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Case 5-2006 — An 11-Year-Old Girl with Loss of Vision in the Right Eye
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     Presentation of Case

    Dr. Torsten Wiegand (Massachusetts Eye and Ear Infirmary): An 11-year-old girl was evaluated at our institution because of a loss of vision in the right eye.

    One month earlier, she had noticed decreased vision in her right eye, without pain, photophobia, excessive lacrimation, or discharge. She told her mother about the problem; since her vision was normal in the left eye, they jointly decided not to seek medical attention but to wait and see if her vision would improve spontaneously.

    Four weeks later, after a routine eye examination at school, the girl was referred to an ophthalmologist for evaluation. On examination, leukokoria was noted in the right eye, and a posterior fibrovascular lesion was seen. She was referred for further evaluation to the Massachusetts Eye and Ear Infirmary, where she was seen later that same day in the emergency department. At that time, visual acuity was limited to light perception in the right eye and was 20/15 in the left eye. On examination by the resident in ophthalmology and the fellow on the retina service, neovascularization of the right iris was seen, with a total exudative retinal detachment; the detached retina was displaced forward to the posterior lens capsule, and telangiectatic vessels were visible on the retinal surface. An ultrasonographic examination confirmed the presence of a total retinal detachment with no evidence of calcification. The results of an examination of the left eye were normal. The patient was scheduled for further evaluation by a specialist in pediatric retinal diseases three days later.

    The patient was born at full term and had met all physical and developmental milestones. She attended sixth grade and played basketball. She had no history of eye problems, and her vision had been normal on previous school eye examinations. Testing by her pediatrician when she was seven years old showed visual acuity of 20/30 in both eyes. A younger brother had strabismus and amblyopia, which were being treated with glasses and a patch. Other family members were well, and there was no other family history of ophthalmologic problems.

    An examination of the eyes again revealed visual acuity of light perception only in the right eye and 20/15 in the left eye. The eye movements were full, with a right hypertropia and exotropia present in primary gaze. Intraocular pressures were 17 mm Hg in the right eye and 15 mm Hg in the left eye. An examination of the anterior segment of the right eye showed a normal conjunctiva, a clear cornea, an abnormally shallow anterior chamber that contained no inflammatory cells, and 4+ (on a scale of 1+ to 4+) neovascularization of the iris. The lens contained a focal-lacunar cataract temporally. The retina was totally detached posterior to the lens capsule and was in contact with it. The retina contained multiple white plaques and numerous telangiectatic vessels, some of which appeared to enter the plaques. An examination by indirect ophthalmoscopy after dilation of the pupil showed a few hard exudates and lipid crystals in and under the retina; a large area of creamy-white opacification in the inferior peripheral retina and the mid-peripheral retina occupied about a third of the retinal surface. Some nonpigmented cells, some of which were in small clumps, were seen in the compressed vitreous anterior to the retina. The results of an examination of the left eye were normal.

    A diagnostic procedure was performed.

    Differential Diagnosis

    Dr. David S. Walton: May we review the imaging studies?

    Dr. Shizuo Mukai: An image from a slit-lamp examination (Figure 1A) shows the retina as totally detached posterior to the lens capsule and in contact with it. White plaques in the retina appeared to obscure the retinal vessels in some areas. There were numerous large, dilated, and tortuous vessels and small telangiectatic vessels with microaneurysms on the surface of the retina. Some of the larger vessels appeared to dive into the plaques, either feeding or draining the plaque-like areas. Further examination of the retina by indirect ophthalmoscopy after dilation of the pupil showed a moderately large area of creamy-white opacification in the inferior peripheral and midperipheral retina, occupying about one third of the retinal surface. A review of the ultrasonographic study performed in the emergency department (Figure 1B) showed a moderately reflective, membranous structure occupying the posterior pole, consistent with a total retinal detachment, with heterogeneous, moderately reflective material in the inferior subretinal space that was suggestive of a mass. Focal areas of highly reflective material in this area suggested calcification.

    Figure 1. Clinical Images of the Right Eye.

