Generality
Retinoblastoma (Rb) is a malignant ocular tumor that develops from cells in the retina. This neoplasm can occur at any age, but onset is more common during infancy before the age of five.
Childhood cancer is aggressive: retinoblastoma can spread to lymph nodes, bones or bone marrow. Rarely, it involves the central nervous system (brain and spinal cord).
About 90% of children with retinoblastoma have a positive prognosis (probability of recovery), provided the diagnosis is early and treatment begins before the spread of the tumor. When possible, the goal of medical intervention is to preserve the patient's vision.
Causes
The series of events leading to tumor onset is complex. This begins when the retinal cells develop a mutation (or deletion), which involves the tumor suppressor gene RB1, located on the q14 band of chromosome 13 (13q14).
Each cell normally has two RB1 genes :
- If at least one copy of the gene works correctly, retinoblastoma does not occur (but increases the risk);
- When both copies of the gene are mutated or missing, uncontrolled cell proliferation occurs.
In many cases, it is not clear what exactly induces changes in the RB1 gene (sporadic retinoblastoma); these may derive from random genetic errors, which occur, for example, during reproduction and cell division. However, it is known that genetic abnormalities underlying retinoblastoma can also be transmitted from parents to children, with a pattern of autosomal dominant inheritance. This means that if a parent is a carrier of a mutated (dominant) gene, each child will have a 50% chance of inheriting it and 50% of having a normal genetic make-up (recessive genes).
| Normal healthy individual | A cell may occasionally inactivate one of its normal RB1 genes (2 inactivating events, one for each allele, are required for the onset of retinoblastoma). | Result: no tumor. |
| Hereditary retinoblastoma (with inherited mutant Rb gene) |
| Result: excessive cell proliferation induces retinoblastoma in most people with inherited mutations. |
| Non-hereditary retinoblastoma (sporadic) |
| Result: only one in 30, 000 normal people develops the tumor. |
Genetic and molecular characteristics
- Retinoblastoma was the first tumor to be associated directly with a genetic abnormality (deletion or mutation of the q14 band of chromosome 13).
- RB1 encodes the pRb protein, which plays a key role in the cell cycle: it allows DNA replication and cell cycle progression, as it participates in the control of the transcription of phase S genes (G1 → † 'S).
- In addition to retinoblastoma, the RB1 gene is inactivated in bladder, breast and lung carcinomas.
Hereditary retinoblastoma
Children with hereditary retinoblastoma tend to develop the disease earlier in life than sporadic cases. Furthermore, these children present an increased risk for other non-ocular tumors, as the anomaly in the RB1 gene is congenital (ie present from birth) and affects all cells of the body (known as germline mutation), including those of both retinas. For this reason, children with the hereditary form often have bilateral retinoblastoma, rather than in one eye.
Symptoms
To learn more: Symptoms Retinoblastoma
The most common and obvious sign of retinoblastoma is the abnormal aspect of the pupil, which presents a greyish-white reflex when it is hit by a beam of light (leucocoria or reflex of the amaurotic cat ). Other signs and symptoms include: reduced vision, pain and redness of the eyes and developmental delay. Some children with retinoblastoma may develop a strabismus (unaligned eyes); in other cases, it is possible to find neovascular glaucoma, which, after some time, can cause enlargement of the eye (buftalmo).
Cancer cells can further invade the eye and other structures:
- Intraocular retinoblastoma . Retinoblastoma can be defined intraocular when the tumor is entirely located within the eye. The neoplasm can be found only in the retina or also affect other parts, such as the choroid, ciliary body and part of the optic nerve. The intraocular retinoblastoma, therefore, is not widespread to the tissues around the outside of the eye.
- Extraocular retinoblastoma . The tumor can proliferate to affect the tissues around the eye (orbital retinoblastoma). The neoplasm can also spread to other areas of the body, such as the brain, spine, bone marrow and lymph nodes (metastatic retinoblastoma).
The presence of orbital extension, uveal involvement and optic nerve invasion are known risk factors for the development of metastatic retinoblastoma.
Diagnosis
In the case of a positive family history, the patient is subjected to regular eye examinations for cancer screening. If congenital retinoblastoma is bilateral, it is usually diagnosed in the first year of life, whereas when it affects only one eye, the presence of the tumor can be confirmed at about 18-30 months of age.
The clinical diagnosis of retinoblastoma is established by examination of the fundus. The tumor, depending on the position, may be visible during a simple eye examination, by indirect ophthalmoscopy. Imaging techniques can be used to confirm the diagnosis, to define the staging of the tumor (where it is, to what extent it is widespread, if it is affecting the functions of other organs of the body, etc.) and to determine whether the treatment has been effective. Investigations may include ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI).
Molecular-genetic diagnosis is possible by identifying the mutation of the RB1 gene. Cytogenetic analysis (ie chromosomes) of peripheral blood lymphocytes is used to detect deletions or rearrangements involving chromosome 13 (13q14.1-q14.2).
Treatments
In the case of retinoblastoma, different therapeutic options can be used.
The objectives of the treatment are:
- Eliminate the tumor and save the patient's life;
- Save the eye, if possible;
- Preserve the vision as much as possible;
- Avoid the onset of other cancers, which can also be caused by treatment, especially in children with hereditary retinoblastoma.
