Retinoblastoma

Retinoblastoma (Rb) is a rare type of eye cancer that arises in the retina, the light-sensitive tissue at the back of the eye. It is the most common primary intraocular cancer in children, typically developing from immature retinal cells ("retinal germ cells" or retinoblasts). As a congenital and often hereditary neoplasm, it is usually diagnosed in early childhood, most often before the age of five.

The tumor grows rapidly and can lead to blindness in the affected eye. If left untreated, it can invade the optic nerve, spread to the brain, and metastasize to distant sites such as the bones, posing a life-threatening risk. However, with early diagnosis and modern treatment, the survival rate for retinoblastoma is over 95% in developed countries.

Signs and Symptoms

The signs of retinoblastoma can be subtle, and it is often a parent or a routine well-child checkup that first detects a problem. The most common and characteristic signs include:

• Leukocoria (White Pupillary Reflex): This is the most frequent sign, present in about 60% of cases. Instead of the normal "red eye" reflex seen in flash photography, the pupil appears white or yellowish. This phenomenon is sometimes called a "cat's eye reflex."
• Strabismus (Crossed Eyes): A new or worsening misalignment of the eyes is the second most common sign. It occurs when the tumor interferes with vision in the central retina, causing the eye to drift inward or outward.
• Diminished Vision: The child may show signs of poor vision, though this can be difficult to detect in infants and toddlers.
• Other Signs: Less common signs include redness, swelling, or pain in the eye; a difference in the color of the iris in each eye; or an enlarged pupil that does not react to light. As the tumor grows, it can cause retinal detachment.

Cause and Genetics

Retinoblastoma is caused by a mutation in a specific gene known as the Retinoblastoma (RB1) gene, which is a tumor suppressor. Every individual has two copies of the RB1 gene in each cell. For a tumor to develop, both copies of the gene within a single retinal cell must be mutated or inactivated. This understanding is based on the "two-hit hypothesis" proposed by Alfred G. Knudsen.

There are two main forms of retinoblastoma:

1. Hereditary (Germline) Retinoblastoma: Accounting for about 40% of cases, these individuals are born with one mutated copy of the RB1 gene in every cell of their body (the "first hit"). They only need a single spontaneous mutation in the second copy of the gene in a retinal cell (the "second hit") to develop a tumor. This puts them at extremely high risk, and consequently:
   • They often develop multiple tumors in one or both eyes.
   • All cases of bilateral retinoblastoma (affecting both eyes, ~30% of total cases) are considered hereditary.
   • They have a significantly increased lifetime risk of developing other cancers, such as osteosarcoma and melanoma.
2. Non-hereditary (Somatic) Retinoblastoma: Accounting for about 60% of cases, these children are born with two normal RB1 genes. The tumor develops only after both copies of the gene are randomly mutated in a single retinal cell. Because this requires two rare events, these individuals typically develop only one tumor in one eye (unilateral).

Because the hereditary form is transmitted as an autosomal-dominant trait with incomplete penetrance (not every person with the gene gets cancer), genetic counseling is strongly recommended for affected families to assess risk for the patient, their siblings, and future offspring.

Diagnosis

A diagnosis of retinoblastoma is made through a comprehensive eye examination and imaging. A biopsy is almost never performed due to the risk of spreading the tumor cells.

• Dilated Eye Examination: An ophthalmologist, often with the child under general anesthesia, will carefully examine the retina to identify and characterize the tumor(s).
• Ocular Ultrasound: This non-invasive imaging technique helps confirm the presence of a solid tumor and can detect calcium deposits within it, which are characteristic of retinoblastoma.
• Magnetic Resonance Imaging (MRI): An MRI of the brain and orbits is essential to determine the tumor's size and to check if it has invaded the optic nerve or spread into the brain.

Treatment

The primary goals of treatment are, in order of priority: 1) to save the child's life, 2) to save the eye, and 3) to preserve as much vision as possible. The choice of therapy depends on the size and location of the tumor(s) and whether one or both eyes are affected.

• Chemotherapy: This is a primary treatment used to shrink tumors. It can be administered systemically (through the veins) or, more commonly now, via intra-arterial chemotherapy (IAC), where a high dose of the drug is delivered directly to the eye through its main artery, minimizing side effects to the rest of the body.
• Focal Therapies: These treatments are used for smaller tumors or after chemotherapy has shrunk a larger one.
  • Photocoagulation: A medical laser is used to heat and destroy the tumor.
  • Cryotherapy: A very cold probe is used to freeze and destroy the tumor.
• Enucleation (Surgical Eye Removal): If a tumor is very large, has caused irreversible damage, or does not respond to other treatments, the eye may need to be removed to prevent the cancer from spreading. As much of the optic nerve as possible is also removed. Afterward, an orbital implant and a custom-made artificial eye are fitted for cosmetic appearance.
• Radiation Therapy: While effective, its use has declined due to the significant risk of long-term side effects, including damage to facial bones and an increased risk of secondary cancers, especially in patients with the hereditary form.

In bilateral cases, a common strategy is to enucleate the more severely affected eye and use a combination of chemotherapy and focal therapies to save the other eye and its vision.