Retinoblastoma

Thomas Carollo and James Bolling, M.D.
Thomas Carollo is a Medical Student at the University of Miami, class of 2003.
James Bolling, M.D. is Chair, Department of Ophthalmology at Mayo Clinic Jacksonville.

Introduction

The diagnosis of Retinoblastoma can be devastating. It means that the patient has a highly malignant childhood cancer and that other children in the family or future children are also at risk for the same cancer. Without treatment cancer will spread through the optic nerve to the brain and cause death in 98% of patients. Treatment may mean blindness or the loss of one or both eyes and patients who survive treatment of Retinoblastoma are at risk for second non-ocular cancers.¹

It is in this clinical setting that we can be of the most help to our patients. Treatment results in complete cure in the majority of patients. Exciting new approaches are resulting in preservation of vision in a many patients. Genetic testing has resulted in highly effective screening for family members. This unique tumor has given us a lot of useful information about oncogenesis.

The first step in helping a patient with Retinoblastoma is with timely diagnosis. The referral for evaluation can come from anyone but is most often made by a primary care physician. The reason for referral is usually a white pupillary reflex. Other presenting signs are strabismus, abnormal pupils, or an abnormal appearance of the eye. Table 1 shows the finding that resulted in referral for the last 20 patients seen with Retinoblastoma at Nemours Children's Clinic in Jacksonville. Figure 1 shows the typical appearance of a patient with leukocoria related to Retinoblastoma.

Retinoblastoma is a malignant intraocular tumor. Untreated retinoblastoma can metastasize from the eye through the optic nerve to the brain by direct extension. Without treatment, patients with retinoblastoma usually die within the first four years of life. Retinoblastoma is a rare disease, affecting approximately one out of every 15,000 live births. Males have a slightly higher incidence than females (1.7 to 1). There are no geographical or racial associations with retinoblastoma, suggesting that environmental factors do not play a causal role in the development of this disease.²

Leukocoria, a white pupillary reflex, is the most common presenting sign. Parents may notice this with direct observation or on photographs. Primary care physicians may notice a white papillary reflex on examination pt seen on a fundoscopic exam. Although retinoblastoma is rarely seen in general pediatric practice, pediatricians are knowledgeable in diagnosing this disease.

The gene encoding for retinoblastoma is RB-1 and is found on the long arm of the 13^th chromosome. RB-1 is a tumor suppressor. Mutations in the RB-1 gene allow cell proliferation to continue unchecked, potentially leading to oncogenesis. Current genetic tests identify roughly 5% of retinoblastoma patients as having inherited the disease from a parent. A case is considered heritable if there is a family history of retinoblastoma, or if a mutation for the disease occurred early in differentiation. Approximately one-third of retinoblastoma cases are heritable. All bilateral cases of retinoblastoma are heritable. For this reason, parents of a child with bilateral retinoblastoma should see a geneticist to discuss the risks of passing the disease to future offspring. The majority of RB cases are sporadic, resulting from two successive mutations in a descending line of retinal cells.

Retinoblastoma is a paradigm of Knudson's two hit hypotheses. Each cell has two copies of DNA, one from each parent. If a child inherits a defective copy of RB-1, or undergoes a mutation early in differentiation, than the child only has one functioning tumor suppressor gene. Further mutations occur roughly 1 every 10⁷ cell divisions. Although this number seems miniscule, retinoblastoma is roughly 80-90% penetrant. This means that the large majority of patients who inherit a defective RB-1 gene undergo a mutation in one of their retinal cells, leading to retinoblastoma. Moreover, the two hit hypotheses explains the higher incidence of secondary cancers, including osteosarcoma, in retinoblastoma patients. As each patient's cell already has one defective copy of RB-1, one mutation can significantly increase the risk of oncogenesis. Clinically, it is important to be aware that all bilateral cases of Retinoblastoma are heritable.³

Grossly retinoblastoma appears chalky white (Figure 2). It is a friable tumor with dense foci of calcification. Tumors may grow from the retina into the sub-retinal space (exophytic) or may grow into the vitreous cavity (endophytic). The histology of retinoblastoma varies depending on the degree of differentiation. In more differentiated cases cells may resemble photoreceptors and form structures called rosettes and fleurettes. Necrosis and calcification are also commonly seen (Figure 3).

Untreated retinoblastoma is a fatal disease. The use of surgery (enucleation) and radiation in the 1950's resulted in complete local control of the tumor in many cases. In the 1970's and 1980's the treatment of small tumors with cryotherapy and brachytherapy radiotherapy gained popularity in many centers. Frequently in bilateral cases, the more severely affected eye was removed. More recently chemotherapy has been used to achieve reduction of local tumors so that a more conservative treatment would be possible for definitive tumor control. Currently the treatment modalities that we advocate include enucleation, external beam irradiation, brachytherapy, photocoagulation, cryotherapy, chemotherapy, chemothermotherapy and chemoreduction.⁴

The treatment varies depending on the number, size, and location (foveal or peripheral retina) of the tumors. With the use of chemotherapy some eyes are being saved that would have been enucleated only 5 years ago. Today, a child who develops retinoblastoma may retain relatively normal levels of vision in many cases. Approximately 80% of children developing this disease will go on to have a fairly normal life.

Prognosis is still in part dependent on early recognition. All physicians who see small children are aware that prompt referral for any child who has a suggestion of a white pupillary reflex or new onset of strabismus is critical. Although retinoblastoma is a malignant tumor, it can be successfully treated in many cases if early, accurate diagnosis and prompt referral are made.

REFERENCES

1. Shields JA, Shields CL. Retinoblastoma: Clinical and pathologic features. In Shields JA, Shield CL (eds). Intraocular Tumors. A Text and Atlas, Philadelphia, WB Saunders Co, 1992, pp 305-332.
2. Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology. 1988; 95:7-20.
3. Shields CL, Shields JA, Minelli S, et al. Regression of retinoblastoma after plaque radiotherapy. Am J Ophthalmology. 1989; 30-537.
4. White L. Chemotherapy in retinoblastoma current status and future directions. Am J Pediatr Hematol Oncol. 1991; 13:189-201.