Prognosis (probability of recovery) and treatment options depend on the following factors:
- Tumor phase;
- Age of the patient and general health conditions;
- Location, size and number of cancer outbreaks;
- Cancer spread to other areas, in addition to the eyeball;
- How likely it is that the vision can be preserved in one or both eyes.
Most cases of retinoblastoma are diagnosed early and treated successfully, before the cancer can metastasize outside the eyeball, with a cure rate of over 90%.
Early stage therapy
Treating a small tumor, confined within the eye, usually involves one of the following options:
- Laser therapy (photocoagulation) : photocoagulation is effective only for smaller tumors. During therapy, the laser is used to destroy the blood vessels supplying the neoplastic mass, through the pupil. Without a source of oxygen and nutrients, cancer cells can die.
- Thermotherapy: the procedure uses a different type of laser to apply heat to the cancer cells. Temperatures are not as high as those used in photocoagulation and some of the blood vessels on the retina can be spared.
- Tumor freezing (cryotherapy) : cryotherapy uses a very cold substance, like liquid nitrogen, to freeze and kill abnormal cells. The doctor uses a small metal probe, which is placed inside or near the neoplastic mass before being cooled. This process of freezing and thawing, repeated a couple of times in each cryotherapy session, leads to the death of cancer cells. The procedure is most effective when the tumor is small and located only in some parts of the eye (especially in the front).
Treatment of larger tumors
The largest tumor masses can be treated with one of the following treatments, often in combination:
- Chemotherapy: chemotherapy is a pharmacological treatment that uses chemical agents, such as cyclophosphamide to reduce tumors in the eye or to eliminate any remaining cancer cells after other treatments. Chemotherapy drugs can be administered orally, intravenously or intra-arterially. Systemic chemotherapy can also be used to treat diffuse retinoblastoma to tissues beyond the eyeball or to other areas of the body.
- Intra-arterial chemotherapy involves the infusion of chemotherapy directly into the ophthalmic artery, which is achieved through a micro-catheter inserted at the inguinal level in the femoral artery; this guarantees unquestionable advantages in terms of greater efficacy and less systemic toxicity.
- Radiotherapy: radiotherapy uses high energy rays to kill cancer cells or slow down their growth rate.
- External radiotherapy . External radiotherapy concentrates beams of high-power radiation generated by a source outside the body.
- Internal radiotherapy (brachytherapy) . The procedure is possible if the tumor is not too large. During internal radiation, the treatment device, which consists of a small disc of radioactive material, is temporarily placed near the retinoblastoma. The radioactive plaque is sutured over the cancer cells and left in place for a few days, during which it slowly delivers radiation to the tumor. The application near the retinoblastoma reduces the possibility that the treatment may produce effects on the healthy tissue of the eye.
- Surgery: when the tumor is too large to be treated by other methods, surgery can be scheduled. Patients with unilateral retinoblastoma may undergo enucleation surgery to remove the diseased eye. They are therefore used prostheses (artificial eye) to fill the area occupied by the eyeball. Children who lose their sight in one of their eyes are usually able to adapt quickly to change. Patients with bilateral retinoblastoma may undergo enucleation if vision cannot be preserved with other treatments.
- Surgery to remove the affected eye (enucleation). During enucleation, surgeons remove the eyeball and part of the optic nerve. In these situations, the intervention can help prevent the spread of cancer to other parts of the body, but clearly there is no possibility that the vision in the affected eye can be saved.
- Surgery to place an implant. Immediately after removing the eyeball, the surgeon inserts an implant into the eye socket. After the patient's recovery, the eye muscles will adapt to the implanted eyeball, so it could move just like the natural eye. Several weeks after surgery, an artificial eye can be placed over the implant. Follow-up is necessary for 2 years or more, to check the other eye and check for signs of relapse in the treated area.
The side effects of retinoblastoma treatment can often be treated or controlled with the help of a doctor. These may include:
- Physical problems, such as difficulty in seeing clearly or, if the eye is removed, a change in the shape and size of the eye cavity;
- Changes in mood, learning or memory.
- Second tumors (new types of cancer).
See also: Drugs for the treatment of Retinoblastoma »
Complications
If the tumor has spread beyond the eye (extraocular retinoblastoma), it can potentially metastasize throughout the body and is more difficult to treat. However, this is fortunately rare.
Treated patients have a risk that retinoblastoma may recur within the eye or in neighboring areas. For this reason, after the therapeutic intervention, the doctor will schedule frequent follow-up examinations. Furthermore, children affected by the hereditary form have an increased risk of developing, over the years, other types of cancer in any part of the body, even after treatment. For this reason, these patients can undergo regular tests to identify the onset of malignancies early.
Prevention
For families with hereditary retinoblastoma
In families with an inherited form of retinoblastoma, preventing tumor onset is not possible. However, the genetic-molecular investigations allow to know if the children have a greater risk of developing retinoblastoma and, in case of positivity, they allow to plan the eye exams already at an early age. In this way, retinoblastoma can be diagnosed very early, when the tumor is limited and the chances of cure and preservation of vision are still good.
Genetic tests can also be used for preventive purposes to determine if:
- The child with retinoblastoma is at risk of other related cancers;
- There is the possibility of transmitting the genetic mutation to future children.
