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Successful treatment of neonatal trilateral retinoblastoma
Short Reports Successful Treatment of Neonatal Trilateral Retinoblastoma R. Bindlish, MD, and G. R. LaRoche, MD, FRCSC
Trilateral retinoblastoma is a rare and almost exclusively fatal disease. Previous treatment regimens have failed to prolong life once the diagnosis is made. We present the first documented case of a patient with neonatal trilateral retinoblastoma successfully treated with chemotherapy and sequential local retinal treatment who is alive and well 26 months after diagnosis.
et al5 have recently shown a chemotherapy regimen of cyclosporin, vincristine, carboplatin, and teniposide to be effective against retinoblastoma. In addition, sequential local therapy, along with chemotherapy, has preserved the eye and eyesight for various stages of retinoblastoma.6 To date, the effectiveness of this latest chemotherapy regimen on the intracranial tumors of TRb is unknown.
INTRODUCTION
CASE PRESENTATION
Trilateral retinoblastoma (TRb) is a rare syndrome consisting of bilateral retinoblastoma associated with a midline intracranial lesion. The midline tumors are usually pineal in origin and show poorly differentiated neuroectodermal tissue. Occasionally these tumors may have a retinoblastoma-like appearance with Flexner-Wintersteiner or Homer Wright rosettes. These lesions represent second primary tumors rather than retinoblastoma metastasis. Death results from cerebrospinal metastasis.1 The overall incidence of TRb is about 3% of bilateral retinoblastoma.2 The intracranial component of TRb is diagnosed 1 to 24 months after retinoblastoma, with the germline retinoblastoma diagnosis at approximately 9.8 months of age. The average survival time is 11.2 months after the initial diagnosis of retinoblastoma, and the mean survival time after intracranial diagnosis is 18 months.2 The heritable form of retinoblastoma may increase the risk of intracranial tumor development because every somatic cell has inherited the first predisposing “hit” of the retinoblastoma gene.3 The treatment of retinoblastoma has varied over the years. Initial therapies have included enucleation, cryotherapy, brachytherapy, and external beam irradiation. The latter 2 are associated with orbital bone growth defects and second primary tumors, especially when more than 60 Gy are administered.4 More recently, photocoagulation has been used. Chemotherapy was previously believed to be ineffective against retinoblastoma, but Chan
M. L. was a 4-day-old infant referred for bilaterally decreased red reflexes. An initial examination at birth revealed poor red reflexes, a flat anterior chamber filled with blood, and a Peter’s-like anomaly in the right eye. Ocular ultrasound and computed tomographic (CT) scan confirmed the presence of a large tumor filling the right eye. The left eye had a hypoplastic iris stroma with extremely poor pupillary dilation and zonular cataract. After cataract extraction, the fundus revealed macular hypoplasia and a small grayish optic nerve head. The right eye was enucleated at 6 days of age. Gross pathologic examination showed the entire globe to be filled with a tumor. Histopathologic examination revealed frequent mitotic figures and both Homer Wright and Flexner-Wintersteiner rosettes. Necrosis and dystrophic calcium were present. No extension of the tumor into the choroid or optic nerve was found. The results of clinical ocular examination and CT were inconclusive for retinoblastoma in the left eye. Four weeks later, the infant returned for left cataract extraction. Because of the increased density of the cataract, adequate assessment of the posterior pole was impossible. A preoperative CT scan revealed a suspicious lesion in the left retina as well as an enhancing cystic pineal lesion 2 cm in diameter. Magnetic resonance imaging (MRI) confirmed the retinal and pineal lesions consistent with TRb. On closer examination of the CT scan done at birth, evidence of the pineal region tumor could be detected. The cataract extraction was delayed, and the infant started the chemotherapy regimen described by Chan et al.5 This consisted of 9 cycles of 2 days of each high-dose cyclosporin (33 mg/kg), along with vincristine (0.025 mg/kg), carboplatin (18.7 mg/kg), and teniposide (7.7 mg/kg) per cycle. After 3 cycles of chemotherapy, the cataract was removed. The anterior segment anomalies prevented proper visualization of the fundus of the remaining eye, thereby precluding adequate tumor treatment. The cataract required a stepwise surgical approach, initially without disruption of the posteri-
From the Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia. Presented in part at the International Retinoblastoma Meeting, Geneva, Switzerland, June 1998. Submitted January 13, 1999. Revision accepted May 10, 1999. Reprint requests: G. R. LaRoche, MD, FRCSC, Department of Ophthalmology, Dalhousie University, IWK Grace Health Centre, 5850 University Avenue, Halifax, Nova Scotia, Canada, B3J 3G9. J AAPOS 1999;3:376-8. Copyright © 1999 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/99 $8.00 + 0 75/1/100974
376
December 1999
Journal of AAPOS
Journal of AAPOS Volume 3 Number 6 December 1999
Bindlish and LaRoche
377
A
B MRI scan of patient (A) showing pineal cystic lesion at 4 weeks of age establishing TRb diagnosis and (B) a partially collapsed, slightly enhancing small lesion after 4 cycles of chemotherapy treatment.
