Clinical Characteristics
Ocular Features: 

Retinoblastoma is the most common intraocular malignancy of childhood occurring in 1 in 18,000 to 1 in 30,000 live births worldwide. The majority of cases are diagnosed before the age of 3 years. The most common clinical feature at time of diagnosis is leukocoria (white pupillary reflex) followed by strabismus. Other presenting features include intraocular inflammation, spontaneous hyphema, hypopyon, heterochromia, proptosis, spontaneous globe perforation, retinal detachment, cataract, neovascularization of iris, glaucoma, nystagmus, tearing and anisocoria.

Retinoblastoma can usually be observed during fundus exam as a white subretinal or vitreous mass, occasionally with multifocal nodules, typically with calcification of the surface. The growth of the tumor can be endophytic, exophytic or diffuse. Endophytic growth of retinoblastoma occurs when the tumor penetrates the inner limiting membrane of the retina and can result in vitreous seeding and growth and can simulate iridocyclitis or endophthalmitis.  Exophytic growth occurs when the tumor grows into the subretinal space, which results in accumulation of subretinal fluid and retinal detachments. If the tumor infiltrates Bruchs membrane, there is an increased risk of invasion of choroidal vessels or ciliary nerves and vessels. Diffuse growth is rare and characterized by slow infiltration of retina with diffuse thickening.

Imaging studies such as ultrasound, computerized tomography, and MRI can show the extent of tumor and the presence of calcification.

Systemic Features: 

In heritable cases there is an increased risk of developing other malignant neoplasms throughout life such as osteosarcomas, cutaneous melanomas, pinealomas, and thyroid carcinomas. The risk for secondary malignancies is higher in areas treated with radiation, where osteogenic sarcoma, fibrosarcoma and soft tissue sarcomas may occur. Patients should be closely monitored for secondary tumors throughout life.


Retinoblastoma is a malignant tumor of the developing retinal cells caused in most cases by mutations in both copies of the RB1 gene.  The RB1 gene is a tumor suppressor gene, located on chromosome 13q14 and is the first human cancer gene to be cloned. The gene codes for the tumor suppressor protein pRB, which by binding to the transcription factor E2F, inhibits the cell from entering the S-phase during mitosis.  Recent evidence suggests that post-mitotic cone precursors are uniquely sensitive to pRB depletion and may be the cells in which retinoblastoma originates.

However, more recent information suggests that the occurrence and viability of retinoblastic cells may be more complex than suggested by simple loss of function of the RB1 alleles.  There is increasing evidence for the role of epigenetic factors such as DNA methylation impacting the differential expression of more than 100 additional genes which may be influencing the retinoblastoma phenotype.  Among these is an upregulation of spleen tyrosine kinase (SYK) required for tumor cell survival which, if inhibited, leads to retinoblastoma cell death in vivo and in vitro.

Pedigrees of familial cases have an autosomal dominant pattern but the disease requires homozygosity of the RB1 mutation.  This complicates genetic counseling for retinoblastoma. One third of cases have a germline mutation with a mutation in only one of the two gene copies in every cell.  A somatic mutation in the second allele then leads to  homozygosity causing tumor development.  Since one of the parents contributed the germinal mutation, and there is high penetrance (as much as 85%), this leads to the autosomal dominant pattern in these families. In 6% of retinoblastoma cases with germline mutations the family history is positive. The risk for developing bilateral and multifocal retinoblastoma is high and the age of onset is around 14 months.  This is the case for virtually all bilateral tumors.  The mean number of tumors is about 5 in the two eyes.  The offspring of a parent with bilateral retinoblastoma have a 45% chance of developing a tumor (they have a 50% chance of inheriting the germline mutant allele).  Reduced penetrance of 10 to 15% lowers the expected occurrence of disease from 50% to 45%.

However, two thirds of cases are of non-germinal origin with both somatic mutations occurring in a single retinal progenitor cell.  Because this is a highly unlikely event, these cases are generally unilateral and unifocal with an average age of onset of 24 months. Sporadic cases constitute about 94% of all retinoblastomas, of which about 60% have unilateral disease with no germline mutations.  Individuals who acquire mutations in both alleles somatically (with single, unilateral tumors) do not have a mutation in their germ cells and therefore usually transfer no tumor risk to their offspring.  Laterality and number of tumors alone, however, cannot be used for accurate predictions in this case since about 15% of patients with unilateral and monofocal tumors actually have germline mutations.  This leaves a residual risk of transferring heritability of about 1-5% in unilateral patients without a family history.

To further complicate the story, recent evidence suggests that retinoblastoma is genetically heterogeneous.  About 6% of patients have no RB1 mutation.  In one study, about half of such individuals have up-regulation of the MYCN oncogene (2p24.3) suggesting a second mechanism leading to clinical retinoblastoma.  For unknown reasons, such tumors tend to  be larger, more aggressive, and discovered at an earlier age than unilateral non-familial RB1 tumors.  The MYCN gene product is a transcription factor important for organ development during embryogenesis.  Its amplification has been implicated in about 25% of neuroblastomas.

Autosomal dominant
Treatment Options: 

Enucleation may be necessary to eliminate the primary tumor, especially large ones, but other treatments can be used successfully to treat smaller tumors and spare vision. Intravenous chemotherapy is the most common treatment, which can be combined with subtenon chemotherapy, cryotherapy, thermotherapy, and plaque brachytherapy. External beam radiation can be used for refractive cases and recurrences. Another treatment alternative is localized ophthalmic artery intra-arterial chemotherapy.

It is necessary to follow all offspring of parents with bilateral tumors throughout the first decade because of the risk for new tumor development, as late as 5 to 7 years of age.   There are even a few case reports of retinoblastoma diagnosed in adults. However, since the retinal cells are generally mature by the age of 2.5 years, such events are very rare.  All parents of children with retinoblastoma should have complete fundus evaluations since rare tumors spontaneously regress leaving retinal scars, which in such a family pattern suggests that a germline mutation was inherited.

Survivors of hereditary retinoblastomas must be followed the rest of their lives, and especially so if radiation treatment was applied, because of the high risk of developing secondary neoplasms.  The risk rises with age.

Article Title: 

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Th?(c)riault BL, Prigoda-Lee NL, Spencer C, Dimaras H, Corson TW, Pang R, Massey C, Godbout R, Jiang Z, Zacksenhaus E, Paton K, Moll AC, Houdayer C, Raizis A, Halliday W, Lam WL, Boutros PC, Lohmann D, Dorsman JC, Gallie BL. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013 Mar 12:327-34.

PubMed ID: 

A novel retinoblastoma therapy from genomic and epigenetic analyses

Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012 Jan 11;481(7381):329-34.

PubMed ID: 
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