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Arch Ophthalmol. 2001;119:450-452.

The occurrence of a midline intracranial primitive neuroectodermal tumor (PNET) with bilateral retinoblastoma has been called "trilateral retinoblastoma."¹ This rare complication of heritable retinoblastoma is associated with an extremely poor prognosis, accounting for up to 50% of tumor-associated mortality among patients with retinoblastoma.²

Primitive neuroectodermal tumors usually occur 2 to 4 years after diagnosis of bilateral retinoblastoma. However, PNETs have been diagnosed in patients with unilateral retinoblastoma 6 months before diagnosis of bilateral retinoblastoma and in 2 siblings of patients with bilateral retinoblastoma with no intraocular disease.³ In most cases, patients with PNET are seen for symptoms of increased intracranial pressure after the tumor is large, and the disease is usually fatal.³

Patients diagnosed with small, asymptomatic PNETs, however, have improved survival rates when treated with chemotherapy and radiation.⁴ This has led to routine neuroimaging among patients with heritable retinoblastoma to detect preclinical intracranial neoplasms in many centers. However, no studies have established which patients are most likely to benefit from routine neuroimaging, how often patients should be screened, or whether routine neuroimaging improves patient outcome.

Of 226 patients with retinoblastoma evaluated between January 1990 and December 1998 at 2 large referral centers, the University of California, San Francisco, and Bascom Palmer Eye Institute, Miami, Fla, we identified 3 patients with PNET.

Report of Cases
Case 1

A 3-month-old girl had bilateral retinoblastoma, Reese-Ellsworth stage IIB in the right eye and stage VA in the left. Her family history was remarkable for retinoblastoma. Initial computed tomographic (CT) scan showed no extraocular or intracranial disease. The left eye was enucleated. At age 38 months, chemotherapy was initiated for a recurrent tumor in the right eye after treatment with cryotherapy and laser. Despite multiple cycles of chemotherapy, the tumor progressed with diffuse vitreous seeding. At age 55 months, the right eye was enucleated. Findings from histopathologic examination demonstrated well-differentiated retinoblastoma confined to the globe. Routine magnetic resonance images (MRIs) of the brain and orbits were obtained every 5 months. At age 60 months, the patient complained of headaches. An MRI scan of the brain and orbits showed no evidence of intracranial disease. At age 62 months, the patient was seen for displacement of the right prosthesis. An MRI demonstrated a new extraconal mass in the right orbit (Figure 1). The mass was felt to be an orbital PNET rather than recurrent retinoblastoma because it was external to dural reflections in the orbit seen on MRI scan. Fine-needle aspiration biopsy revealed a poorly differentiated round blue cell tumor consistent with PNET. Metastatic evaluation disclosed no other evidence of tumor. Despite prompt exenteration, chemotherapy, and radiation, the patient died 9 months after PNET diagnosis.

View larger version (62K): [in this window] [in a new window] Figure 1. Case 1. A magnetic resonance image in a 62-month-old patient with bilateral retinoblastoma demonstrated a new extraconal mass in the right orbit. The mass was felt to be an orbital primitive neuroectodermal tumor because it was external to dural reflections in the orbit.

Case 2

A 7-week-old girl with no family history of retinoblastoma was seen for unilateral retinoblastoma (Reese-Ellsworth stage VA) in the left eye.⁵ Initial CT scan showed no extraocular or intracranial disease. The left eye was enucleated. Results of histopathologic examination demonstrated well-differentiated retinoblastoma confined to the globe. The patient was examined under anesthesia every month for 2 months, then every 2 months for 6 months, then every 3 months, and did not develop retinoblastoma in the right eye. At age 22 months, the patient developed nausea and vomiting. An emergent CT scan demonstrated a tumor in the pineal region consistent with PNET (Figure 2). Despite chemotherapy, the patient died 4 months after PNET diagnosis.

View larger version (49K): [in this window] [in a new window] Figure 2. Case 2. A computed tomographic scan of the brain performed without contrast at age 22 months demonstrated a tumor in the pineal region, consistent with primitive neuroectodermal tumor.

