What is retinoblastoma?

Retinoblastoma is a malignant tumor of the immature retina caused by mutations – or alterations – in the RB1 gene, and generally occurs before the age of 5. The tumor may affect only one eye or both eyes. The hereditary form of retinoblastoma, is associated with an increased risk of developing malignant tumors, usually pineoblastomas. Moreover, secondary tumors can also occur over time, such as malignant bone or soft tissue tumors (osteosarcomas or soft tissue sarcomas), tumors of the nasal cavity, eye, or eye socket, malignant skin tumors (melanomas), and brain tumors.

How is retinoblastoma diagnosed?

Clinical Diagnostics

Retinoblastoma is suspected whenever a person exhibits one or more of the following findings:

  • Leukocoria (white flashing in the pupil)

  • Strabismus (squinting)

  • Changed appearance of the eye

  • Reduced vision

The diagnosis of “retinoblastoma” can be clinically verified by an ophthalmological examination.

Genetic Diagnostics

Hereditary retinoblastoma is suspected with the following findings:

  • Every patient with the diagnosis of “retinoblastoma,” including one-sided and two-sided involvement

  • A patient with retinoma (a benign retinal tumor also caused by a mutation in the RB1 gene; it may be a precursor of retinoblastoma)

  • A person in whose family a retinoblastoma has already occurred

The diagnosis of “hereditary retinoblastoma” is confirmed by genetic testing, which determines whether there is a mutation – or change – in the RB1 gene. Since a hereditary disease is involved, blood-related family members of a person with a proven mutation should also undergo genetic testing.

Other Clinical Features

A clinical distinction is made between unilateral, bilateral, and trilateral retinoblastoma.

Unilateral Retinoblastoma:

Only one eye is affected with this form. Overall, unilateral retinoblastoma is found in around 60% of all retinoblastoma patients, with the one-sided form occurring in only 10-15% of patients with hereditary retinoblastoma. The average age at diagnosis is 24 months.

Bilateral Retinoblastoma:

Both eyes are affected in this form. Overall, bilateral retinoblastoma is found in around 40% of all retinoblastoma patients, with the two-sided form occurring in the majority of patients with hereditary retinoblastoma. The average age at diagnosis is 15 months. Both eyes are usually already affected by the time the diagnosis is made.

Trilateral Retinoblastoma:

In this form, there is a malignant brain tumor in addition to the two-sided (or rarely one-sided) retinoblastoma. While a pineoblastoma is usually involved, tumors centrally located in the middle cranial fossa have also been described.

Other Tumors:

In patients with retinoblastoma, there is an increased risk of other tumors occurring outside of the eye, called secondary tumors, which are the following:

  • Osteosarcomas (malignant bone tumors)

  • Soft tissue tumors, usually leiomyosarcomas (malignant tumors of the smooth muscles) or rhabdomyosarcomas (malignant soft tissue tumors)

  • Melanomas (malignant skin tumors, called “black skin cancer”)

They usually develop during adolescence or adulthood. The probability of secondary tumors occurring is much higher in retinoblastoma patients who have already undergone percutaneous radiation therapy.

What is the risk of cancer?

A retinoblastoma develops in 90-95% of cases when both alleles are mutated – when both copies of the RB1 gene are altered. This is generally bilateral in the hereditary form, meaning that it affects both eyes. The probability that patients with a bilateral retinoblastoma will also develop a malignant brain tumor – usually a pineoblastoma – is approximately 5%. For patients who have not been exposed to radiation, the probability reported is < 2%. The survival rate for patients with a retinoblastoma located in the eye is > 95% with an early diagnosis and adequate treatment.

The risk of developing secondary tumors depends on whether percutaneous radiation was performed or not. The probability of developing a secondary tumor by the age of 50 is 38% for patients with prior radiation treatment and 21% for patients who did not undergo radiation therapy. The average age at the time a secondary tumor occurs is between 15 and 17 years.

What causes retinoblastoma?

Retinoblastoma is caused by a mutation – or change – in the RB1 gene. This gene encodes the RB protein, which is an important element in cell regulation. This protein prevents damaged genetic information from being further replicated in our cells, representing a protective mechanism in our body. However, if the gene is altered, the protein will no longer be produced correctly or not be produced at all and will therefore be unable to carry out its function, thereby leading to the development of tumors.

