SIMULTANEOUS PRESENTATION OF RETINOBLASTOMA AND MORNING GLORY DISK ANOMALY Charles C. Wykoff, MD, PHD,* Sander R. Dubovy, MD,* Julio C. Barredo, MD,† Timothy G. Murray, MD, FACS*
Purpose: To describe a patient with retinoblastoma and morning glory disk anomaly (MGDA). Method: Observational case report. Results: A 7-month-old girl with bilateral retinoblastoma was found to have concurrent MGDA in the less involved eye. The more severely affected eye was enucleated due to progressive disease not amenable to aggressive systemic and local treatment; histologic analysis was performed. Conclusion: Prompt ocular examination of a pediatric patient should be performed in the presence of concerning findings such as leukokoria or strabismus. In addition, more than one ocular abnormality may coexist, such as retinoblastoma and MGDA, necessitating complete examination. RETINAL CASES & BRIEF REPORTS 3:354 –357, 2009
From the *Department of Ophthalmology, Bascom Palmer Eye Institute, and the †Department of Pediatric Hematology–Oncology, University of Miami Miller School of Medicine, Miami, Florida.
no reported cases of retinoblastoma and MGDA occurring simultaneously in an eye. MGDA is a congenital, typically unilateral anomaly of unknown etiology in which the optic nerve head lies centrally within an excavation of the posterior globe.9 It is not typically an inherited condition or part of a multisystem genetic disorder, although it has been reported as part of the renal– coloboma syndrome, trisomy 4q, moyamoya disease, and basal encephalocele.10 –13 Visual acuity in the affected eye can range from 20/20 to no light perception but is usually between 20/200 and counting fingers. To our knowledge, we describe the first case of retinoblastoma in an eye with MGDA.
R
etinoblastoma and morning glory disk anomaly (MGDA) are well described in the pediatric population. Retinoblastoma is the most common ocular tumor of childhood, with an incidence of ⬇1 in 15,000 live births, comprising 3% of tumors in children younger than 15 years of age.1,2 Retinoblastoma is bilateral in one third of cases and classically occurs as an isolated disease, unassociated with other ocular conditions.3 Rarely, retinoblastoma has been found in an eye with other coincident diseases such as retinopathy of prematurity, persistent hyperplastic primary vitreous, Coat disease, and medulloepithelioma.4 –7 Although a single case of MGDA presenting as a pseudoretinoblastoma has been reported,8 by a PubMed literature search, there have been
Case Report A 7-month-old girl presented with leukokoria. The patient was a healthy full-term baby delivered by an uneventful cesarean section in a developing country and had met all of her developmental milestones. At 2 months of age, the parents noted leukokoria in the left eye, and after delays in both seeking medical attention and correct diagnosis, the patient was referred for evaluation of a concerning intraocular mass. There was no family history of retinoblastoma or other ocular conditions. Clinical examination revealed vision to be central, steady, and maintained in the right eye and noncentral, nonsteady, and non-
Supported by the National Institutes of Health and an unrestricted grant to the University of Miami from Research to Prevent Blindness, Inc. The authors have no proprietary interests in this article. Reprint requests: Timothy G. Murray, MD, FACS, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami, FL 33136; e-mail: [email protected]
354
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Fig. 1. Fundus photographs before treatment (A and B) and after treatment (C and D). A, Right eye: morning glory disk anomaly (arrow) and a juxtapapillary retinoblastoma with intrinsic vascularity without vitreous or subretinal seeding. B, Left eye: large retinoblastoma involving the macula, filling approximately one half of the globe with a complex exudative retinal detachment with vitreous and subretinal seeding (arrowhead). C, Right eye: morning glory disk anomaly (arrow) adjacent to an involuted juxtapapillary retinoblastoma showing a type IV regression pattern after systemic chemotherapy and diode laser ablative therapy. D, Left eye: the juxtapapillary retinoblastoma seen in B has progressed to obscure viewing of the optic nerve head despite aggressive systemic and local treatment. Extensive tumor vascularization and vitreous seeding (star) are seen.