or capsule for fear of malignant cell seeding. The initial operation allowed immediate initiation and planning of sequential laser ablative treatments. Three focal retinoblastoma tumors were seen superior to the disc and were photocoagulated with argon laser. The infant received a total of 9 courses of chemotherapy over a 7-month period. Sufficient tumor control was obtained before a more extensive lensectomy and posterior capsulectomy treatment and monitoring. Repeat MRI study showed resolution of the pineal region
tumor after 4 cycles (Figure). After treatment the tumors in the left eye showed type 2 regression pattern. After 26 months, the infant remained tumor free on repeat examinations under anesthesia and neuroimaging.
DISCUSSION This case significantly challenged our strategy for management of retinoblastoma. This neonate had 1 eye completely filled with tumor at birth, bilateral dysplastic ante-
378 Bindlish and LaRoche rior segments, and a pineal cystic tumor—an unusual presentation for retinoblastoma. In light of normal chromasomal studies, including fluorescence in situ hybridization, we have no explanation for these associated ocular abnormalities with retinoblastoma. The differential diagnosis of the cystic midline pineal lesion in this case generated multiple discussions among our multidisciplinary team. Because all TRbs occur in the midline and involve the pineal or suprasellar-parasellar region, the possibilities included primary intracranial tumors such as pinealoblastoma, pinealocytoma, germinoma, primitive neuroectodermal tumor, ependymoblastoma, or ependymoma, as well as secondary spread of the intraocular retinoblastoma. Because the tumor responded to chemotherapy, a malignancy is more likely than a benign cystic lesion in the absence of pathologic confirmation. TRb has a bleak prognosis. Only 1 report in the literature describes 3 long-term survivors.7 Early diagnosis facilitated by serial neuroimaging appears to improve the survival, especially when made before symptoms appeared, as in this case. The present case has been followed up closely for 26 months since diagnosis, and so far no recurrence has been found. In general, the life expectancy of TRb does not exceed 18
Journal of AAPOS Volume 3 Number 6 December 1999
months. However, this case suggests that the chemotherapy protocol, including cyclosporin proposed by Chan et al,5 can be effective in controlling intracranial primitive neuroectodermal tumors associated with bilateral retinoblastoma. The long-term success of this treatment is still unknown. References 1. Amoaku WMK, Willshaw HE, Parkes SE, Shah KJ, Mann JR. Trilateral retinoblastoma. Cancer 1996;78:858-63. 2. De Potter P, Shields CL, Shields JA. Clinical variations of trilateral retinoblastoma. J Pediatr Ophthalmol Strabismus 1994;31:26-31. 3. Marcus DM, Brooks SE, Leff G, McCormick R, Thompson T, Anfinson S, et al. Trilateral retinoblastoma: insights into histogenesis and management. Surv Ophthalmol 1998;43:59-70. 4. Wong FL, Boice JD, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA 1997;278:1262-7. 5. Chan HSL, DeBoer G, Thiessen JJ, Budning A, Kingston JE, O’Brien JM, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without radiation. Clin Cancer Res 1996;2:1499-508. 6. Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321-8. 7. Nelson HS, Friedman WJ, Oakes EC, Halperin R, Tien GN, Fuller B, et al. Successful therapy for trilateral retinoblastoma. Ophthalmology 1992;114:23-9.
