Trilateral Retinoblastoma

SURVEY OF OPHTHALMOLOGY VOLUME 43 • NUMBER 1 • JULY–AUGUST 1998

CLINICAL PATHOLOGIC REVIEW DAVID APPLE AND MILTON BONIUK, EDITORS

Trilateral Retinoblastoma: Insights Into Histogenesis and Management DENNIS M. MARCUS, MD,1 STEVEN E. BROOKS, MD,1,2 GAYLE LEFF, MD,1 ROBERT MCCORMICK, MD,1 TODD THOMPSON, MD,1 SCOTT ANFINSON, MD,1 JACQUES LASUDRY, MD,3 AND DANIEL M. ALBERT, MD4 1

Departments of Ophthalmology and 2 Pediatrics, Medical College of Georgia, Augusta, Georgia, USA, 3 Service D’Ophtalmogie, Limoges, France, and 4 Department of Ophthalmology, University of Wisconsin, Madison, Wisconsin, USA Abstract. Trilateral retinoblastoma (TRb) is a syndrome involving midline intracranial malignancies in children with the heritable form of retinoblastoma. All cases of TRb reported from 1971 to 1997 were reviewed. The histopathologic findings, clinical features, treatment modalities, and survival rates from 80 cases were evaluated. Histopathologic findings from intracranial malignancies demonstrated primitive neuroectodermal tumors in 61.5% of cases. Various degrees of neuronal or photoreceptor differentiation were seen in the other 38.5% of cases. Autopsy, histopathologic, and radiologic examinations did not show a more definitive site of origin of these intracranial tumors, although “pinealoblastoma” was often the diagnosis reported. These findings, together with analysis of the histopathologic similarities among human primitive neuroectodermal tumors, pinealoblastoma, retinoblastoma, and ependymoblastoma, suggest that TRb more likely arises from a germinal layer of predisposed primitive subependymal neuroblasts that are not necessarily destined for pineal or photoreceptor differentiation. Trilateral tumors have also been found in transgenic mice expressing the simian virus 40 T-antigen. Transgenic murine intracranial tumors are primitive neuroectodermal tumors arising from the subependymal layer. Transgenic mice with the murine interphotoreceptor cell binding protein promoter and simian virus 40 T-antigen also develop pineal tumors. Trilateral retinoblastoma is usually fatal, with an average survival time of 11.2 months. Therapies include radiation, systemic chemotherapy, intrathecal chemotherapy, and surgical resection/craniotomy in combination with radiation and/or chemotherapy. Survival may be prolonged with combination chemotherapy (24.6 months) and if neuroradiologic screening identifies TRb before symptoms are present (23.5 months). Recent success with platinumbased chemoreduction of intraocular retinoblastoma may indicate a similar role for platinum-based chemotherapy in the treatment of TRb. Routine central nervous system imaging should be considered in the management of TRb. (Surv Ophthalmol 43:59–70, 1998 © 1998 by Elsevier Science Inc. All rights reserved.) Key words. brain cancer • chemotherapy • childhood cancer • pineal gland • PNET • retinoblastoma • retinoblastoma gene • subependymal matrix • trilateral retinoblastoma

described by Jakobiec and coworkers39 in 1977 and was subsequently termed TRb by Bader and coworkers5 in 1980. These suprasellar and parasellar malignan-

Trilateral retinoblastoma (TRb) refers to the constellation of midline intracranial malignancy and bilateral retinoblastoma (Rb). This association was first 59 © 1998 by Elsevier Science Inc. All rights reserved.

0039-6257/98/$19.00 PII S0039-6257(98)00019-8

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cies in the pineal region represent second, nonocular primary tumors in patients with heritable Rb. Trilateral retinoblastoma is rare and is usually lethal. We reviewed the 80 reported cases of TRb to gain further insight into this uncommon disease.4,8,10–12,18, 20,23,25,26,36,39,41–43,45,49,51,53,56,58–60,66,69,70,79,81,83,85,87,90,97,98

Genetics The inheritance and molecular genetics of Rb are well characterized and have been described elsewhere.48,78,93 The gene responsible for Rb is localized to the 13q14 locus.22,78 The Rb gene is mutated or deleted in both nonheritable and heritable forms of Rb.22,94 The Rb gene protein product is a nucleophosphoprotein that suppresses cell growth, functioning as a tumor suppressor gene or antioncogene.30 Only one normal Rb gene is necessary to suppress tumor formation. Alteration or deletion of both alleles is required for the development of Rb and a variety of extraocular tumors.94 Patients with heritable Rb are born with a predisposition to second, nonocular primary malignancies, as every somatic cell has inherited the first predisposing “hit” of the Rb gene.1,2,94 Trilateral retinoblastoma occurs in a subgroup of patients with heritable Rb who develop a second, primary nonocular malignancy.1,2,5,8,39 Alteration of the Rb gene occurs in other malignancies (osteosarcoma, soft-tissue sarcoma, smallcell lung carcinoma, breast carcinoma, etc.) and may or may not occur in association with ocular Rb.63 Abnormalities of the Rb gene have also been observed in central nervous system (CNS) tumors associated or unassociated with ocular Rb. Central nervous system tumors associated with Rb (second nonocular tumors) were reported by Abramson et al, who observed second intracranial malignancies, such as glioblastoma, meningioma, pinealoma, astrocytoma, and anaplastic or unclassifiable tumors.1,2 Abnormalities of the Rb gene have been demonstrated in intracranial malignancies unassociated with ocular Rb, such as astrocytomas,34,86 neuroblastomas,65 and choroid plexus tumors.14 Williams et al demonstrated that pinealoblastomas develop in mice with combined p53 and Rb mutations.91 This information indicates that abnormalities in the Rb gene may contribute to the development of variety of intracranial malignancies, including TRb.