maintained in the left eye. There was a left afferent pupillary defect. Examination during anesthesia revealed a normal anterior segment in each eye. Dilated funduscopic examination and ultrasonography of the right eye revealed MGDA and a mass nasal to the optic nerve head measuring 1.6 mm ⫻ 5 mm ⫻ 5 mm with intrinsic vascularity without active vitreous or subretinal seeding (Fig. 1A). A much larger tumor mass involving the macula and all of the inferotemporal fundus measuring 9 mm in maximal height with a complex exudative retinal detachment and both vitreous and subretinal seeding was seen in the left eye (Fig. 1B). Ultrasonography documented multiple foci of calcification in both eyes, and magnetic resonance imaging of orbits and brain revealed bilateral gadoliniumenhancing intraocular lesions without evidence of extraocular tumor foci, both consistent with a diagnosis of retinoblastoma. Given the extent of disease, nine cycles of chemotherapy using carboplatin, vincristine, and etoposide were administered at presentation. The patient also underwent indirect diode laser ablative therapy to the retinoblastoma tumor foci (19 treatments to the right eye and 17 treatments to the left eye). The tumor in the right eye underwent a complete involutional response with type IV regression seen in the peripapillary region over 17 months of treatment (Fig. 1C). Given the local extent of disease in the left eye and an incomplete response to systemic chemotherapy and laser ablative therapy, adjunctive carboplatin chemotherapy using a 20-mg sub–Tenon space injection was given 5 times, and cryotherapy was applied twice. Despite these interventions, the tumor progressed to obscure the optic nerve head. In addition, progressive vitreous and subretinal seeding was observed, and a new tumor developed anteriorly (Fig. 1D). To prevent metastasis of the tumor, enucleation of the left eye was performed 15 months after initiation of treatment.
Histopathologic analysis of the enucleated left eye revealed a large peripapillary tumor with ⬇60% viable cells (Fig. 2, A and B). Vitreous seeds and a second tumor focus at the ora serrata with extension into the choroid in a 2 ⫻ 0.2-mm area were also identified (Fig. 2, C and D). Flexner–Wintersteiner and Homer Wright rosettes as well as a moderate amount of calcification were also seen. In addition, a focus of tumor cells was identified on the anterior surface of the iris without trabecular meshwork involvement. No optic nerve involvement was identified within 100 serial sections.
Discussion This patient presented with bilateral, asymmetric, advanced, stage 5B, germline-associated retinoblastoma. In addition, the less involved eye had MGDA. Although treatment of the right eye resulted in complete involution of the tumor, the long-term visual prognosis of the eye is likely limited due to associated MGDA. Unfortunately, the left eye was enucleated due to progressive disease not amenable to aggressive systemic and local treatments. In the current case, treatment of retinoblastoma was initiated 5 months after the initial ocular abnormality was noted by the parents. This holdup was due to delays both in seeking medical attention
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Fig. 2. Histopathologic analysis of retinoblastoma following enucleation of the left eye. Tissues were fixed in 10% formalin, processed sequentially with dehydration, clearing, and infiltration, and embedded in paraffin. Paraffin sections were stained with hematoxylin–eosin. A, Low power of endophytic retinoblastoma composed of basophilic cells with foci of calcification (arrowhead) extending over the optic nerve (asterisk) (original magnification, ⫻20). B, High power of tumor demonstrating basophilic viable tumor cells admixed with foci of calcification (arrowhead) (original magnification, ⫻200). C, Low power of second tumor focus arising at the ora serrata (original magnification, ⫻20). D, High power of tumor with Flexner– Wintersteiner rosettes (arrows) and tumor extension into the choroid (original magnification, ⫻200).
and in diagnosis. Similar delays have been described in many developing and developed countries and are typically attributed to access to health care, parental education, and failure of health care workers to detect early signs of retinoblastoma.14 –17 Importantly, the longer the interval between onset of symptoms and diagnosis, the greater the risk of disseminated disease.15,18 The most common clinical presentations of retinoblastoma are leukokoria and strabismus,1 with other less common presentations being heterochromia, hyphema, glaucoma, and orbital inflammation. This report underscores the importance of prompt examination of pediatric eyes in the presence of such concerning findings. In addition, it highlights the fact that more than one ocular abnormality may coexist, such as retinoblastoma and MGDA, necessitating complete examination. Key words: delayed diagnosis, enucleation, morning glory disk anomaly, pediatric, retinoblastoma.
References 1.
2.
3.
4.
5.
6.
7.
Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 1999;36:8–18. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol 1990;108:128–132. Shields JA. Differential diagnosis of retinoblastoma. In: Intraocular Tumors: A Text and Atlas. Philadelphia, PA: WB Saunders; 1992:22. Irvine AR, Albert DM, Sang DN. Retinal neoplasia and dysplasia. II. Retinoblastoma occurring with persistence and hyperplasia of the primary vitreous. Invest Ophthalmol Vis Sci 1977;16:403–407. Shields CL, Uysal Y, Benevides R, et al. Retinoblastoma in an eye with features of Coats’ disease. J Pediatr Ophthalmol Strabismus 2006;43:313–315. Minoda K, Hirose Y, Sugano I, et al. Occurrence of sequential intraocular tumors: malignant medulloepithelioma subsequent to retinoblastoma. Jpn J Ophthalmol 1993;37:293–300. Benz MS, Escalona-Caamano EM, Murray TG. Simultaneous
357
RETINOBLASTOMA AND MGDA
8.