Trilateral retinoblastoma is a rare and almost exclusively fatal disease. Previous treatment regimens have failed to prolong life once the diagnosis is made. We present the first documented case of a patient with neonatal trilateral retinoblastoma successfully treated with chemotherapy and sequential local retinal treatment who is alive and well 26 months after diagnosis.
et al5 have recently shown a chemotherapy regimen of cyclosporin, vincristine, carboplatin, and teniposide to be effective against retinoblastoma. In addition, sequential local therapy, along with chemotherapy, has preserved the eye and eyesight for various stages of retinoblastoma.6 To date, the effectiveness of this latest chemotherapy regimen on the intracranial tumors of TRb is unknown.
INTRODUCTION
CASE PRESENTATION
Trilateral retinoblastoma (TRb) is a rare syndrome consisting of bilateral retinoblastoma associated with a midline intracranial lesion. The midline tumors are usually pineal in origin and show poorly differentiated neuroectodermal tissue. Occasionally these tumors may have a retinoblastoma-like appearance with Flexner-Wintersteiner or Homer Wright rosettes. These lesions represent second primary tumors rather than retinoblastoma metastasis. Death results from cerebrospinal metastasis.1 The overall incidence of TRb is about 3% of bilateral retinoblastoma.2 The intracranial component of TRb is diagnosed 1 to 24 months after retinoblastoma, with the germline retinoblastoma diagnosis at approximately 9.8 months of age. The average survival time is 11.2 months after the initial diagnosis of retinoblastoma, and the mean survival time after intracranial diagnosis is 18 months.2 The heritable form of retinoblastoma may increase the risk of intracranial tumor development because every somatic cell has inherited the first predisposing “hit” of the retinoblastoma gene.3 The treatment of retinoblastoma has varied over the years. Initial therapies have included enucleation, cryotherapy, brachytherapy, and external beam irradiation. The latter 2 are associated with orbital bone growth defects and second primary tumors, especially when more than 60 Gy are administered.4 More recently, photocoagulation has been used. Chemotherapy was previously believed to be ineffective against retinoblastoma, but Chan
M. L. was a 4-day-old infant referred for bilaterally decreased red reflexes. An initial examination at birth revealed poor red reflexes, a flat anterior chamber filled with blood, and a Peter’s-like anomaly in the right eye. Ocular ultrasound and computed tomographic (CT) scan confirmed the presence of a large tumor filling the right eye. The left eye had a hypoplastic iris stroma with extremely poor pupillary dilation and zonular cataract. After cataract extraction, the fundus revealed macular hypoplasia and a small grayish optic nerve head. The right eye was enucleated at 6 days of age. Gross pathologic examination showed the entire globe to be filled with a tumor. Histopathologic examination revealed frequent mitotic figures and both Homer Wright and Flexner-Wintersteiner rosettes. Necrosis and dystrophic calcium were present. No extension of the tumor into the choroid or optic nerve was found. The results of clinical ocular examination and CT were inconclusive for retinoblastoma in the left eye. Four weeks later, the infant returned for left cataract extraction. Because of the increased density of the cataract, adequate assessment of the posterior pole was impossible. A preoperative CT scan revealed a suspicious lesion in the left retina as well as an enhancing cystic pineal lesion 2 cm in diameter. Magnetic resonance imaging (MRI) confirmed the retinal and pineal lesions consistent with TRb. On closer examination of the CT scan done at birth, evidence of the pineal region tumor could be detected. The cataract extraction was delayed, and the infant started the chemotherapy regimen described by Chan et al.5 This consisted of 9 cycles of 2 days of each high-dose cyclosporin (33 mg/kg), along with vincristine (0.025 mg/kg), carboplatin (18.7 mg/kg), and teniposide (7.7 mg/kg) per cycle. After 3 cycles of chemotherapy, the cataract was removed. The anterior segment anomalies prevented proper visualization of the fundus of the remaining eye, thereby precluding adequate tumor treatment. The cataract required a stepwise surgical approach, initially without disruption of the posteri-
From the Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia. Presented in part at the International Retinoblastoma Meeting, Geneva, Switzerland, June 1998. Submitted January 13, 1999. Revision accepted May 10, 1999. Reprint requests: G. R. LaRoche, MD, FRCSC, Department of Ophthalmology, Dalhousie University, IWK Grace Health Centre, 5850 University Avenue, Halifax, Nova Scotia, Canada, B3J 3G9. J AAPOS 1999;3:376-8. Copyright © 1999 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/99 $8.00 + 0 75/1/100974
376
December 1999
Journal of AAPOS
Journal of AAPOS Volume 3 Number 6 December 1999
Bindlish and LaRoche
377
A
B MRI scan of patient (A) showing pineal cystic lesion at 4 weeks of age establishing TRb diagnosis and (B) a partially collapsed, slightly enhancing small lesion after 4 cycles of chemotherapy treatment.
