Mazel tov! You have just given birth to your first child. You take the baby home, have a celebration, welcome the grandparents and settle down to life and the responsibility of caring for the child. Chief among these responsibilities is the need to select a pediatrician, which you do by chatting with your friends, reviewing websites and doing Facebook (soon you will have the option of choosing my daughter Dana who has another year as chief resident in her pediatrics residency). The baby gets to have check-ups incredibly frequently—week one, first month, two months, four months etc.
Part of each check-up is a physical examination. A routine part of this exam is checking for the red reflex. This is a part of the eye examination in which the ophthalmoscope is shone into the pupil and the retina reflects back as a reddish color. If this does not occur, it indicates a problem on the retina. A major part of the differential for the absence of the red reflex is the possibility of retinoblastoma.
Retinoblastomas are extremely rare cancers of the retina that occur in young children. Perhaps 300 are diagnosed annually in the U.S. with an incidence rate of 1/100,000/year in those 0 to 4 years of age.
If the tumor is small and localized, and if it seems possible to salvage sight in the eye, removal or enucleation of the eye will be avoided if possible. Instead, localized treatments will be utilized—cryotherapy, thermotherapy or chemotherapy with radiation therapy. If the tumor is large or if it is clear that vision is already compromised, then enucleation will be the treatment of choice. With these treatments, the cure rate nowadays is greater than 90%.
In 25-40% of patients, a new tumor will subsequently develop in the other eye. This heralds the fact that this is a genetic rather than a sporadic form of retinoblastoma. If the first eye was enucleated, then extra efforts will be made to utilize radiation therapy so as to avoid enucleating the second eye and making the child blind. As we described in a prior article, this genetic syndrome is related to a mutated Rb1 gene, an autosomal dominant gene that is a tumor-suppressor gene.
An interesting observation has been that for survivors of retinoblastoma, there is an increased risk of second malignancies, in particular of osteogenic sarcoma. These second malignancies usually occur at least 10 years after the treatment of the retinoblastoma. One study, for example, described the experience of 857 retinoblastoma patients. With time, 10 of them (1.1%) developed osteogenic sarcomas. Provocatively, of these 10, nine were in patients with bilateral retinoblastomas. Hence it is apparent that the Rb1 gene, in addition to increasing the risk of retinoblastoma, also increases the risk of osteogenic sarcoma. The tumors occurred between the ages of 7 and 24 years of age.
Under normal circumstances, osteogenic sarcomas occur most commonly in the long bones of the extremities. Among these 10 patients, however, four of the 10 osteogenic sarcomas occurred in the orbit, the temporal bone or the skull base. Thus, they were within the radiation field for the eye tumors. Osteogenic sarcomas that arise spontaneously in the bones of the skull are extremely uncommon or rare.
What this illustrates is the interaction between two risk factors. Radiation exposure is a known risk factor for sarcomas, and the presence of the Rb1 mutation is a risk factor for this tumor as well. The presence of two major risk factors leads to their interacting to cause an even greater risk. Interactions can be additive, multiplicative or synergistic. Thus, it is apparent that the risk of osteogenic sarcoma experienced by children who are Rb1 mutation carriers who undergo radiation therapy is greater than the product of the risk of either of the two exposures alone.
Such synergistic interactions occur in many settings. Joint tobacco exposure and alcohol exposure can lead to extremely high risks for cancers of the oral cavity, larynx and esophagus. Likewise, while asbestos exposure can raise the risk of lung cancer, its effects become dramatically enhanced in cigarette smokers where synergy comes into play.
Knowledge of such interactions can be utilized to lead to preventive strategies. Both chemotherapy and radiation therapy, utilized together in certain patients with Hodgkin lymphoma, were shown to create a very high risk for future leukemia in Hodgkin survivors. Therefore, current treatment strategies make an effort to limit treatment to one of these modalities whenever possible in order to avoid or reduce this risk.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
