An inherited cancer

Published : Apr 09, 2004 00:00 IST

India is one of the countries that have the largest numbers of persons affected with retinoblastoma, a cancer of the eye that is found in children and can be treated effectively if detected early.

RETINOBLASTOMA, cancer of the eye among children, is one of the most common tumours and is responsible for over 5 per cent of the blindness among children in India. With a rate of incidence of one in 15,000 infants, India has one of the largest numbers of retinoblastoma patients in the world. If left untreated, the disease can cause death.

Retinoblastoma starts in the retina. Eyes develop very early, even in the womb. During the early stages of development, eyes contain cells called retinoblasts, which grow rapidly until about the fifth year. Later, they stop growing and mature into retinal cells. Rarely does something go wrong in this process. But whensome retinoblasts continue to grow rapidly and out of control they become cancerous.

If the growth of these cells is not controlled, they can form a tumour that fills much of the globe (eyeball). The cells may break away from the retinal tumour and float through the vitreous to reach other parts of the eye and form more tumours. If these tumours block the channels through which the fluid in the eye circulates, the pressure inside the eye can rise, resulting in glaucoma, which leads to the loss of vision in the affected eye. Glaucoma is one of the serious complications of retinoblastoma.

Most often retinoblastoma can be detected and treated before it spreads outside the globe. Retinoblastoma cells can spread to other parts of the body as well. They sometimes grow along the optic nerve to reach the brain. The cells can also grow through the covering layers of the globe into the eye socket, eyelids, and nearby tissues. Once tissues outside the globe are affected, the cancer can spread to the lymph nodes (small bean-shaped collections of immune system cells), to the internal organs and the bones.

Retinoblastoma was the first cancer to be associated directly with a genetic abnormality (deletions or mutation of the q14 band of chromosome 13). It can occur sporadically (without a family history) or be inherited (with a family history).

In case of genetic mutation, there is a 45-50 per cent chance that the sibling of the affected child will also have retinoblastoma. If there is no family history or mutation, the risk of the sibling having retinoblastoma is 2-5 per cent. The average age of children with retinoblastoma is 18 months.

More than 75 per cent of children with retinoblastoma are first noted to have "white-pupil" (leukocoria), poorly aligned eyes (strabismus), or a red and painful eye (usually due to glaucoma). As other eye diseases such as congenital cataract, Toxocara canis, Coat's disease and persistent hypertrophic primary vitreous (PHPV) too have similar symptoms, retinoblastoma is detected through specialised blood tests, CAT scans, and ultrasound evaluations. For full confirmation, a biopsy may be performed, but it is usually avoided in order to prevent cancer cells from spreading outside the eye.

In the past few years, considerable progress has been made in understanding how certain changes in a person's DNA (deoxyribonucleic acid) can cause retinal cells to become cancerous. DNA carries the instructions for nearly everything the cells do. A child usually resembles its parents because they are the source of the DNA. However, the DNA affects more than the outward appearance. It is also a benchmark of a person's susceptibility to certain diseases, including some types of cancer. Some genes (parts of the DNA) contain instructions that control the growth and division of cells. Genes that promote cell division are called oncogenes. Others that slow cell division or cause cells to die at the right time are called tumour-suppressor genes.

Cancers can be caused by DNA mutations (defects) that activate oncogenes or de-activate tumour-suppressor genes. The most important gene involved in retinoblastoma is the tumour-suppressor gene Rb (also known as Rb1). About 40 per cent of the children with retinoblastoma inherit an abnormal Rb gene from one parent; 90 per cent of those who inherit an abnormal Rb gene from a parent develop retinoblastoma in one or both eyes; and 10 per cent of them develop a tumour of the pineal (an area of the brain).

Mutant Rb genes are present in every cell of the body of a child who inherits them from a parent and therefore can be detected by doing a DNA test. Because every person has two Rb genes but passes only one to the children (a child gets the other gene from the other parent), the odds of a parent passing the mutant gene on to a child are one to two.

The defective gene responsible for the inherited form of retinoblastoma was discovered in 1986. This discovery, together with technical advances in analysing DNA changes, has made genetic testing a possibility. In some cases it is possible to predict whether or not a patient's siblings will be affected by retinoblastoma.

Sixty per cent of children with retinoblastoma do not inherit gene mutations. Changes would have happened to their Rb genes, post birth. These acquired changes rarely have any apparent cause and may result from random errors that occur when cells reproduce and divide.

Retinoblastoma can be treated if detected early. Research efforts are concentrated on destroying the cancer without damaging vision in the affected eye. Efforts are on to deliver radiation therapy accurately, develop new instruments for cryo- and laser-therapy; supplement local treatment with chemotherapy to prevent the spread of retinoblastoma outside the eye; and test the benefits of very high doses of chemotherapy followed by bone marrow transplantation where the retinoblastoma has spread beyond the eye.

Survivors of the hereditary form of retinoblastoma face an increased risk of developing other types of cancer. This risk is a lifelong one. Though it is difficult to predict its exact extent, studies show that those with the hereditary form of retinoblastoma have a 30 per cent lifetime risk of developing some other type of cancer at any age. The risk rises to 50 per cent if the child receives external beam radiation therapy.

Several experimental protocols are being evaluated using chemotherapy, laser therapy (to shrink the retinoblastoma before treating the tumour), cryotherapy (freezing the tumour), and local "plaque" radiation. Where applicable, these techniques are thought to be safer than external beam irradiation for retinoblastoma.

The Chennai-based Sankara Nethralaya, a pioneer in the field of diagnosis and treatment of ocular oncology, is one of the few centres in India that treat retinoblastoma and do research on it. According to Dr. Mahesh Shanmugam, senior consultant with the hospital's department of vitreo retinal surgery, these kinds of inherited diseases may be more common in India than in developed countries. According to him, the main problem in India is that patients seek treatment when the disease is at an advanced stage. Sankara Nethralaya, which has been treating tumours of the eye since its inception 25 years ago with chemotherapy, recently added to its options brachy or plaque therapy, which delivers radiation only to the tumour, avoiding unnecessary exposure of the other structures of the eye to radiation. The radioactive seeds (iodine 125) used for brachy therapy were not easily available in India until it was developed recently by the Bhabha Atomic Research Centre (BARC) with the collaboration of Sankara Nethralaya. With brachy therapy, says Dr. Mahesh Shanmugam, "we can save the eye". At Sanakara Nethralaya, the diagnosis, treatment and rehabilitation of retinoblastoma is a collaborative effort of the departments of oncology, pathology and genetics.

The treatment cost is usually the main problem, but not so in Sankara Nethralaya. The hospital offers laser at Rs.1,000 a sitting and cryo at Rs.500 a sitting, rates that are much lower than those in most hospitals in the country. But it does chemotherapy in collaboration with other hospitals, and it is a little more expensive at Rs.5,000-8,000 a cycle. Most children with retinoblastoma need six cycles. At Sankara Nethralaya, poor patients are treated free of cost.

Sankara Nethralaya's genetics and molecular biology department contributes immensely to the understanding of retinoblastoma. Its state-of-the-art research in techniques to identify Rb1 mutations in retinoblastoma patients has enabled the understanding of the molecular genetic basis (genotype and phenotype) of the disease.

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