Around 40% of patients have a hereditary form of retinoblastoma. Every gene is present twice in our body, meaning that we have two alleles per gene. These patients carry only one mutated allele of the RB1 gene and are therefore heterozygous. In 80% of cases, this mutation comes from a new mutation – called a de novo mutation – which occured in the mother’s ovum or the father’s sperm. For retinoblastoma to develop, however, both alleles of the RB1 gene need to be mutated. Whenever the first mutation is already present, a second mutation occurs in the retinal precursor cells in around 95% of cases, meaning that the second allele of the RB1 gene is mutated as well, causing a retinoblastoma to develop.

Retinoblastoma is inherited as an autosomal-dominant disease, where the mutation of one allele is inherited from one parent and the mutation of the other allele, in the retinal precursor cells, develops spontaneously.

Is there a treatment?

The treatment of retinoblastoma depends on a large number of factors and should be planned and carried out in collaboration with pediatric oncologists, ophthalmologists, pathologists, and radiation therapists. Removing the tumor to ensure survival is of primary importance, making every effort to preserve the patient’s visual capacity and avoid secondary tumors developing while doing so. The treatment chosen varies depending on the stage, location, and size of the tumor, the number of tumors, the prevalence and type of tumors not located in the eye, and the resources that are available. Treatment options include local and systemic chemotherapy, cold therapy, laser therapy, internal radiation therapy, removal of the eyeball, plus – as a last resort – the use of percutaneous radiation therapy.

If possible, every kind of ionizing radiation should be avoided, including X-rays, CT, and percutaneous radiation, in order to keep the risk of developing a secondary tumors to a minimum.

Surveillance Recommendations for the Early Detection of Cancer

Genetic Counseling

This plays an important role for patients with hereditary retinoblastoma, especially with regard to screening examinations and the risk of developing secondary tumors, and also when providing care to siblings. Moreover, genetic counseling should be offered again once patients who have survived a retinoblastoma reach childbearing age.

Surveillance Recommendations

The following examinations are recommended for patients with hereditary retinoblastoma or a positive family history (i.e. at least one family member with a retinoblastoma):

Preventive Care of Retinoblastomas in the Eye

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Age Frequency
Birth to 8 weeks Examinations without sedation every 2 to 4 weeks
8 weeks to 12 months Examinations with sedation once a month
12 to 24 months Examinations with sedation every 2 months
24 to 36 months Examinations with sedation every 3 months
36 to 48 months Examinations with sedation every 4 months
48 to 60 months Examinations with sedation every 6 months
5 to 7 years Examinations without sedation every 6 months
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Preventive Care of Trilateral Retinoblastomas (Retinoblastoma in the Eye + a Brain Tumor)

  • MRI of the head at the time of diagnosis

  • A few centers recommend an MRI of the head every 6 months until the age of 5.

Preventive Care of Secondary Tumors

  • Patients are informed about the risk of developing secondary tumors and asked to consult a doctor if they notice any signs or symptoms.

  • Examinations of the skin should be conducted as part of regular preventive examinations during childhood. They should be continued every year by the family doctor or a dermatologist.

  • A few centers recommend annual whole-body MRI examinations starting at 8 years of age.

Prenatal Diagnostics

Due to the small amount of data available for analysis, there are no standardized recommendations to date.

Based on current knowledge, no more favorable outcome can be expected for the results of treatment in patients in which a predisposition to tumors has already been determined before birth. For this reason, prenatal diagnostics addressing this objective are not recommended in Germany.

When examining the eyes as part of the first neonatal examination, it is important to look for any signs of retinoblastoma (leukocoria, strabismus) that may already be evident. The initial ophthalmological examination for the specific early detection of retinoblastomas should be conducted at an ophthalmology center specialized in retinoblastomas within 14 days after birth.

There is no evidence that ophthalmological examinations for early detection are necessary if it is possible using predictive diagnostics directly after birth to rule out the chance that the child has inherited the known disease-causing change in the family (specific examination). To this end, the consent of the parents should already be obtained before birth so that cord blood can be taken at birth for the genetic diagnostics. A report is available for most disease-causing changes within 1 week of sampling and therefore before the date for the otherwise necessary initial ophthalmological examination at a center specialized in retinoblastomas.

Self-Care and Support

What should I pay special attention to?

If possible, every kind of ionizing radiation should be avoided, including X-rays, CT, and percutaneous radiation, in order to keep the risk of developing a secondary tumors to a minimum.

If any new complaints or symptoms occur, patients who have survived a retinoblastoma need to consult a doctor to detect and treat any potential secondary tumors as early as possible.

In addition, it is vital for patients of childbearing age who have survived a retinoblastoma to receive genetic counseling.

Support Groups and Additional Information