Histopathology OCULAR FINDINGS IN RB

The histopathologic features of intraocular Rb have been well described.57 Immunohistochemical studies have helped to provide clues to the cell of origin of ocular Rb and may provide insight into the histogenesis of TRb. Photoreceptor cell proteins,

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such as S-antigen,19,21,61 interphotoreceptor cell binding protein,27,74 rod-cell opsins,32,88 and cone-cell specific transducins,9,38 have been demonstrated in Rb tissue and cell lines. Synaptophysin has also been demonstrated as a neuronal component of Rbs.46,95 Glial cell protein expression, such as neurofibrillary elements of glial cells,84 retinaldehyde binding protein,32 glial fibrillary acidic protein, and S-100,16,21,32, 67,93 have also been demonstrated. This variable expression pattern of immunoreactive proteins gives rise to the hypothesis that a primitive neuroepithelial cell with potential to undergo varying differentiation represents the likely cell of origin of ocular Rb. OCULAR FINDINGS IN TRB

Histopathology and/or signs of extraretinal invasion have been reported in 38 cases.4,11,18,20,23,25,39,42,43, 45,59,60,66,69,79,81,83,87,90,97,98 The ocular findings in patients with TRb were variable, particularly regarding the degree of photoreceptor cell differentiation. The histologic descriptions of the ocular tumors all had a background of small, undifferentiated cells with large basophilic nuclei and scant cytoplasm. Areas of calcification and necrosis with perivascular preservation of cells were frequently noted. Eleven cases showed photoreceptor cell differentiation4,11,23,25,39,42, 45,59,60,66,70,81,90,97 with Flexner-Wintersteiner rosettes4, 11,39,60,66,70,81,90,97 or fluerettes,42 whereas eight cases had poorly differentiated retinal tumors.4,11,20,43,45,83,87, 97,98 Two cases demonstrated a well-differentiated tumor in one eye and a poorly differentiated tumor in the contralateral eye.11,97 Extraretinal invasion occurred in 11 (29%) and included choroidal and superficial optic nerve invasion.4,11,18,45,69,70,79,97 Invasion beyond the lamina cribrosa was never observed, indicating that TRb could not be explained by intracranial extension of the ocular tumor (Fig. 1). CNS FINDINGS IN TRB

The histopathologic findings of the intracranial tumors are also quite varied. Of 80 cases, 26 (33%) describe intracranial histopathologic findings.4,11,12, 18,20,23,26,39,42,51,56,58,59,60,69,70,79,83,90,98 Primitive or undifferentiated tumors were described in 10 cases;4,18,20,23,39, 42,56,58,69,90,97 poorly differentiated neuroectodermal tumors with “some early signs of differentiation” were described in 3 cases;26,70 undifferentiated tumors with “rosette clusters unlike Flexner-Wintersteiner rosettes” were described in 3 cases;4,11,51,79,97 tumors with rosettes and possible fleurettes were described in 2 cases;4,39,59,97 a tumor with Homer Wright rosettes was described in one case;83 Flexner-Wintersteiner rosettes were noted in five cases,4,12,42,45,97,98 and tumors with Flexner-Wintersteiner rosettes and fleurettes were described in two cases.60,65 Electron microscopic examination performed in three tu-

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Fig. 2. Primitive neuroectodermal tumor in a patient with retinoblastoma demonstrating undifferentiated cells and perivascular pseudorosettes (hematoxylin and eosin, 200 3). (Photograph courtesy of L. Rubinstein.)

Fig. 1. Intraocular retinoblastoma from a patient with trilateral retinoblastoma demonstrating Flexner-Wintersteiner rosettes (arrowhead) with extension of tumor (T) to but without invasion of the optic nerve (O) (hematoxylin and eosin, 100 3). (Photograph courtesy of I. Whittle.)

