Retinoblastoma, a primary ocular malignancy arising from immature retinoblasts, is diagnosed in about 300 children per year in the United States. It is the most common ocular malignancy in children.
In its normal form, the retinoblastoma gene (Rb1) is a tumor suppressor gene that resides in the q14 region of chromosome 13. Inactivation of both normal alleles of the retinoblastoma gene will result in the development of retinoblastoma. Inactivation of the gene may be inherited, but most cases (60 percent) are due to somatic mutations.
Retinoblastoma may directly invade the optic nerve and extrascleral tissue, which can lead to brain extension and metastasis. If untreated, retinoblastoma usually results in death within five years of onset.
Retinoblastoma presents in comparable frequency in both genders at a mean age of 18 months. Bilateral tumors tend to present earlier (average age of 12 months), whereas unilateral cases occur later (average age of 23 months). The most common presenting symptom of retinoblastoma is leukocoria. The second is strabismus, followed by glaucoma, red eye and tearing.
The appearance of retinoblastoma can vary depending upon its growth pattern. Endophytic tumors tend to appear as white, vascularized, circular masses sitting on the retina. Exophytic tumors often manifest as a retinal detachment. Some retinoblastomas possess a mixed endophytic-exophytic growth pattern and, therefore, have a varied appearance. Finally, retinoblastoma may grow in a manner that infiltrates the retina diffusely, which results in overall retinal thickening.
Caption: Retinoblastoma is the most common
ocular malignancy in children.
In addition to direct visualization of the tumor, indirect ophthalmoscopy allows determination of the extent of tumor involvement and detection of intravitreal foci. Evaluation of the anterior chamber with the slit lamp identifies iris invasion and any malignant cells.
Several imaging modalities are helpful in assessing the presence and extent of retinoblastoma. Ultrasonography demonstrates a mass with high reflectivity due to calcification. Calcification is also highlighted on CT and, therefore, CT can verify the findings on ultrasound. MRI is less useful, but it may determine whether the tumor has invaded the optic nerve or brain.
A baseline complete blood count is indicated in all children with newly diagnosed retinoblastoma. However, because retinoblastoma is often diagnosed prior to invasion of extraocular structures, it is of low yield to perform other ancillary testing for systemic metastasis at initial evaluation. Bone scan, bone marrow biopsy and lumbar puncture are reserved for situations in which extraocular spread is suspected.
The differential diagnosis includes Coats’ disease, toxocariasis, persistent hyperplastic primary vitreous, retinal capillary hemangioma and various other inflammatory processes.
The most common staging method used to classify retinoblastoma is the Reese-Ellsworth (RE) scale. In RE, cases can be placed into one of five groups based on tumor size, location and multiplicity. Group 1 possesses the most favorable prognosis and includes tumors less than 4 disc diameters located at or behind the equator. Group 5 carries the worst prognosis and involves tumors that encompass over half the retina and those with vitreous seeding.
Treatment of Intraocular Retinoblastoma
Therapeutic advancement has led to survival rates of over 90 percent. Treatment decisions should incorporate staging of the tumor, laterality and vision potential. Options for treatment are multiple and include the following:
Enucleation. This remains the treatment of choice for large unilateral tumors, situations with low visual prognosis, long-standing retinal detachment, neovascular glaucoma, and extensive tumor involvement of nerve, choroid or anterior chamber.1 The eye should be removed with an optic nerve stump of about 15 millimeters so as to decrease the chance of metastasis. An orbital integrated implant may be placed at the time of enucleation for later improved cosmesis after prosthesis fitting.
External beam radiation. In the past, external beam radiation therapy (EBRT) was the most common treatment (aside from enucleation) for retinoblastoma. Since the advent of chemotherapy, EBRT has been relegated to the treatment of severe disease. Appropriate candidates are those with advanced disease who have unresponsive or recurrent disease after other treatment modalities, namely chemoreduction and focal consolidation. They often have multiple bilateral tumors with vitreous seeding or orbital invasion. For patients in RE group 5, EBRT with chemotherapy and enucleation is often necessary as a life saving measure. Radiation is delivered to the affected eye and orbit in doses of 40 to 50 Grays, over the course of five weeks. Adverse events associated with EBRT are numerous and include radiation-induced tumor, facial dysmorphism, retinopathy, cataract and optic neuropathy.1
Systemic chemotherapy. Systemic chemotherapy, also called chemoreduction, followed by focal tumor consolidation is now the first-line therapy for tumors falling in RE groups 1 to 3. These are most commonly bilateral tumors that may at the time of diagnosis be accompanied with retinal detachment. As such, the size and location of each retinoblastoma lesion may not initially be clear.
