Retinoblastoma

Retinoblastoma (Rb) is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers (95-98%), with more than nine out of every ten sufferers surviving into adulthood.

Classification
There are two forms of the disease; a heritable form and non-heritable form (all cancers are considered genetic in that mutations of the genome are required for their development, but this does not imply that they are heritable, or transmitted to offspring). Approximately 55% of children with Rb have the non-heritable form. If there is no history of the disease within the family, the disease is labeled "sporadic", but this does not necessarily indicate that it is the non-heritable form.

In about two thirds of cases, only one eye is affected (unilateral retinoblastoma); in the other third, tumours develop in both eyes (bilateral retinoblastoma). The number and size of tumours on each eye may vary. In certain cases, the pineal gland is also affected (trilateral retinoblastoma). The position, size and quantity of tumours are considered when choosing the type of treatment for the disease.

Signs and symptoms
The most common and obvious sign of retinoblastoma is an abnormal appearance of the pupil, leukocoria. Other less common and less specific signs and symptoms are: deterioration of vision, a red and irritated eye, faltering growth or delayed development. Some children with retinoblastoma can develop a squint, commonly referred to as "cross-eyed" or "wall-eyed" (strabismus). Retinoblastoma presents with advanced disease in developing countries and eye enlargement is a common finding.

Depending on the position of the tumors, they may be visible during a simple eye exam using an ophthalmoscope to look through the pupil. A positive diagnosis is usually made only with an examination under anesthetic (EUA). A white eye reflection is not always a positive indication of retinoblastoma and can be caused by light being reflected badly or by other conditions such as Coats's Disease.

In a photograph, the photographic fault red eye may be a sign of retinoblastoma, if in the photograph it is in one eye and not in the other eye. A more clear sign is "white eye" or "cat's eye".

Frequency of retinoblastoma
Retinoblastoma is rare and affects approximately 1 in 15,000 live births. In the UK, around 40 to 50 new cases are diagnosed each year.

Most children are diagnosed before the age of five years old. In the UK, bilateral cases usually present within the first year with the average age at diagnosis being 9 months. Diagnosis of unilateral cases peaks between 24 and 30 months.

Cause of retinoblastoma
In children with the heritable genetic form of retinoblastoma there is a mutation on chromosome 13, called the RB1 gene.The genetic codes found in chromosomes control the way in which cells grow and develop within the body. If a portion of the code is missing or altered (mutation) a cancer may develop.

The defective RB1 gene can be inherited from either parent; in some children, however, the mutation occurs in the early stages of fetal development. It is unknown what causes the gene abnormality; it is most likely to be a random mistake during the copy process which occurs when a cell divides.

Inherited forms of retinoblastomas are more likely to be bilateral; in addition, they may be associated with pinealoblastoma (also known as trilateral retinoblastoma) with a dismal outcome. The genetic codes found in chromosomes control the way in which cells grow and develop within the body.

Several methods have been developed to detect the RB1 gene mutations. Attempts to correlate gene mutations to the stage at presentation have not shown convincing evidence of a correlation.

Diagnosis
Screening for retinoblastoma should be part of a "well baby" screening for newborns during the first three months of life, to include:
 * The red reflex: checking for a normal reddish-orange reflection from the eye's retina with an ophthalmoscope or retinoscope from approximately 30 cm / 1 foot, usually done in a dimly lit or dark room.
 * The corneal light reflex/Hirchberg test: checking for symmetrical reflection of beam of light in the same spot on each eye when a light is shined into each cornea, to help determine whether the eyes are crossed.
 * Eye examination: checking for any structural abnormalities.

Differential diagnosis

 * 1. Persistent hyperplastic primary vitreous (PHPV): congenital developmental anomaly of the eye resulting from failure of the embryological, primary vitreous and hyaloid vasculature to regress, whereby the eye is shorter, develops a cataract, and may present with whitening of the pupil.
 * 2. Coat's disease: a typically unilateral disease characterised by abnormal development of blood vessels behind the retina, leading to blood vessel abnormalities in the retina and retinal detachment to mimic retinoblastoma.
 * 3. Toxocara canis: an infectious disease of the eye associated with exposure to infected puppies, which causes a retinal lesion leading to retinal detachment.
 * 4. Retinopathy of prematurity (ROP): associated with low birth weight infants who receive supplemental oxygen in the period immediately after birth, it involves damage to the retinal tissue and may lead to retinal detachment.

If the eye examination is abnormal, further testing may include imaging studies, such as Computerized Tomography (CT), Magnetic Resonance Imaging (MRI), and Ultrasound. CT and MRI can help define the structure abnormalities and reveal any calcium depositions. Ultrasound can help define the height and thickness of the tumor. Bone marrow examination or lumbar puncture may also be done to determine any metastases to bones or the brain.

Morphology
Gross and microscopic appearances of retinoblastoma are identical in both hereditary and sporadic types. Macroscopically, viable tumor cells are found near blood vessels, while zones of necrosis are found in relatively avascular areas. Microscopically, both undifferentiated and differentiated elements may be present. Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei; differentiated elements include Flexner-Wintersteiner rosettes, Homer-Wright rosettes, and fluerettes from photoreceptor differentiation.

Genetic testing
Identifying the RB1 gene mutation that led to a child's retinoblastoma can be important in the clinical care of the affected individual and in the care of (future) siblings and offspring.
 * 1) Bilaterally affected individuals  and 13-15% of unilaterally affected individuals, are expected to show an RB1 mutation in blood.  By identifying the RB1 mutation in the affected individual, (future) siblings, children, and other relatives can be tested for the mutation; if they do not carry the mutation, child relatives are not at risk of retinoblastoma so need not undergo the trauma and expense of examinations under anaesthetic.  For the 85% of unilaterally affected  patients found not to carry either of their eye tumor RB1 mutations  in blood, neither molecular  testing nor clinical surveillance of siblings is required.
 * 2) If  the  RB1 mutation of an affected individual is identified, amniotic cells in an at-risk pregnancy can be tested for the family  mutation;  any fetus that carries the mutation can be delivered early, allowing early treatment of any eye tumors, leading to better visual outcomes.
 * 3)  For cases of unilateral retinoblastoma where no eye tumor  is available for testing, if no RB1 mutation is detected in blood after high sensitivity molecular testing (i.e. >93% RB1 mutation detection sensitivity),  the risk of a germline RB1 mutation is reduced to less than 1%, a level at which only clinic examination (and not examinations under anaesthetic) is recommended for the affected individual and their future offspring (National Retinoblastoma Strategy, Canadian Guidelines for Care).

Treatment
Treatment of retinoblastoma varies from country to country. The first priority is to preserve the life of the child, then to preserve the vision and thirdly to minimize any complications or side effects of the treatment. The exact course of treatment will depend on the individual case and will be decided by the ophthalmologist in discussion with the paediatric oncologist.

Many treatment options exist, including chemotherapy (administered locally via a thin catheter threaded through the groin, through the aorta and the neck, into the optic vessels), cryotherapy, radioactive plaques, laser therapy, external beam radiotherapy and surgical removal of the eyeball. Any combinations of these treatments may be adopted.

In recent years, there has been an effort to find alternatives to enucleation and radiation therapy.