9. 10. 11.
12.
presentation of retinopathy of prematurity and bilateral familial retinoblastoma in a premature infant. J Pediatr Ophthalmol Strabismus 2003;40:98–100. Shields JA, Parsons HM, Shields CL, Shah P. Lesions simulating retinoblastoma. J Pediatr Ophthalmol Strabismus 1991;28:338–340. Brodsky MC. Congenital optic disk anomalies. Surv Ophthalmol 1994;39:89–112. Dureau P, Attie-Bitach T, Salomon R, et al. Renal coloboma syndrome. Ophthalmology 2001;108:1912–1916. Nucci P, Mets MB, Gabianelli EB. Trisomy 4q with morning glory disc anomaly. Ophthalmic Paediatr Genet 1990;11: 143–145. Krishnan C, Roy A, Traboulsi E. Morning glory disk anomaly, choroidal coloboma, and congenital constrictive malformations of the internal carotid arteries (moyamoya disease). Ophthalmic Genet 2000;21:21–24.
13. 14.
15.
16.
17.
18.
Caprioli J, Lesser RL. Basal encephalocele and morning glory syndrome. Br J Ophthalmol 1983;67:349–351. Haik BG, Siedlecki A, Ellsworth RM, Sturgis-Buckhout L. Documented delays in the diagnosis of retinoblastoma. Ann Ophthalmol 1985;17:731–732. Erwenne CM, Franco EL. Age and lateness of referral as determinants of extra-ocular retinoblastoma. Ophthalmic Paediatr Genet 1989;10:179–184. Chantada G, Fandino A, Manzitti J, et al. Late diagnosis of retinoblastoma in a developing country. Arch Dis Child 1999; 80:171–174. Goddard AG, Kingston JE, Hungerford JL. Delay in diagnosis of retinoblastoma: risk factors and treatment outcome. Br J Ophthalmol 1999;83:1320–1323. DerKinderen DJ, Koten JW, Van Romunde LK, et al. Early diagnosis of bilateral retinoblastoma reduces death and blindness. Int J Cancer 1989;44:35–39.
Purpose: To describe a patient with retinoblastoma and morning glory disk anomaly (MGDA). Method: Observational case report. Results: A 7-month-old girl with bilateral retinoblastoma was found to have concurrent MGDA in the less involved eye. The more severely affected eye was enucleated due to progressive disease not amenable to aggressive systemic and local treatment; histologic analysis was performed. Conclusion: Prompt ocular examination of a pediatric patient should be performed in the presence of concerning findings such as leukokoria or strabismus. In addition, more than one ocular abnormality may coexist, such as retinoblastoma and MGDA, necessitating complete examination. RETINAL CASES & BRIEF REPORTS 3:354 –357, 2009
From the *Department of Ophthalmology, Bascom Palmer Eye Institute, and the †Department of Pediatric Hematology–Oncology, University of Miami Miller School of Medicine, Miami, Florida.
no reported cases of retinoblastoma and MGDA occurring simultaneously in an eye. MGDA is a congenital, typically unilateral anomaly of unknown etiology in which the optic nerve head lies centrally within an excavation of the posterior globe.9 It is not typically an inherited condition or part of a multisystem genetic disorder, although it has been reported as part of the renal– coloboma syndrome, trisomy 4q, moyamoya disease, and basal encephalocele.10 –13 Visual acuity in the affected eye can range from 20/20 to no light perception but is usually between 20/200 and counting fingers. To our knowledge, we describe the first case of retinoblastoma in an eye with MGDA.
