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Retinal Insider

Edited by Carl Regillo, MD

How to Diagnose and Treat Retinoblastoma

Earlier detection and better treatments have improved the prognosis for retinoblastoma.

Ingrid U. Scott, MD, MPH
Miami

Joan M. O’Brien, MD
San Francisco

Not many years ago, retinoblastoma meant almost certain enucleation. Thanks to earlier detection and improved treatments, patients with retinoblastoma face significantly improved options in recent years. This article reviews the etiology, diagnosis and current treatment choices.

Etiology
The most common primary intraocular tumor of childhood, retinoblastoma accounts for about 1 percent of all cancer deaths among persons under 16 years of age in the United States,1 and for some 5 percent of childhood blindness.2 Retinoblastoma is the third most common intraocular malignancy, behind choroidal melanoma and metastasis.

The prevalence of retinoblastoma has been reported to have increased over the past 60 years from 1 in 34,000 live births to 1 in 20,000 live births.3,4 There is no known gender or racial predilection for the disease.5 Approximately 60 percent of retinoblastoma is unilateral on presentation, while approximately 40 percent of cases present bilaterally.6,7 Mean age at diagnosis is 18 months; children with bilateral tumors are typically diagnosed at a younger age (mean, 13-15 months) than children with unilateral disease (mean, 24 months).8,9 Most patients with retinoblastoma present by the age of 3 years, and over 90 percent of cases are diagnosed before the age of 5. However, retinoblastoma has been newly diagnosed in children between 7 and 18 years, and rare cases in adults up to 74 years of age have been reported.


Leukocoria (white pupil), one of the most common presenting signs in a child with unilateral retinoblastoma.

Diagnosis
In almost all series of retinoblastoma patients, the most common presenting sign has been leukocoria, which is present in 54-62 percent of patients with retinoblastoma in the United States.10,11 Leukocoria in retinoblastoma is caused by a tumor floating in the vitreous cavity, as in endophytic retinoblastoma (tumors that grow toward the vitreous cavity), or by detached retina behind the lens, as in exophytic retinoblastoma (tumors that grow toward the subretinal space).

The second most common finding in retinoblastoma is strabismus, which occurs in 18-22 percent of cases,10,11 and is caused by a tumor or detachment of the retina within the macula. Two to 10 percent of retinoblastoma patients present with inflammation, which often leads to delayed diagnosis of the tumor. Other rare presenting signs of retinoblastoma include anisocoria, hyphema, glaucoma, proptosis, heterochromia, hypopyon, tearing, cataract, nystagmus and spontaneous globe perforation.

The diagnosis of retinoblastoma in patients under 5 years of age is usually made after signs of the disease are noted by the patients’ parents or pediatrician. Among patients older than 5 years, it is the patients who first notice the signs or symptoms of the tumor in about 77 percent of cases. Presenting signs and symptoms among older patients include decreased vision (35 percent), leukocoria (35 percent), strabismus (15 percent), floaters (4 percent), and pain (4 percent).

The lesion that most often simulates retinoblastoma is persistent fetal vasculature, or persistent hyperplastic primary vitreous. This congenital condition is usually noted during the first few days or weeks of life, occurs unilaterally in a microphthalmic eye, and generally consists of a retrolental fibrovascular mass with dragged ciliary processes and a secondary cataract. Retinoblastoma usually becomes clinically apparent several months after birth, is bilateral in one-third of cases, and occurs in normal-sized eyes without traction on the ciliary processes or associated cataract.

Another simulating condition, Coats’ disease, usually becomes clinically evident during the first decade of life, occurs predominantly in males, and is characterized by unilateral retinal telangiectasia, progressive yellow subretinal exudation, and exudative retinal detachment without a distinct mass and without calcification.12 In contrast, retinoblastoma usually becomes apparent before 3 years of age, is bilateral in one-third of cases, has no gender predilection, characteristically demonstrates calcification, and is rarely associated with the irregular caliber telangiectatic vessels characteristic of Coats’ disease.12

Most retinoblastoma cases can be diagnosed on the basis of clinical history, with special attention given to a careful family history, and ophthalmoscopic examination. We find that the most important diagnostic technique is binocular indirect ophthalmoscopy with meticulous scleral depression, which can demonstrate tumors less than 1 mm in size. Echography may detect lesions as small as 2 mm in size, and has been shown to be 98.4 percent sensitive for retinoblastoma diagnosis. A-scan demonstrates high internal reflectivity and rapid attenuation of the normal orbital pattern, while B-scan typically reveals a mass containing discrete, highly reflective echoes consistent with calcific foci. B-scan characteristically demonstrates attenuation or absence of the normal soft tissue echoes in the orbit behind the tumor due to attenuation and reflection of the sound by calcification. We generally obtain a brain and orbital CT at initial diagnosis to confirm the appearance of intraocular calcification and to exclude the possibility of a concomitant primitive neuroectodermal tumor (or “trilateral retinoblastoma”).


Digital fundus photograph of the patient seen on page 153, shows a large retinoblastoma tumor, occupying more than 50 percent of the globe (large white area). Vitreous seeding and areas of hemorrhage are visible.