Intravenous chemotherapy is initiated in conjunction with a pediatric oncologist. The most commonly employed regimen is six cycles of vincristine (Oncovin and others), etoposide (Etopophos and others) and carboplatin (Paraplatin) administered over an 18-week period with an exam under anesthesia and fundus photography prior to each treatment to follow tumor response. Reduction of the tumor with chemotherapy is followed with tumor consolidation by adjuvant focal treatments. These treatments include localized thermotherapy, cryotherapy, plaque radiotherapy or laser photocoagulation to individual lesions. This regimen increases the potential for preservation of vision without many of the ocular complications that accompany radiotherapy.2
The agents used in chemoreduction do, however, have inherent toxicity and may cause adverse effects. Parents of patients about to undergo chemoreduction must be warned about the possibility of myelosupression, neurological and gastrointestinal toxicity, infection and fever.1 Moreover, those receiving chemoreduction run a risk of developing secondary malignancy.3
Transpupillary thermotherapy. TTT involves delivery of a thermal infrared laser to the tumor for at least one minute, in an effort to induce necrosis. The laser used delivers less heat than photocoagulation. TTT can be used as an adjunct to chemoreduction. Whether it can be used as a primary treatment is the topic of current debate. A recent study has shown that TTT alone can successfully treat retinoblastoma tumors less than 1.5 disc diameters.4 Complications of thermotherapy include focal iris atrophy, retinal traction, retinal detachment and focal cataract.5
Plaque radiotherapy. Plaque radiotherapy involves localized radiation at a dose of 40 to 45 Gy. Plaque radiotherapy is a more localized form of therapy than EBRT and therefore is less prone to result in excess damage. It may be used as an adjunct to chemoreduction and in some cases as primary therapy. Recent studies have shown plaque radiotherapy to be especially useful in tumors that have failed treatment by other means.6 Side effects include retinopathy and optic neuropathy.
Laser photocoagulation. This involves using a xenon laser to create one to two rows of burns in a circular pattern around the tumor’s base, in an attempt to compromise its vascular supply. Laser photocoagulation is best for small tumors with a diameter of 3 mm or less and thickness of 2 mm or less, with no vitreous involvement.7 It must often be repeated to achieve tumor regression.
Cryotherapy. Cryotherapy can be used as primary or secondary treatment for tumors less than or equal to 5 mm in diameter and 3 mm in thickness and with a small amount of vitreous seeding. In general, it has been noted that cryotherapy is most relevant for tumors anterior to the equator of the eye. Adverse events associated with cryotherapy include vitreous hemorrhage and subretinal fluid.7
Treatment of Extraocular Retinoblastoma
Retinoblastoma can invade the central nervous system and orbit. It can metastasize to bone, marrow and lungs. Retinoblastoma is deemed high risk for metastasis on microscopic examination when tumor invades the optic nerve or surrounding ocular coats. Chemotherapy is indicated for tumors that extend into the optic nerve beyond the lamina cribrosa.8 The prognosis for metastatic disease is poor. Current research on treatment for metastatic retinoblastoma has focused on various high-dose chemotherapeutic regimens coupled with autologous stem cell rescue.
- Exam under anesthesia (EUA) with photos every four weeks while undergoing chemoreduction for bilateral cases and then as follows: every eight to 12 weeks until ages 2 to 3, every four months until age 4, every six months until age 5, every six months in office until ages 6 to 7, then once a year.
- CT scans every four months until age 3, then every six months till age 5.
- EUA with photos every eight to 12 weeks for unilateral cases status postenucleation until ages 2 to 3, then a dilated fundus exam in the office every four to six months until age 6.
- EUA with photos every four weeks for unilateral cases undergoing treatment and then every three months until age 3, every four to six months in the office until age 5, then yearly.
1 De Potter, P. Curr Opin Ophthalmol 2002; 13:331–336.
2 Shields, C. L. et al. Retina 2004;24(6): 849–862.
3 Felice, M. S. et al. Med Pediatr Oncol 1998;30:160–164.
4 Abramson, D. H. and A. C. Schefler. Ophthalmology 2004;111:984–991.
5 Shields, C. L. et al. Arch Ophthalmol 1999;117:885–893.
6 Shields, C. L. et al. Ophthalmology 2001;108: 2116–2121.
7 Kaiser, P. K. et al. Digital Journal of Ophthalmology 2004. Accessed Sept. 9, 2004.
8 Uusitalo, M. S. et al. Arch Ophthalmol 2001;119:41–48.
Mr. Etter is a fourth-year medical student at Jefferson Medical College in Philadelphia and Dr. Bansal is clinical associate professor of ophthalmology at Duke University.