mors demonstrated primitive cells containing few organelles and areas of occasional rosette formation with evidence of photoreceptor differentiation,39 undifferentiated small cells with rare rosettelike structures similar but not identical to Flexner-Wintersteiner rosettes,11 cilia indicating a neuroectodermal origin,11 and poorly differentiated neuroblastic cells with no evidence of photoreceptor differentiation.98 In summary, of the 26 cases in which CNS histopathology was described, 61.5% were undifferentiated and may be considered primitive neuroectodermal tumors (PNETs) (Fig. 2), whereas 38.5% demonstrated various degrees of neuronal or photoreceptor differentiation (Fig. 3). In no instance was pineal tissue identified within tumors. One case even described the presence of a completely normal pineal gland. The histopathologic findings in TRb, therefore, provide no evidence of a frank pineal origin. Documentation of intracranial tumor spread was provided in 36 cases at the time of autopsy.4,11,12,18,20, 23,26,36,39,42,45,51,56,58,59,60,69,79,83,85,97 Observations included

seeding along the spinal cord and canal (25 cases),4, 18,20,23,36,42,45,56,60,69,79,85,97 diffuse meningeal involvement (8 cases),4,11,42,56,79,85,97 ependymal and subependymal involvement (4 cases),4,20,26,36,56,69,97 cerebrospinal fluid and ventricular system spread (6 cases),11,42,58,60,79,87,97 invasion into various areas of brain parenchyma (9 cases),4,11,18,56,60,79,97 and optic nerve invasion (1 case).58 There was no spread beyond the original intracranial tumor in four

Fig. 3. Trilateral retinoblastoma demonstrating photoreceptor differentiation in the form of Flexner-Wintersteiner rosettes (large arrow) and fluerettes (small arrows) (hematoxylin and eosin, 200 3). (Photograph courtesy of S. Brownstein.)

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Fig. 4. Trilateral retinoblastoma demonstrating diffuse meningeal spread within the ventricular space (B 5 brain parenchyma; V 5 ventricular space) (hematoxylin and eosin, 100 3). (Photograph courtesy of L. Rubinstein.)

cases.4,12,39,51,59,83,97 Thus, at autopsy some form of neural axis spread was demonstrated in 89% of cases (Figs. 4 and 5).

Radiologic Findings in TRB Both computed tomography (CT) and magnetic resonance imaging (MRI) may demonstrate the occurrence of TRb. On noncontrast CT the lesions appear isodense or mildly hyperdense and may demonstrate calcification. Enhancement occurs after intravenous contrast injection. On MRI the tumors are generally hypointense on T1-weighted images with significant enhancement with the use of intravenous gadolinium. Signal intensity is variable on T2weighted images.26,64 The neuroimaging modality used was identified in 67 cases.4,8,10,11,12,18,20,23,25,26,36,39,42,43,45,49,51,53,56,58,59,60,66, 69,70,79,81,83,85,87,90,97,98 Computed tomography was used in 49 cases,4,10,11,12,18,20,23,25,26,36,39,42,43,45,51,53,56,58,59,60,66,69,79, 81,83,85,90,97,98 and MRI was used in 9,18,26,49,66,69,70 2 of which also used CT. In 6 cases it was stated only that CT or MRI was used for diagnosis, but did not specify which modality was used for particular cases.8 Other studies used older modalities such as tomodensitometry,87 ventriculography,45 and carotid angiography.45 Although radiologic findings were reported in 53 cases, relatively nonspecific terms regarding tumor location were used (“pineal region tumor” or “mass in the pineal region”) in 36 cases.4,10,11,18,25,26,36,42,43,45, 49,51,53,60,66,70,79,81,90,97,98 Nine cases of suprasellar and parasellar masses were also described in similarly general terms.4,12,18,20,23,39,45,51,59,69,83,97 Five cases were described as being in the ventricular system.4,20,23,56,58,

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Fig. 5. Autopsy finding of diffuse neural-axis spread from midline intracranial malignancy (hematoxylin and eosin, 2 3). (Photograph courtesy of S. Stefanko.)

Other locations included “midline” in one case85 and cerebellum in another.26 Review of the radiologic features does not indicate a frank pineal origin, despite the frequency of describing these lesions as “pinealoblastomas” (Fig. 6). 87,97

Histogenesis of TRB The notion that TRb represents a second primary tumor, rather than metastasis from intraocular Rb, has been well established since the original description of the syndrome.4,39 Intracranial spread of intraocular Rb usually results from poorly differentiated tumors spreading directly along the optic nerve and extending into the CNS.63 Jakobiec et al first observed that the majority of intracranial tumors appeared to be primitive neuroblastic or neuroepithelial in origin.39 They also noted that childhood intracranial tumors were predominantly named on the basis of location and that TRb was histologically similar to other tumors in different regions. In lower vertebrates, the pineal organ has a photoreceptor function that diminishes in phylogeny. Phylogenetic studies indicate that the pineal organ develops from a photoreceptor organ to a secretory gland involved in diurnal rhythm and melatonin secretion.92 Pineal photoreceptor differentiation, such as cilia with 910 microtubules, has been observed in neonatal rats, human embryos, and human pineal tumors.3,6,35,47,72,75,80,96 The human pineal organ and retina express common immunologic antigens, such as S-antigen and interphotoreceptor retinoid binding protein.73 Bader et al first suggested that susceptibility to trilateral neuroblastic tumors was restricted

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Fig. 6. Axial (left) and sagittal (right) T1-weighted magnetic resonance imaging images of the brain after gadopentetate dimeglumine administration. A 4–5-cm enhancing mass in the pineal region was “compatible with a pinealoblastoma” (reprinted from Finelli et al26 with the permission of the authors and American Society of Neuroradiology).