Treatment Modalities
  • Enucleation. Enucleation remains the most frequent treatment for retinoblastoma. Indications include unilateral tumors that occupy more than half of the globe, extensive vitreous seeding by the tumor, total retinal detachment, iris neovascularization, ciliary body and iris involvement with the tumor or limited visual potential.13 With earlier tumor detection, as well as improved and increased usage of more conservative eye-sparing therapeutic methods, the frequency of enucleation has declined significantly over the past 40 years.14,15 In one study of patients with unilateral retinoblastoma, for instance, 4 percent of eyes were salvaged from 1974 to 1978, compared with 25 percent of eyes from 1984 through 1988.15
  • Radiation. Retinoblastoma is an extremely radiosensitive tumor, and external beam radiotherapy is most often used to treat patients with bilateral retinoblastoma that is not amenable to focal treatment. Radiation therapy has been associated with increased second tumor risk and midface hypoplasia in this population.16,17,18,19 We generally prefer external beam radiotherapy when tumor recurs after focal therapy or chemoreduction. Advantages of plaque radiotherapy over external beam radiotherapy include more localized delivery of radiation, thereby minimizing exposure to ocular structures uninvolved with tumor, reduction in midface hypoplasia, and potential reduction in second tumor risk. Plaque radiotherapy also has advantages over cryotherapy and photocoagulation in that the former can be effective for tumors up to 16 mm in diameter and 3 mm in thickness, and for those tumors with localized vitreous seeds.
  • Photocoagulation. We consider photocoagulation for treatment of small tumors that do not involve the optic disc or fovea. Photocoagulation is generally successful for tumors 3 mm in diameter and 2 mm in thickness, and confined to the retina without vitreous seeding. We recommend placing confluent burns over the tumor surface, using sufficient power to produce subtle retinal whitening. Multiple sessions may be necessary, and may allow this modality to be effective in controlling larger tumors.
  • Cryotherapy. Cryotherapy is effective for small peripheral retinoblastomas anterior to the equator where laser may damage the lens or iris. In general, cryotherapy is effective for tumors up to 3.5 mm in diameter and 2 mm in thickness, and with vitreous seeding less than 0.5 mm from the tumor apex. We recommend the triple freeze-thaw technique; the treatment may need to be repeated, typically at two- to three-week intervals.
  • Chemotherapy. Chemotherapy is used for patients with extraocular tumor extension or metastasis, patients at high risk for metastatic disease, patients with bilateral disease, and in conjunction with other therapies to enhance the efficacy of local therapeutic modalities. Chemotherapy often achieves tumor volume reduction, which renders tumors amenable to focal treatment. Recently, multiple-agent chemotherapy with etoposide, carboplatin, and vincristine combined with transpupillary hyperthermia or laser ablation has demonstrated excellent local control of retinoblastoma. Studies suggest that agents such as cyclosporine A effectively reverse the multi-drug-resistant phenotype that is seen in those intraocular retinoblastomas (up to 24 percent) which express increased levels of P-glycoprotein. A proposed international clinical trial funded by the National Cancer Institute is evaluating systemic chemoreduction in patients with large bilateral retinoblastoma tumors.


Dr. Scott is an assistant professor of ophthalmology at the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine. Contact her at (305) 326-6447; email: iscott@miami.med.ed. Dr. O’Brien is the director of ocular oncology department in the Department of Ophthalmology at the UC, San Francisco School of Medicine. Contact her at (415) 476-0779; e-mail: aleja@itsa.ucsf.edu.

  1. Miller RW. Fifty-two forms of childhood cancer: United States mortality experience 1960-1966. J Pediatr 1969;75:685-689.
  2. Fraser GR, Friedman AI. The Causes of Blindness in Children. Baltimore, MD: Johns Hopkins Press; 1969.
  3. Devesa SS. The incidence of retinoblastoma. Am J Ophthalmol 1975;80:263-265.
  4. Tarkkanen A, Tuovinen E. Retinoblastoma in Finland, 1912-1964. Acta Ophthalmol 1971;49:293-300.
  5. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States, 1974 through 1985. Arch Ophthalmol 1990;108:128-132.
  6. Sanders BM, Draper GH, Kingston JE. Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival. Br J Ophthalmol 1988;72:576-583.
  7. Augsburger JJ, Oehlschlager U, Manzitti Je. Multinational clinical and pathologic registry of retinoblastoma. Retinoblastoma International Collaborative Study report 2. Graefe’s Arch Clin Exp Ophthalmol 1995;233:469-475.
  8. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820-823.
  9. Rubenfeld M, Abramson DH, Ellsworth RM, et al. Correlations between age at diagnosis and stage of ocular disease. Ophthalmology 1986;93:1016-1019.
  10. Balmer A, Chill DC. Retinoblastoma. In: Syndromes and Retinoblastoma. Basel, Switzerland: Kargel;1983:36-96.
  11. Shields JA, Augsburger JJ. Current approaches to the diagnosis and management of retinoblastoma. Surv Ophthalmol 1981;25:347-372.
  12. Shields JA, Shields CL. Intraocular Tumors. A Text and Atlas. Philadelphia, PA: Saunders;1992:341-362.
  13. Shields JA, Shields CL, Donoso LA, et al. Changing concepts in the management of retinoblastoma. Ophthal Surg 1990;21:72-76.
  14. Abramson DH, Niksarli K, Ellsworth RM, et al. Changing trends in the management of retinoblastoma; 1951-1965 versus 1966-1980. J Pediatr Ophthalmol Strabismus 1994;31:32-37.
  15. Shields JA, Chields CL, Sivalingam V. Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol 1989;108:185-188.
  16. Vogel F. Genetics of retinoblastoma. Hum Genet 1979;52:1-54.
  17. Abramson DH, Ellsworth RM, Kitchin FD, et al. Second nonocular tumors in retinoblastoma survivors: are they radiation induced? Ophthalmology 1984;91:1351-1355.
  18. Roarty JD, McClean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583-1587.
  19. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 1993;85:1102-1103.

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