Case 3

An 18-month-old girl with no family history of retinoblastoma was seen for 4 months of unilateral leukocoria in the left eye. Findings on examination revealed Reese-Ellsworth stage VB retinoblastoma in the left eye and no disease in the right eye. A CT scan showed no extraocular or intracranial disease. The left eye was enucleated. Results of histopathologic examination demonstrated well-differentiated retinoblastoma confined to the globe. The patient underwent examination with anesthesia. At age 21 months, the patient developed unremitting headaches. An emergent MRI showed a tumor in the pineal region, consistent with PNET. Following chemotherapy and radiation, the patient remained without disease 18 months after PNET diagnosis.

Comment
In the current study, routine neuroimaging among patients with heritable retinoblastoma did not lead to presymptomatic diagnosis of PNET in any patient. At the time of retinoblastoma diagnosis, all patients were screened with CT of the brain and orbits under anesthesia, without contrast, with 3.75-mm cuts through the brain and 1-mm cuts through the orbits. Patients with recognized heritable retinoblastoma (patients with bilateral retinoblastoma or a family history of retinoblastoma) underwent additional routine MRIs of the brain and orbits every 6 months. In any patient with new neurologic symptoms, an MRI of the head was obtained immediately. No family refused neuroimaging studies.

Of 226 patients seen at these institutions over 9 years, 83 had heritable retinoblastoma and underwent routine neuroimaging every 6 months. The 143 patients with unilateral, unifocal disease and no family history of retinoblastoma did not undergo routine neuroimaging after the initial baseline study at the time of retinoblastoma diagnosis. Mean follow-up time was 44.8 months, with a range of 0 to 139 months.

A limitation of this study is that 56 (25%) of 226 patients were followed up for less than 2 years, and some of these patients may develop PNET in the future, during the 2 to 4 years following retinoblastoma diagnosis. In the current series, 1 of the 86 patients who were screened developed PNET, which was diagnosed after the patient was seen for symptoms and not as a result of routine neuroimaging. Two of 3 PNET patients were not recognized to have heritable retinoblastoma and did not undergo routine neuroimaging.

The current series of 226 patients with retinoblastoma did not demonstrate improved outcome due to early diagnosis of PNET by routine neuroimaging of patients with recognized heritable retinoblastoma. Because PNET occurs infrequently, many patients with retinoblastoma must be studied to investigate the utility of routine neuroimaging in diagnosing this condition. An international, prospective, multicenter collaborative trial is necessary to determine the appropriate regimen for routine neuroimaging in patients with both heritable and presumed nonheritable retinoblastoma.

AUTHOR INFORMATION

Jacque L. Duncan, MD; Ingrid U. Scott, MD, MPH; Timothy G. Murray, MD; Dan S. Gombos, MD; Kurtis van Quill; Joan M. O'Brien, MD
San Francisco, Calif

Corresponding author: Joan M. O'Brien, MD, Box 0730, University of California, San Francisco, San Francisco, CA 94143-0730 (e-mail: aleja{at}itsa.ucsf.edu).

REFERENCES
1. Bader JL, Miller RW, Meadows AT, Zimmerman LE, Champion LAA, Voute PA. Trilateral retinoblastoma. Lancet. 1980;2:582-583. 2. Blach LE, McCormick B, Abramson DH, Ellsworth RM. Trilateral retinoblastoma: incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys. 1994;29:729-733. WEB OF SCIENCE | PUBMED 3. Kivelä T. Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol. 1999;17:1829-1837. FREE FULL TEXT 4. Nelson SC, Friedman HS, Oakes WJ, et al. Successful therapy for trilateral retinoblastoma. Am J Ophthalmol. 1992;114:23-29. WEB OF SCIENCE | PUBMED 5. Ibarra MS, O'Brien JM. Is screening for primitive neuroectodermal tumors in patients with unilateral retinoblastoma necessary? J AAPOS. 2000;4:54-56.

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