    On slit-lamp examination (Panel A), the retina is totally detached and is in contact with the posterior capsule of the lens. There are prominent vascular changes on the retinal surface; many of the larger vessels are dilated and tortuous (arrowheads), and the smaller vessels show telangiectasia with microaneurysms. There are plaque-like areas in the retina that obscure some of the vessels, and some of the larger vessels appear to dive into the plaques (arrows). Yellowish material is seen under the retina, but relatively little of it is refractile to light. Ultrasonographic examination of the right eye (Panel B) shows a highly reflective membrane within the globe, representing the detached retina (arrowheads). Heterogeneous, moderately reflective material is seen in the subretinal space (in the upper part of this image) consistent with a mass (arrows). The size and the contour of the globe are normal. A fluorescein angiogram of the right eye (Panel C), obtained 50 seconds after intravenous injection of the dye, shows that many of the larger retinal vessels are dilated and tortuous, and some of them appear to dive into the plaque-like areas (arrows). The smaller vessels show extensive telangiectasia and the formation of microaneurysms (arrowheads). Fluorescein leaks into the plaques early in the transit of the dye, and the vessels appear to be obscured in the area of the plaques.

    Dr. Walton: The patient's history of healthy eyes throughout childhood and the documentation of 20/30 visual acuity in each eye when she was seven years of age narrows an initially broad field of diagnostic possibilities. The failure of the development of good vision in one eye or the loss of vision in early childhood is frequently associated with an early secondary eye deviation that might otherwise be asymptomatic. This association helps to explain why the investigation of eye deviations and routine vision testing during childhood is so important.

    The absence of a marked eye deviation suggests that the visual loss in this patient was not only acquired but also of relatively short duration, possibly only a few months or less. She reported poor vision in the affected eye, which was soon confirmed during a compulsory vision evaluation at school. Young children rarely report visual problems, whereas older children more often are evaluated for symptomatic vision loss that is unassociated with discomfort or a history of trauma. There was no history of prematurity, hereditary ocular disease, ocular trauma, or other ocular or systemic conditions that would predispose the patient to eye disease, such as high myopia (severe nearsightedness that predisposes the patient to retinal detachment) or juvenile rheumatoid arthritis.

    An eye examination revealed light-perception acuity in the right eye, leukokoria (a white light reflex rather than a red light reflex in the pupil), and a complete retinal detachment, which explains the visual deficit and the loss of the pupillary red light reflex, which would be the normal reflex. An inspection of the anterior segment of the right eye showed no evidence of inflammation. Neovascularization of the iris was present; this is a nonspecific abnormality that occurs when vasogenic factors are produced intraocularly, secondary to retinal ischemia or detachment. The retina was visualized anteriorly behind the lens and possessed many abnormal blood vessels of variable size, multiple small white plaques, and one large, creamy-white opacification, but no definite mass lesion. Evidence of exudation was seen under the retina, confirming the initial clinical impression of an exudative retinal detachment, rather than one resulting from the formation of a hole in the retina, as is seen after trauma or with retinal degenerative conditions.

    Leukokoria may be caused by a cataract; in this child, the lens was normal, and a detached retina was causing the condition. The history and a detailed examination confirmed the presence of an acquired exudative retinal detachment; in childhood, this condition may be due to inflammatory, vascular, neoplastic, or systemic causes (Table 1).1 Toxocariasis and Coats' disease make up more than 45 percent of cases of children with leukokoria who are referred for evaluation for possible retinoblastoma, after the more obvious cataractous cause is ruled out.1

    Table 1. Causes of Exudative Retinal Detachment in Childhood.

    Inflammatory Disorders

    Ocular toxocariasis is unilateral and typically causes ocular symptoms in the absence of other clinical signs. It is an unusual late manifestation of visceral larva migrans, caused by an intraocular infestation of larvae of Toxocara canis, the dog ascarid. Typically, an inflammatory lesion develops in the posterior chamber of the eye around the deceased larva, associated with traction bands in the vitreous; in rare cases, the reaction can be more extensive, causing endophthalmitis and secondary exudative retinal detachment, as seen in this case. Typically, a serum enzyme-linked immunosorbent assay for T. canis antibodies is positive at low titers, but because of the frequent occurrence of this infection in childhood, its specificity is low. The test was not done in this case. Other inflammatory causes of exudative retinal detachment are usually accompanied by defining clinical abnormalities that were not present in this case (Table 1).