or capsule for fear of malignant cell seeding. The initial operation allowed immediate initiation and planning of sequential laser ablative treatments. Three focal retinoblastoma tumors were seen superior to the disc and were photocoagulated with argon laser. The infant received a total of 9 courses of chemotherapy over a 7-month period. Sufficient tumor control was obtained before a more extensive lensectomy and posterior capsulectomy treatment and monitoring. Repeat MRI study showed resolution of the pineal region
tumor after 4 cycles (Figure). After treatment the tumors in the left eye showed type 2 regression pattern. After 26 months, the infant remained tumor free on repeat examinations under anesthesia and neuroimaging.
DISCUSSION This case significantly challenged our strategy for management of retinoblastoma. This neonate had 1 eye completely filled with tumor at birth, bilateral dysplastic ante-
378 Bindlish and LaRoche rior segments, and a pineal cystic tumor—an unusual presentation for retinoblastoma. In light of normal chromasomal studies, including fluorescence in situ hybridization, we have no explanation for these associated ocular abnormalities with retinoblastoma. The differential diagnosis of the cystic midline pineal lesion in this case generated multiple discussions among our multidisciplinary team. Because all TRbs occur in the midline and involve the pineal or suprasellar-parasellar region, the possibilities included primary intracranial tumors such as pinealoblastoma, pinealocytoma, germinoma, primitive neuroectodermal tumor, ependymoblastoma, or ependymoma, as well as secondary spread of the intraocular retinoblastoma. Because the tumor responded to chemotherapy, a malignancy is more likely than a benign cystic lesion in the absence of pathologic confirmation. TRb has a bleak prognosis. Only 1 report in the literature describes 3 long-term survivors.7 Early diagnosis facilitated by serial neuroimaging appears to improve the survival, especially when made before symptoms appeared, as in this case. The present case has been followed up closely for 26 months since diagnosis, and so far no recurrence has been found. In general, the life expectancy of TRb does not exceed 18
Journal of AAPOS Volume 3 Number 6 December 1999
months. However, this case suggests that the chemotherapy protocol, including cyclosporin proposed by Chan et al,5 can be effective in controlling intracranial primitive neuroectodermal tumors associated with bilateral retinoblastoma. The long-term success of this treatment is still unknown. References 1. Amoaku WMK, Willshaw HE, Parkes SE, Shah KJ, Mann JR. Trilateral retinoblastoma. Cancer 1996;78:858-63. 2. De Potter P, Shields CL, Shields JA. Clinical variations of trilateral retinoblastoma. J Pediatr Ophthalmol Strabismus 1994;31:26-31. 3. Marcus DM, Brooks SE, Leff G, McCormick R, Thompson T, Anfinson S, et al. Trilateral retinoblastoma: insights into histogenesis and management. Surv Ophthalmol 1998;43:59-70. 4. Wong FL, Boice JD, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA 1997;278:1262-7. 5. Chan HSL, DeBoer G, Thiessen JJ, Budning A, Kingston JE, O’Brien JM, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without radiation. Clin Cancer Res 1996;2:1499-508. 6. Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321-8. 7. Nelson HS, Friedman WJ, Oakes EC, Halperin R, Tien GN, Fuller B, et al. Successful therapy for trilateral retinoblastoma. Ophthalmology 1992;114:23-9.