C | Three weekly,6 cycles of carboplatin(18.6 mg) on day 1vincristine(0.05mg) on day 1etoposide(5mg) on day 1 and 2 |
| D(high dose CVE regimen) | Three weekly,6-12 cycles of carboplatin(28mg) on day 1vincristine(0.25mg) on day 1etoposide(12mg) on day 1 and 2 |
Focal therapy
Cryotherapy is indicated for a small tumor located anterior to the equator.
Laser photocoagulation is used for a small tumor located posterior to the equator.
Diode laser is used for a small tumor located posterior to the equator away from macula.
Radiotherapy is very effective against localised vitreous disease and for the elevated tumors when laser is ineffective.
External beam radiotherapy (EBR)once the mainstay of treatment is now reserved for diffuse disease in the only remaining eye.
Treatment of choice for E group tumors is enucleation (removal of the entire eyeball along with optic nerve) when Tumor involves more than half of the retina,optic nerve and anterior chamber and glaucoma is present. Chemotherapy consisting of carboplatin,vincristine and etoposide which may be combined with cyclosporine should be supplemented .
Management Of Unilateral Retinoblastoma
Prognosis
The prognosis of untreated retinoblastoma is almost always bad and the patient invariably dies.
Rarely Spontaneous regression with resultant cure and shrinkage of eyeball occurs due to necrosis followed by calcification; suggesting the role of some immunological phenomenon .
If the eyeball is enucleated before the occurrence of extraocular extension prognosis is fair (survival rate 70 to 85% )
Poor Prognostic factors are optic nerve involvement, differentiated tumor cells and massive choroidal invasion
Conclusion
Retinoblastoma is a most common intraocular malignancy, usually seen in children which is characterised by leucocoria and painful red eyes. Retinoblastoma might extend into the optic nerve which leads to bad prognosis, hence this must be treated using chemotherapy (CVE Regimen) and focal therapy.