    Vascular Disorders

    Coats' disease is a developmental vascular disease of the retina. It characteristically causes a chronic, unilateral, progressive retinal detachment associated with massive subretinal exudation from leaking telangiectatic retinal blood vessels. It is more common in males, is usually detected early in childhood, and cannot be recognized by any noninvasive test. Retinal capillary hemangiomatosis and a circumscribed choroidal hemangioma also may cause an indolent retinal detachment. In this case, the age and sex of the patient and the relatively rapid onset of vision loss, as well as the focal creamy-white opacification of the detached retina with diffuse abnormal blood vessels, would argue against Coats' disease or a primary vascular lesion.

    Neoplasms

    Ocular neoplasms include primary ocular tumors or involvement by systemic conditions such as leukemia, neuroblastoma, and hepatocellular carcinoma.2 There was no evidence in this patient of an extraocular malignant tumor. Primary ocular tumors include the rare malignant uveal melanoma of childhood, ciliary-body medulloepithelioma, and retinoblastoma, which is the most common childhood intraocular malignant tumor.

    Retinoblastoma is typically a disease of early childhood; most cases are recognized by the time the patient is three years of age, and 90 percent of cases are diagnosed by the time the patient reaches five years of age.3 The disease is often asymptomatic in young children; in one study, the patients presented with leukokoria (60 percent of the cases) or strabismus (20 percent).4 Retinoblastomas may be endophytic, with tumor growth into the vitreous (60 percent of cases), or exophytic, with growth into the subretinal space (39 percent).5 Atypical manifestations of retinoblastoma are recognized late and are characteristically associated with advanced tumors.6 Enucleation is required in approximately 30 percent of cases of unilateral tumors,7 and the overall survival rate for patients with retinoblastoma is now greater than 90 percent.

    The findings in this case are typical of the cases of retinoblastoma that occur in older children, which make up 10 percent of all cases of retinoblastoma8; virtually all are unilateral, there is a lack of a family history of retinoblastoma, and the patients present with a retinal mass lesion.

    A rare subtype of late-onset retinoblastoma, the diffuse infiltrating retinoblastoma, which accounts for about 1.5 percent of cases, is characterized by diffuse infiltration of the retina with tumor cells. This subtype should be considered as a possible diagnosis in this patient, who does not have an obvious mass lesion.9 This disorder was identified in 1958,10 and fewer than 40 cases have been reported.11 The clinical features that distinguish this condition are summarized in Table 2.8,9,12 The diagnosis is often delayed, with the most frequent alternative clinical diagnosis being uveitis. Despite the initial misdiagnosis, which is not uncommon, the prognosis for this disease is favorable, with a survival rate over 95 percent after enucleation.9

    Table 2. Diffuse Infiltrating Retinoblastoma versus Typical Retinoblastoma.

    In summary, the findings in this 11-year-old patient are most consistent with the unusual occurrence of a retinoblastoma in an older child,13 and they are suggestive of the diffuse infiltrating subtype. An intraocular diagnostic needle aspiration may have been considered to establish the diagnosis, but because of a high level of clinical concern about retinoblastoma and the fact that the patient was blind in the affected eye, it is likely that an enucleation was performed.

    Dr. Nancy Lee Harris (Pathology): Dr. Mukai, would you tell us what you did for the patient?

    Dr. Mukai: We first performed a fluorescein angiogram of the right eye (Figure 1C), which clearly shows that many of the larger retinal vessels are dilated and tortuous, and some of them appear to dive into or arise from the plaque-like areas seen on the slit-lamp examination. The smaller vessels show extensive telangiectasia and formation of microaneurysms. Fluorescein leaks into the plaques early in the transit of the dye, and the vessels appear to be obscured in the area of the plaques.

    We performed an enucleation of the right eye two days later. On intraoperative gross examination of the enucleated globe, there was no evidence of extraocular tumor, tumor at the surgical margin of the optic nerve, or optic-nerve enlargement.

    Clinical Diagnosis

    Retinoblastoma.

    Dr. David S. Walton's Diagnosis

    Atypical retinoblastoma, possibly the diffuse infiltrating type.