to pinealoblasts, given their phylogenetic and embryologic relationship to the retina.4 Consequently, the concept of the pineal organ as the “third eye” has been emphasized in subsequent reports of TRb and seems to have influenced the tendency to diagnose the intracranial tumors as pinealoblastoma. Based on the available literature, we believe that TRb should be considered within the spectrum of PNETs, as there is little conclusive radiologic or histopathologic evidence that TRb arises exclusively from pinealoblasts. To further examine this issue, it is necessary to describe the various related intracranial childhood tumors, often made up of small, basophilic tumor cells. PRIMITIVE NEUROECTODERMAL TUMOR

Primitive neuroectodermal tumor is a term coined by Hart and Earle in 1973 to describe undifferentiated tumors resembling germinal or matrix cells of the embryonic neural tube that maintain the capacity to undergo differentiation along neuronal or glial lines.33 Histologically, PNETs have small, undifferentiated cells with dark, irregular nuclei containing abundant mitotic figures6,7,15,28 and may demonstrate neuronal features, such as Homer Wright rosettes,6,7 or glial differentiation6,15,28 and immunoreactivity. With increasing differentiation, the tumors are

named according to their closest anatomic resemblance. According to Becker and Hinton, differentiated PNETs fall into the following categories: ependymoblastoma, pinealoblastoma, retinoblastoma, medulloepithelioma, neuroblastoma, polar spongioblastoma, melanotic medulloblastoma, and myomedulloblastoma.6 With respect to TRb, the inclusion of ependymoblastoma, pinealoblastoma, and retinoblastoma is of particular interest, given the location of these tumors and their possible common origin. PINEALOBLASTOMA

Pinealoblastomas are high-grade tumors of neuroectodermal origin.3 On histologic examination the tumors are composed of small primitive cells with scant cytoplasm3,75 and may demonstrate Homer Wright or neuroblastic rosettes,3 neuronal and glial differentiation,17 photoreceptor differentiation,72 or Flexner-Wintersteiner rosettes and fleurettes.3,6,35,47, 72,75,80 Pinealoblastomas are most appropriately considered to be tumors of primitive origin that are capable of various degrees of differentiation, including retinal differentiation. The pineal gland demonstrates transient neuroectodermal photoreceptor differentiation during normal development, which led Bader et al to suggest that hereditary multicentric Rb

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arises in vestigial photoreceptor tissue in the pineal organ as well as in the retinoblasts of the retina.4 EPENDYMOBLASTOMA

Ependymoblastoma, another form of PNET, is distinct from malignant ependymomas.52,76 Histologically, ependymoblastomas are composed of uniform arrangements of small primitive cells with scant cytoplasm and numerous mitotic figures.17 Ependymal differentiation and ependymoblastic rosettes are observed in this tumor.62 Ependymal rosettes are composed of narrow columnar cells with cytoplasmic projections toward a central lumen, which is surrounded by an eosinophilic-limiting membrane.50,62, 76 The rosettes often resemble Flexner-Wintersteiner rosettes62,71,76 and have been described as similar to the rosettes seen in Rb.80 The diagnosis of ependymoblastoma also rests on location of the tumor within the ventricular system. EMBRYOLOGY

Eye development starts as an outpouching of the wall of the diencephalon.13 The cells that give rise to the optic cup are part of a neuroectodermal matrix of primitive cells found in the diencephalon.39 This germinal layer, or subependymal plate, may also serve as the source of development of primary neuroectodermal brain tumors.6,31,39 This layer persists under the ventricular ependyma well into the neonatal period39 and suggests a possible cell group of origin for TRb tumor. Jakobiec et al postulated such a scenario in their initial report of the syndrome.39 Given the lack of definitive radiologic or histopathologic evidence of a pineal origin, the frequent suprasellar or parasellar location of TRb, and TRb’s propensity to disseminate throughout the subependymal neural axis space, we suggest that subependymal primitive cells are the likely origin of TRb. Subependymal cells may be predisposed to tumorigenesis after the first “hit” of the Rb gene and have the capability to differentiate into Rb, pinealoblastoma, or ependymoblastoma, or remain undifferentiated as a PNET. This hypothesis also raises the question of whether some cases of presumed neural axis dissemination in TRb are actually a form of multifocal subependymal neoplasia. ANIMAL MODEL AND GENETIC RESEARCH

A transgenic murine model for TRb has been described.68 Because of insertion of the transgene at a retinal-specific enhancer region, simian virus 40 T-antigen is expressed in the retina and inactivates the Rb gene protein product, leading to bilateral multifocal ocular tumors.68 Mice that express the transgene also develop midline CNS tumors similar

