The retinoblastoma gene (RB1), encoded on chromosome 13q14, was the first described tumor suppressor gene. Constitutional loss of one RB1 allele causes cancer predisposition, and loss of the second allele in a developing retinal cell leads to retinoblastoma.

Retinoblastoma can be sporadic or inherited. Sporadic tumors are unilateral and unifocal and occur at an older age, while inherited tumors occur at an earlier age and are often bilateral and multifocal. One-third of all cases have bilateral tumors. All cases with bilateral disease have germline mutations of RB1 and are heritable (Fig. 12.1). Only a small proportion of unilateral tumors are heritable. Alfred Knudson’s “two-hit” model of oncogenesis proposes that two mutational events are required for development of retinoblastoma. In inherited retinoblastoma, the first hit is the mutation in the RB1 inherited in the germline, and the second is acquired in the somatic retinal cell. In sporadic retinoblastoma, both mutations occur in the somatic retinal cell. Most cases of hereditary retinoblastoma have spontaneous new germline mutation, while their parents have both wild-type RB1 alleles. The risk of an offspring inheriting an RB1 mutation from a parent with germline mutation of RB1 is 50 % and 97 % of these offsprings with the inherited mutation will go on to develop retinoblastoma. A constitutional (germline) mutation of RB1 also causes an increased risk of a second cancer of the lung, soft tissue, bladder, skin, bone, and brain, and this risk is even higher when these patients are treated with radiation therapy for their retinoblastoma. A small proportion (10–15 %) of unilateral tumors are also hereditary.

Leukocoria (white pupillary reflex) is the most common presentation (Fig. 12.2). Retinoblastoma must be differentiated from Coat’s disease, cataract, toxocariasis, and retinopathy of prematurity which may also present with leukocoria. Pain may be present secondary to glaucoma; other presenting features are strabismus, redness of the eye, and poor vision. Orbital inflammation and fungating orbital mass are signs of advanced disease (Fig. 12.3). In developing countries, retinoblastoma presents very late in its extraocular stage, either with an orbital mass (proptosis) or with distant metastasis in the bone, bone marrow, lymph nodes, and central nervous system (Fig. 12.4a, b) Chawla et al. (2015).

Diagnosis is established by characteristic ophthalmologic findings, often requiring examination under anesthesia. Imaging studies such as ultrasound, CT scan or MRI (preferable) scans are used for assessment of orbital, optic nerve, and intracranial extension (Fig. 12.5).

Rarely, children with hereditary retinoblastoma have pineal tumor (trilateral retinoblastoma) that may be found on imaging. CSF and bone marrow evaluation should only be done if indicated clinically, or by other imaging studies (i.e., in advanced disease).

Both eyes should be examined under general anesthesia.

Second malignant neoplasms are a major concern in retinoblastoma survival. Approximately 30 % of individuals cured of hereditary forms of RB will have a second malignancy within 30 years. Osteosarcoma is the commonest second malignancy; other second neoplasms include rhabdomyosarcoma and melanoma.

The patients of are usually diagnosed upon ophthalmic examination based on the International Classification System for Retinoblastoma (Table 12.2). The (International Retinoblastoma Staging System (IRSS) shown in Table 12.3a) is based on histopathology and imaging findings and takes into account that EORB with spread to regional lymphnode (LN) has a rate of overall survival comparable to non metastatic extraocular retinoblastoma (EORB).