    Pathological Discussion

    Dr. Thaddeus P. Dryja: A tumor occupied approximately half the volume of the vitreous cavity (Figure 2A). It arose from the retina and was composed of small cells with basophilic nuclei, scanty cytoplasm, and numerous mitoses (Figure 2B). Viable tumor cells were clustered around blood vessels, and necrotic tumor cells and calcium deposits were seen between these clusters. Small foci of tumor were attached to the remaining retina and were in the subretinal space under areas of retinal detachment. The anterior segment of the globe was normal except for neovascularization on the anterior surface of the iris. Tumor cells fill the choroid in a region extending approximately a quarter of the circumference of the globe (Figure 2C). The tumor extended through the sclera in one region, but it did not extend into the optic nerve. The anatomical diagnosis was retinoblastoma with two features that confer an increased risk for metastasis — that is, massive choroidal invasion and extrascleral extension.14

    Figure 2. Pathological Specimens of the Enucleated Eye.

    On gross dissection (Panel A), the enucleated eye has a detached retina (white arrow) pushed against the lens by subretinal fluid (white asterisk). The detached retina is connected to a white tumor (black asterisk) with numerous calcifications (black arrowheads). On microscopical examination (Panel B), viable tumor cells with scanty cytoplasm are packed around blood vessels (three arrows); the tumor cells most distant from the vessels are necrotic (asterisks). The Panel B inset shows a high-power view of a Flexner–Wintersteiner rosette (black arrow), a few of which were observed. A mitosis is also shown (white arrow). The choroid (Panel C, white asterisks) is packed with tumor cells in the region shown. The subretinal space inside of the eye is at the top of Panel C. External to the sclera (black asterisk), there are tumor cells (black arrow) adjacent to a vortex vein (lower right corner). Panels B and C are stained with hematoxylin and eosin.

    Retinoblastomas all have biallelic inactivation of the RB gene on chromosome 13q14. The mutation in the first allele is a germ-line mutation in 40 percent of the cases, either inherited from a parent (10 percent) or newly arising (30 percent). In 60 percent of the cases, the first allele becomes mutant in a retinal precursor cell. The mutation in the second allele subsequently occurs in the retina.15,16 This "two-hit" mechanism explains why most patients with the initial mutation in the germ line have multiple retinoblastomas arising in both eyes, usually at a young age (less than one year), whereas in patients whose initial mutation is in the retina, a single tumor almost always develops in only one eye and often at a later age, as probably happened in this patient.17 The protein normally produced by the RB gene (pRB) forms a complex with the transcription factor E2F, preventing activation of the genes necessary for DNA replication and cell division.18 Without pRB, cells continuously replicate, which is a property of cancer. Many osteosarcomas, melanomas, sarcomas, and lung carcinomas have RB mutations, and patients with hereditary retinoblastoma are at increased risk for these tumors.19,20

    Detection of the RB gene mutation in the leukocytes or tumor cells of a patient with retinoblastoma may provide valuable information to guide the frequency of follow-up evaluations for the early diagnosis of additional tumors. Even though only about 10 percent of patients such as this one, with unilateral retinoblastoma and no family history, have a germ-line mutation and are thus predisposed to the development of new retinoblastomas, all such patients now receive frequent follow-up eye examination. DNA analysis can reduce health care costs through elimination of the follow-up evaluations of patients and close relatives,21 and it enhances genetic counseling of other family members who might be at high risk for tumors related to an RB gene mutation.22 However, the high cost and complexity of the analysis have delayed the implementation of universal genetic screening in new cases. Genetic testing was not done in this case.

    Dr. Walton: In patients with retinoblastoma, new tumors characteristically cease to develop after the patients are three to four years of age. In the subgroup of atypical older patients with retinoblastoma, we have a group who characteristically present with the disease between 5 and 18 years of age.23 These patients are clinically different. How can we explain the occasional occurrence of retinoblastoma in older patients and its different clinical behavior in these patients?

    Dr. Dryja: The retina in older children and adults is composed of terminally differentiated neurons that apparently cannot proliferate even if they lose both copies of the retinoblastoma gene. The retinoblastoma that occasionally develops in an older child or adult perhaps indicates that a small population of embryonic retinal precursor cells resides in the retina, and rarely one of those cells loses both RB alleles and can progress to form a tumor. Alternatively, other oncogenic events may be required to form a retinoblastoma in cells lacking functional RB alleles. In an occasional case, these events might be slow in accumulating, giving rise to an older-onset case.