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to TRb.54 Murine intracranial tumors are undifferentiated and are PNETs that arise from the subependymal matrix of the cerebral aqueduct.54 Larger murine tumors with extensive neural axis or ventricular dissemination are observed and are analogous to human cases in which histopathologic reports describe end-stage findings. The early finding of a subependymal origin in these mice may help support the hypothesis of a similar histogenesis in human TRb. Interestingly, the pineal gland was sectioned in 15 of 19 mice and was tumor free in all instances. Trilateral tumors have also been found in three other simian virus 40 T-antigen transgenic murine models that contain different tissue-specific promoters (murine interphotoreceptor cell binding protein [IRBP], human IRBP, and a A-crystalline promoters).37,55 The ocular tumors in these mice may be ascribed to the promoter-driven, tissue-specific expression of simian virus 40 T-antigen to the retina (IRBP promoters) or lens (a A-crystalline).55 All three murine models with different promoters develop CNS tumors independent of the tissue-specific promoter and are PNETs that arise from the subependymal layer.55 This further supports a possible susceptibility of subependymal cells to Rb gene mutation or protein inactivation by viral oncogenes.55 In addition to subependymal PNETs of the third ventricle, transgenic mice with the murine IRBP promoter also develop retinal photoreceptor and pineal tumors.37 The pineal and bilateral photoreceptor tumors are promoter driven and not unexpected, because IRBP is normally expressed within the eye and pineal gland.37 The finding of a pineal tumor, however, emphasizes the phylogenetic relationship of the retina and pineal gland.

Clinical Characteristics GENDER, LATERALITY, INHERITANCE, AGE AT DIAGNOSIS

In the 80 cases of TRb identified in the literature (Table 1), the male-to-female ratio was 1:1.1. Bilateral ocular Rb occurred in 71 patients (89%),4,8,10,11, 18,20,23,25,26,36,39,41,42,43,45,49,51,53,58,60,66,69,70,81,83,85,87,97,98 and unilateral, heritable Rb occurred in 9 (11%).4,12,18,39,45,51, 59,69,79,90,97 Among the patients in whom it was mentioned, family history was positive in 404,8,10,11,12,18,20,23, 25,26,36,41,42,45,49,51,56,58,69,70,79,87,97 and negative in 33.4,8,11,18, 20,23,26,39,42,43,45,51,59,60,66,69,81,83,90,97,98 Seventy-seven patients (96%) had bilateral ocular tumors and/or a positive family history, indicating that TRb occurs secondary to an inherited or germline Rb mutation. Three patients4,18,39,59,69,90,97 demonstrated unilateral Rb without a family history. The average age at diagnosis of ocular Rb diagnosis in the unilateral cases was

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TRILATERAL RETINOBLASTOMA TABLE 1

Clinical Characteristics of Trilateral Retinoblastoma Characteristic Male-to-female ratio Laterality (%) Bilateral ocular tumors Unilateral (positive family history of ocular retinoblastoma in all but 3 cases) Family history of ocular retinoblastoma (%) Positive Negative Average age at diagnosis of ocular retinoblastoma (mo) Average age at diagnosis of intracranial TRb (mo) Presenting signs and symptoms of intracranial tumor (%) Signs/symptoms of increased intracranial pressure Asymptomatic Average survival time (mo)

Finding 1.0:1.1 89 11 52 48 9.8 30.7

72 23 11.2

were performed in 1,12,51,97 and external beam irradiation and brachytherapy were performed in 1.4,18,56, 69,97 Ocular treatment was not reported in 2 of the patients.97 In some cases the development of TRb may be related to irradiation of healthy but genetically predisposed intracranial structures during the initial treatment of ocular disease. The dosimetry and location of portal entry of external-beam ocular irradiation has been evaluated. Lateral portal entry of ocular radiation with shielding blocks for specified brain fields may protect the nontarget intracranial tissue.45,53 Further protection of healthy intracranial tissue may be observed with chemoreduction and localized modalities for ocular disease,30,44,64,77 as these modalities may often eliminate the need for external beam irradiation for the treatment of ocular disease. The long-term effects of ocular chemoreduction on the incidence of second nonocular tumors is, however, unknown. SIGNS AND SYMPTOMS OF TRB

9.8 months. An age of 9.8 months at presentation is more consistent with the younger average age at diagnosis seen in unilateral ocular Rb with germline heritable Rb than the older age (24-month average) of diagnosis typically seen in unilateral, nonheritable Rb. The mean age at TRb diagnosis was 30.7 months (2.6 years [range, 1–142 months]) with an average interval between Rb and TRb diagnosis of 24.6 months (2.1 years). OCULAR TREATMENT

Of the 71 patients with bilateral Rb, bilateral enucleation was performed in 5.4,8,39,97,98 Unilateral enucleation was performed in 34 patients;4,11,18,23,25,36,42,43, 45,49,60,66,69,70,81,83,87,97 5 of these eyes had undergone unsuccessful external beam irradiation. Therapy for the fellow eye consisted of external beam irradiation in 18 patients,4,11,18,20,23,36,42,45,66,70,81,87,97 photocoagulation or cryotherapy alone in 5,18,42,66,69 and plaque brachytherapy alone in 3.18,25,45 The remaining 8 patients4,11,18,42,43,45,49,60,69,83,97 were treated with a combination of these modalities. Of the 26 patients on whom enucleation was not performed, 124,8,18,20,36,45,58,69,97 had bilateral external beam irradiation alone, 88,10,18,45,53,66,69 had external beam irradiation with cryotherapy or photocoagulation, and the remaining patients4,8,20,26,42,51,69,97 had a combination of modalities. In 6 patients with bilateral Rb, treatment was not described.4,26,41,85,97 In the 9 patients4,12,18,39,45,51,59,69,79,90,97 with unilateral Rb, enucleation was performed in 3, 4,39,45,59,90,97 chemotherapy and external beam irradiation were performed in 1,79 photocoagulation and cryotherapy