R
etinoblastoma and morning glory disk anomaly (MGDA) are well described in the pediatric population. Retinoblastoma is the most common ocular tumor of childhood, with an incidence of ⬇1 in 15,000 live births, comprising 3% of tumors in children younger than 15 years of age.1,2 Retinoblastoma is bilateral in one third of cases and classically occurs as an isolated disease, unassociated with other ocular conditions.3 Rarely, retinoblastoma has been found in an eye with other coincident diseases such as retinopathy of prematurity, persistent hyperplastic primary vitreous, Coat disease, and medulloepithelioma.4 –7 Although a single case of MGDA presenting as a pseudoretinoblastoma has been reported,8 by a PubMed literature search, there have been
Case Report A 7-month-old girl presented with leukokoria. The patient was a healthy full-term baby delivered by an uneventful cesarean section in a developing country and had met all of her developmental milestones. At 2 months of age, the parents noted leukokoria in the left eye, and after delays in both seeking medical attention and correct diagnosis, the patient was referred for evaluation of a concerning intraocular mass. There was no family history of retinoblastoma or other ocular conditions. Clinical examination revealed vision to be central, steady, and maintained in the right eye and noncentral, nonsteady, and non-
Supported by the National Institutes of Health and an unrestricted grant to the University of Miami from Research to Prevent Blindness, Inc. The authors have no proprietary interests in this article. Reprint requests: Timothy G. Murray, MD, FACS, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami, FL 33136; e-mail: [email protected]
354
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RETINOBLASTOMA AND MGDA
Fig. 1. Fundus photographs before treatment (A and B) and after treatment (C and D). A, Right eye: morning glory disk anomaly (arrow) and a juxtapapillary retinoblastoma with intrinsic vascularity without vitreous or subretinal seeding. B, Left eye: large retinoblastoma involving the macula, filling approximately one half of the globe with a complex exudative retinal detachment with vitreous and subretinal seeding (arrowhead). C, Right eye: morning glory disk anomaly (arrow) adjacent to an involuted juxtapapillary retinoblastoma showing a type IV regression pattern after systemic chemotherapy and diode laser ablative therapy. D, Left eye: the juxtapapillary retinoblastoma seen in B has progressed to obscure viewing of the optic nerve head despite aggressive systemic and local treatment. Extensive tumor vascularization and vitreous seeding (star) are seen.
maintained in the left eye. There was a left afferent pupillary defect. Examination during anesthesia revealed a normal anterior segment in each eye. Dilated funduscopic examination and ultrasonography of the right eye revealed MGDA and a mass nasal to the optic nerve head measuring 1.6 mm ⫻ 5 mm ⫻ 5 mm with intrinsic vascularity without active vitreous or subretinal seeding (Fig. 1A). A much larger tumor mass involving the macula and all of the inferotemporal fundus measuring 9 mm in maximal height with a complex exudative retinal detachment and both vitreous and subretinal seeding was seen in the left eye (Fig. 1B). Ultrasonography documented multiple foci of calcification in both eyes, and magnetic resonance imaging of orbits and brain revealed bilateral gadoliniumenhancing intraocular lesions without evidence of extraocular tumor foci, both consistent with a diagnosis of retinoblastoma. Given the extent of disease, nine cycles of chemotherapy using carboplatin, vincristine, and etoposide were administered at presentation. The patient also underwent indirect diode laser ablative therapy to the retinoblastoma tumor foci (19 treatments to the right eye and 17 treatments to the left eye). The tumor in the right eye underwent a complete involutional response with type IV regression seen in the peripapillary region over 17 months of treatment (Fig. 1C). Given the local extent of disease in the left eye and an incomplete response to systemic chemotherapy and laser ablative therapy, adjunctive carboplatin chemotherapy using a 20-mg sub–Tenon space injection was given 5 times, and cryotherapy was applied twice. Despite these interventions, the tumor progressed to obscure the optic nerve head. In addition, progressive vitreous and subretinal seeding was observed, and a new tumor developed anteriorly (Fig. 1D). To prevent metastasis of the tumor, enucleation of the left eye was performed 15 months after initiation of treatment.
Histopathologic analysis of the enucleated left eye revealed a large peripapillary tumor with ⬇60% viable cells (Fig. 2, A and B). Vitreous seeds and a second tumor focus at the ora serrata with extension into the choroid in a 2 ⫻ 0.2-mm area were also identified (Fig. 2, C and D). Flexner–Wintersteiner and Homer Wright rosettes as well as a moderate amount of calcification were also seen. In addition, a focus of tumor cells was identified on the anterior surface of the iris without trabecular meshwork involvement. No optic nerve involvement was identified within 100 serial sections.
Discussion This patient presented with bilateral, asymmetric, advanced, stage 5B, germline-associated retinoblastoma. In addition, the less involved eye had MGDA. Although treatment of the right eye resulted in complete involution of the tumor, the long-term visual prognosis of the eye is likely limited due to associated MGDA. Unfortunately, the left eye was enucleated due to progressive disease not amenable to aggressive systemic and local treatments. In the current case, treatment of retinoblastoma was initiated 5 months after the initial ocular abnormality was noted by the parents. This holdup was due to delays both in seeking medical attention
356
RETINAL CASES & BRIEF REPORTSℜ
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2009
●
VOLUME 3
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NUMBER 4
Fig. 2. Histopathologic analysis of retinoblastoma following enucleation of the left eye. Tissues were fixed in 10% formalin, processed sequentially with dehydration, clearing, and infiltration, and embedded in paraffin. Paraffin sections were stained with hematoxylin–eosin. A, Low power of endophytic retinoblastoma composed of basophilic cells with foci of calcification (arrowhead) extending over the optic nerve (asterisk) (original magnification, ⫻20). B, High power of tumor demonstrating basophilic viable tumor cells admixed with foci of calcification (arrowhead) (original magnification, ⫻200). C, Low power of second tumor focus arising at the ora serrata (original magnification, ⫻20). D, High power of tumor with Flexner– Wintersteiner rosettes (arrows) and tumor extension into the choroid (original magnification, ⫻200).