    Dr. Harris: Dr. Grabowski and Dr. Munzenrider, would you describe the treatment of this patient?

    Dr. Eric F. Grabowski: There are four clinical stages of retinoblastoma: intraocular, regional, central nervous system (intracranial or cerebrospinal fluid), and hematogenous, for which the treatment differs. The workup to establish the correct stage of disease includes a careful review of pathological specimens of the globe and optic nerve (when one or both eyes are enucleated), a diagnostic lumbar puncture, bilateral bone marrow aspiration and biopsy, a magnetic resonance imaging (MRI) scan of the brain and orbits, and a bone scan.

    In this patient, evaluation revealed episcleral tumor and two risk factors for central nervous system or hematogenous disease. First, half of the vitreous space was filled with tumor, and second, extensive choroidal tumor was present. The second finding, in our experience, is often found together with optic-nerve involvement. Fortunately, we found no evidence of optic-nerve tumor. There was no evidence of distant metastasis. Therefore, this case was staged as having regional (orbital) extension of the tumor.

    The therapy we proposed after enucleation consisted of alternating courses of chemotherapy with the combination of vincristine, carboplatin, and etoposide and the combination of vincristine, doxorubicin, and ifosfamide. In addition, proton-beam radiation therapy was administered to the right orbit. Chemotherapy was administered for a total of eight courses over 30 weeks, and four intrathecal treatments with cytarabine and methotrexate were given at intervals of one to two weeks for central nervous system prophylaxis. The rate of disease-free survival for patients, such as this child, with regional tumor is 40 to 50 percent when data from all published studies are pooled. However, two studies suggest that aggressive treatment for such a tumor should result in a disease-free survival of 80 percent or more.23,24

    Dr. John E. Munzenrider: External-beam radiation therapy is typically delivered with high-energy x-rays. Proton-beam therapy, which is now available at this hospital,25 is a qualitatively different technique that offers advantages in dose distribution. Clinical proton beams have a finite depth of penetration in tissue of a defined density and a rapid loss of energy at the end of the beam's range, known as the Bragg peak. The dose distribution across the tissue volume can be made uniform by selecting an appropriate distribution of proton energies to produce a spread-out Bragg peak, which delivers a uniform dose to the tumor and virtually no dose to surrounding tissues. These properties are especially attractive for the treatment of children,26,27,28,29 since irradiation of normally developing tissues may impair their growth and development and result in late, second malignant tumors in long-term survivors.

    Primary proton treatment for intraocular retinoblastomas can be planned to avoid treatment of the brain, pituitary gland and hypothalamus, lens, optic nerves and chiasm, and bone.30 However, the locally advanced unilateral disease with which this patient presented was appropriately treated by enucleation, rather than by primary irradiation. Because of the extraocular extension found in the surgical specimen, radiation to the orbit was indicated to decrease the probability of local recurrence. Since the orbit was the target, a technique appropriate for a patient with an orbital, rather than an ocular, tumor was used.29 The treatment plan targeted four fields with four proton beams, each entering at a different angle, to focus the prescribed dose, 42 cGy equivalents, within the defined target volume and to limit the dose to the surrounding normal structures of the head and neck.

    Dr. Grabowski: This patient had repeated MRI of her brain and orbits one month after completing her therapy, the results of which showed no evidence of recurrent tumor. She is adapting very well psychologically to monocular vision and her new prosthetic eye.

    Dr. Mukai: When I examined her 20 months after the original diagnosis and enucleation, she was free of tumor.

    Anatomical Diagnosis

    Retinoblastoma.

    No potential conflict of interest relevant to this article was reported.

    Source Information

    From the Pediatric Service, Massachusetts General Hospital (D.S.W., E.F.G.); the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary (D.S.W., S.M., T.P.D.); the Department of Radiation Oncology, Massachusetts General Hospital (J.E.M.); and the Departments of Ophthalmology (D.S.W., S.M., T.P.D.), Pediatrics (D.S.W., E.F.G.), and Radiation Oncology (J.E.M.), Harvard Medical School — all in Boston.

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