Presenting signs and symptoms were documented in 53 patients.4,8,10,11,12,18,20,23,25,26,36,39,42,43,45,49,51,53,56,58,59, 60,66,69,70,79,81,85,87,90,97,98 Thirty-eight (72%) presented with signs and symptoms of increased intracranial pressure, including headache, nausea, vomiting, anorexia, lethargy, somnolence, and papilledema.4,8,10, 11,12,18,23,25,26,36,39,42,43,45,49,51,58,59,60,69,70,79,81,85,87,90,97,98 Twelve patients were asymptomatic, and the intracranial mass was discovered on screening CT or MRI.18,26,53, 66,69 Other less frequent signs and symptoms include sixth nerve palsy, seizures, ataxia, progressive weakness, personality change, decreased visual acuity, upgaze paralysis, seizure, flushing, sweating, ophthalmoplegia, pyrexia, constipation, and meningeal signs. Of note, hydrocephalus or enlarged ventricles were documented in 29 patients,4,10,11,18,23,25,26,36,39,42,43, 45,49,51,56,59,60,69,70,79,81,83,85,90,97,98 and 7 of the patients with hydrocephalus were asymptomatic. DIFFERENTIAL DIAGNOSIS

In a child with an intracranial tumor and history of Rb, the differential diagnosis includes intracranial extension of ocular Rb and second, nonocular primary CNS tumors. Second intracranial tumors in patients with heritable Rb are divided into those within the field of radiation and those outside the field of radiation. Within the field of radiation, osteosarcoma, soft-tissue sarcoma, glioblastoma, astrocytoma, and neurofibroma may be observed, but may be distinguished from TRb by radiologic diagnosis (Fig. 7). Outside of the field of radiation, osteosarcomas, pinealoma, astrocytoma, and neuroepithelioma may be observed.1,2

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of TRb throughout the neural axis and spinal column, which occurred in 43 of the 62 patients with recorded outcomes.4,11,12,18,20,23,26,36,39,42,51,56,58,59,60,69,79,83, 85,87,97 Eleven patients died before any spinal seeding occurred. Fifty-seven of 80 patients received treatment for TRb,4,8,10,11,12,18,20,23,25,26,36,39,42,45,49,51,53,56,58,60,66, 69,70,79,83,87,90,97,98 and 8 patients did not receive any therapy for TRb.4,8,18,45,81,97 No mention of treatment was made in the other 15 patients.4,39,41,43,85,97 Of the 57 patients receiving treatment, the average survival time was 12.0 months, whereas the 8 patients who did not receive treatment had an average survival time of 1.4 months. These results may reflect the possibility that children who did not receive treatment had more advanced disease at the time of diagnosis.

Management HISTORICAL EVOLUTION OF TRB TREATMENT

Fig. 7. Axial T1-weighted MRI of brain after gadopenetate dimeglumine administration, demonstrating a large supratentorial mass in a child with a history of bilateral retinoblastoma. The cortical, nonmidline location was consistent with the pathologic diagnosis of glioblastoma multiforme rather than trilateral retinoblastoma.

Radiographic studies provide the best means of narrowing the differential diagnosis. Because all TRbs occur in the midline and involve the pineal or suprasellar/parasellar region, the tumors that occur typically in this region include pinealoblastoma, pinealocytoma, germinoma (atypical teratoma), PNETs, ependymoblastoma, ependymoma, pituitary tumors, and optic nerve or chiasmal glioma. As discussed previously, the ultimate differentiation between PNETs, intracranial retinoblastoma, pinealoblastoma, and ependymoblastoma is difficult.

Survival Trilateral retinoblastoma is usually fatal, and few cases demonstrate long-term survival. The time of survival was reported in 69 (86%) of 80 patients4,8,10, 11,12,18,20,23,25,26,36,39,41,42,43,45,49,51,56,58,59,60,69,79,81,83,85,87,90,97,98

The average survival time of all reported patients with TRb is 11.2 months (7 patients were still alive at the time of case publication). The mean age at death was 42.5 months (3.5 years [range, 11–142 months]). The longest reported survival time is 96 months (still alive at publication).66 The most common cause of death is presumed metastatic seeding

Trilateral retinoblastoma was treated initially with palliative measures, such as dexamethasone for cerebral edema and ventriculoperitoneal shunting for increased intracranial pressure,41 radiation to the pineal region and craniospinal axis,41,59 and craniotomy.59 With the realization that TRb represented second, nonocular intracranial tumors rather than metastatic spread from ocular Rb, early recommendations for treatment were based on experience with other childhood intracranial tumors.45 In particular, radiotherapeutic approaches for pineal region tumors, such as pinealoblastomas and pineal germinomas, influenced the method of treatment selected.25, 45,60,82,89