and in diagnosis. Similar delays have been described in many developing and developed countries and are typically attributed to access to health care, parental education, and failure of health care workers to detect early signs of retinoblastoma.14 –17 Importantly, the longer the interval between onset of symptoms and diagnosis, the greater the risk of disseminated disease.15,18 The most common clinical presentations of retinoblastoma are leukokoria and strabismus,1 with other less common presentations being heterochromia, hyphema, glaucoma, and orbital inflammation. This report underscores the importance of prompt examination of pediatric eyes in the presence of such concerning findings. In addition, it highlights the fact that more than one ocular abnormality may coexist, such as retinoblastoma and MGDA, necessitating complete examination. Key words: delayed diagnosis, enucleation, morning glory disk anomaly, pediatric, retinoblastoma.
References 1.
2.
3.
4.
5.
6.
7.
Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 1999;36:8–18. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol 1990;108:128–132. Shields JA. Differential diagnosis of retinoblastoma. In: Intraocular Tumors: A Text and Atlas. Philadelphia, PA: WB Saunders; 1992:22. Irvine AR, Albert DM, Sang DN. Retinal neoplasia and dysplasia. II. Retinoblastoma occurring with persistence and hyperplasia of the primary vitreous. Invest Ophthalmol Vis Sci 1977;16:403–407. Shields CL, Uysal Y, Benevides R, et al. Retinoblastoma in an eye with features of Coats’ disease. J Pediatr Ophthalmol Strabismus 2006;43:313–315. Minoda K, Hirose Y, Sugano I, et al. Occurrence of sequential intraocular tumors: malignant medulloepithelioma subsequent to retinoblastoma. Jpn J Ophthalmol 1993;37:293–300. Benz MS, Escalona-Caamano EM, Murray TG. Simultaneous
357
RETINOBLASTOMA AND MGDA
8.
9. 10. 11.
12.
presentation of retinopathy of prematurity and bilateral familial retinoblastoma in a premature infant. J Pediatr Ophthalmol Strabismus 2003;40:98–100. Shields JA, Parsons HM, Shields CL, Shah P. Lesions simulating retinoblastoma. J Pediatr Ophthalmol Strabismus 1991;28:338–340. Brodsky MC. Congenital optic disk anomalies. Surv Ophthalmol 1994;39:89–112. Dureau P, Attie-Bitach T, Salomon R, et al. Renal coloboma syndrome. Ophthalmology 2001;108:1912–1916. Nucci P, Mets MB, Gabianelli EB. Trisomy 4q with morning glory disc anomaly. Ophthalmic Paediatr Genet 1990;11: 143–145. Krishnan C, Roy A, Traboulsi E. Morning glory disk anomaly, choroidal coloboma, and congenital constrictive malformations of the internal carotid arteries (moyamoya disease). Ophthalmic Genet 2000;21:21–24.
13. 14.
15.
16.
17.
18.
Caprioli J, Lesser RL. Basal encephalocele and morning glory syndrome. Br J Ophthalmol 1983;67:349–351. Haik BG, Siedlecki A, Ellsworth RM, Sturgis-Buckhout L. Documented delays in the diagnosis of retinoblastoma. Ann Ophthalmol 1985;17:731–732. Erwenne CM, Franco EL. Age and lateness of referral as determinants of extra-ocular retinoblastoma. Ophthalmic Paediatr Genet 1989;10:179–184. Chantada G, Fandino A, Manzitti J, et al. Late diagnosis of retinoblastoma in a developing country. Arch Dis Child 1999; 80:171–174. Goddard AG, Kingston JE, Hungerford JL. Delay in diagnosis of retinoblastoma: risk factors and treatment outcome. Br J Ophthalmol 1999;83:1320–1323. DerKinderen DJ, Koten JW, Van Romunde LK, et al. Early diagnosis of bilateral retinoblastoma reduces death and blindness. Int J Cancer 1989;44:35–39.