Treatment Protocols and Results The success achieved with intensive chemotherapy for the treatment of neuroblastoma and medulloblastoma with vincristine, cyclophosphamide, and etoposide combined with intrathecal methotrexate led to their adoption in the treatment of TRb.45 Although concerns were raised regarding the risk of myelosuppression with chemotherapy,79 some success was achieved with combination chemotherapy in patients with TRb.51 The Duke Pediatric Neuro-Oncology program protocol advocated the use of two to four chemotherapeutic agents before conventional radiation. Children with rapidly progressive disease receive radiotherapy before completion of the chemotherapy course (cisplatin, lomustine, and vincristine).51 The radiation dose administered in this protocol is 36 Gy to the entire craniospinal axis at a rate of 180.0 cGy/d, and a supplemental radiation dose of 55.8 Gy to the primary region.58 Combination “eightin-one” chemotherapy has also been used in the treatment of TRb.36 In addition to these chemothera-

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peutic agents, prophylactic intrathecal methotrexate and craniospinal axis irradiation were introduced into the regimen to combat potential subarachnoid tumor spread. This treatment strategy has led to partial or complete response to chemotherapy, with three children alive at the time of publication.66 Of the 57 patients whose treatment was described, chemotherapy alone was used in 7 (12%), with an average survival time of 24.6 months.8,18,66,69 Three of these 7 patients were still alive at the time of case publication,18,66 and, therefore, the average length of survival time in this group may be underestimated. Intrathecal therapy has been incorporated into the regimen in 14 of 57 reported cases.8,10,12,18,20,36,42,51,66,69, 97 The average length of survival time for this group was 19.8 months; 4 of 14 patients were alive at the time of case publication.10,66 In 23 of 57 patients a combination of radiation and chemotherapy without surgical intervention was used.8,18,23,45,53,60,66,69,79,97 The average length of survival time was 11.7 months. One child who received radiation and chemotherapy was alive at the time the cases were reported.66 Treatment of five patients with TRb included the agent cisplatin or a derivative, carboplatin.8,10,49 The average length of survival in these patients was 7.2 months; however, the platinum treatment was not initiated until the late stages of disease in each of these cases. One child receiving this treatment was alive at the time of case publication.10 The recent success with cisplatin- and carboplatin-based chemoreduction of intraocular Rb indicates that platinumbased chemotherapy for TRb may improve survival times if initiated early in therapy.30,44,64,77 We recommend consideration of platinum-based chemotherapy with intrathecal therapy and neural axis radiation for the treatment of TRb. Radiation therapy alone to the primary tumor and craniospinal axis was performed in 10 of 57 patients for whom treatment for TRb was reported.4,11,43,45,97 The average survival time of patients treated with radiation alone was 6.5 months. Treatment ranged from 20 to 59.2 Gy to the primary tumor and 30 to 41 Gy to the craniospinal axis. Holladay et al recommend radiation doses of 55 Gy directly to the primary tumor and 30–36 Gy to the craniospinal axis.36 Experience with TRb and medulloblastoma suggests that radiation in doses greater than 50 Gy may result in lengthened survival time.36 However, early experience with neuroectodermal and TRb tumors demonstrated possible increased morbidity after irradiation in the very young patient. Treatment strategies, such as combination cyclophosphamide, vincristine, cisplatin, and etoposide, may delay the use of radiation in infants with various types of neuroectodermal tumors.23,24,66

Surgical resection/craniotomy in combination with radiation and/or chemotherapy was performed in 14 of 57 patients.4,12,20,25,26,42,45,51,69,70,90,97 The average survival time was 11.1 months, and 2 patients were alive at the time of publication. SCREENING

The recommendation of routine screening with imaging studies for early detection of TRb is controversial, as its low incidence may not warrant routine imaging.45 Meadows noted that to diagnose TRb in an early treatable form, screening would be required every 3 months and, therefore, would not be physically or economically practical.58 De Potter described 13 patients, of whom 7 were asymptomatic and 6 were symptomatic at the time of radiologic diagnosis.18 Despite aggressive combined treatment with chemotherapy and radiation therapy, 12 of 13 patients died at a mean interval of 11 months. The Tumor Board at Children’s Hospital in Philadelphia concluded that immediate imaging should be performed in a patient with heritable Rb if signs or symptoms pointing to an intracranial lesion develop.58 A CT scan or an MRI is recommended for an initial assessment for bilateral Rb, with special attention to the pineal gland and suprasellar region and ventricles. Follow-up examination should include evaluation for CNS changes and neuroimaging only if pertinent signs are present.36,69,97 Despite recommendations against routine neuroradiologic screening, longer survival has been observed in TRb diagnosed by CT or MRI before the onset of symptoms.66,69 Contrast-enhanced MRI has been proposed by Pesin and Shields as the modality for routine screening, because of the soft-tissue contrast definition, nonionizing aspect, and safety of gadolinium-DTPA as a contrast agent in MRI.69 A schedule for neuroimaging every 3 months for 2 years, every 4 months for the next 2 years, and every 6 months for the next 5 years has been proposed.66 When neuroradiologic screening is undertaken, it has the additional benefit of increasing physician and parent awareness of the subtle changes of a child’s behavior.49 In 12 of 54 patients, intracranial disease was identified before the presentation of neurologic symptoms.18,26,53,66,69 The average length of survival of these patients was 23.5 months, a survival time 12.3 months longer than all 69 patients whose survival times were reported. Six of the 12 patients were alive at the time of case publication.18,26,53,66 However, it is possible that neuroradiologic screening leads to longer survival as an epiphenomenon based solely on earlier diagnosis rather than impact on TRb progression.

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Given TRb’s fatality and prolonged survival time with earlier diagnosis and aggressive treatment, we believe that the costs and inconvenience of routine MRI screening are warranted. The benefit of detecting both TRb and other CNS and periorbital second tumors may be observed. We anticipate that routine screening of the CNS with MRI every 3–6 months in patients with heritable Rb may lead to more successful outcomes in TRb. SCREENING FOR TRB DISSEMINATION

Trilateral retinoblastoma’s propensity for cell dissemination throughout the neurospinal axis often leads to the poor prognosis. Before MRI was available, myelography was used to assess neural axis spread.45,58 A more recent screening method, 123I metaiodobenzylguanide scintigraphy, has been proposed as an alternative to myelography.10 This procedure is less invasive and less dangerous than myelography in the presence of hydrocephalus. PALLIATIVE THERAPY

Therapy for the palliation of hydrocephalus, cerebral edema, and increased intracranial pressure secondary to the intracranial tumor includes ventriculoperitoneal (VP) shunt or dexamethasone. Eighteen of 80 patients4,10,11,18,23,26,36,42,49,51,56,60,69,81,83,87,90,97,98 received diversion of the cerebrospinal fluid via VP shunting, and two23,45,79,97 received dexamethasone for cerebral edema. The average survival time in the group with VP placement was 7.6 months. Ventriculoperitoneal shunting has been controversial because of its potential for extraneural dissemination of tumor cells, and, traditionally, VP shunting has been reserved for cases with increased intracranial pressure refractory to medical therapy.29 Despite the increased risk of dissemination associated with VP shunting, there has not been a greater frequency of metastatic dissemination with VP shunting.29,40 Nonetheless, the risk of dissemination must be borne in mind when VP shunts are placed; they should be used only when absolutely necessary for prolonged survival. An alternative therapy to VP shunt placement is an Ommaya device or open ventricular drainage.36 In reviewing the past 20 years of case studies, it is evident that the treatment scheme for TRb has progressively resulted in increased survival time for patients. The combinations of surgery; intensive combination chemotherapy, including intrathecal therapy and the addition of platinum-based chemotherapy; radiation to the primary tumor; and prophylactic radiation of the neural axis may have all been factors in the increased survival time in this patient population. Despite these advances in therapy, TRb is usually lethal. We recommend consideration of MRI

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screening, platinum-based combination chemotherapy with intrathecal therapy, and neural axis radiation for the treatment of TRb.

Summary Trilateral retinoblastoma refers to the constellation of midline intracranial malignancy and heritable Rb. These intracranial tumors are second primary tumors occurring in patients with inherited or germline abnormalities of the Rb gene. The ocular histopathologic findings in patients with TRb are variable, especially regarding photoreceptor cell differentiation. Review of the CNS histopathologic findings indicates that 61.5% of tumors are undifferentiated and may be considered PNETs, and 38.5% demonstrate various degrees of neuronal or photoreceptor differentiation. At autopsy, neural axis spread is observed in 89% of cases. Review of the radiologic features does not indicate a frank pineal origin, despite the frequent description of these lesions as “pinealoblastomas.” Trilateral retinoblastoma should be considered within the spectrum of PNETs, as there is little conclusive radiologic or histopathologic evidence that proves it arises exclusively from pinealoblasts. Analysis of the histopathologic similarities among human PNETs, pinealoblastoma, retinoblastoma, and transgenic murine PNETs suggests that subependymal primitive cells are the likely origin of TRb. The mean age at diagnosis of TRb is 30.7 months (range, 1–142 months). The majority of patients present with signs and symptoms of increased intracranial pressure, although 12 of the 80 patients described in the literature were asymptomatic. Trilateral retinoblastoma is usually fatal, as intracranial tumors often demonstrate neural axis spread. During the past 20 years, the treatment scheme for TRb has progressively resulted in increased survival time for patients. We recommend consideration of MRI screening, platinum-based combination chemotherapy with intrathecal therapy, and neural axis radiation for the treatment of TRb. It is hoped that reevaluation of treatment plans and concepts regarding the histogenesis and molecular basis of TRb will extend the length of survival in these children.

Method of Literature Search A MEDLINE search was performed to identify cases of TRb in the world literature. Cases with heritable, unilateral Rb with intracranial malignancy were included. Cases with intracranial malignancy in the absence of Rb or family history of Rb were excluded.

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Supported in part by an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, NY. We would like to acknowledge Kenneth Weiss, MD, for reviewing the radiologic features and Keith Green, PhD, for reviewing the manuscript. Reprint address: Reprint address: Dennis M. Marcus, MD, Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912, USA.