- Email: [email protected]
Discussion by Steven A. Madreperla, MD, PhD
Ophthalmology Volume 107, Number 12, December 2000 6. Ridley M, Green J, Johnson G. Retinal angiomatosis: the ocular manifestations of von Hippel-Lindau disease. Can J Ophthalmol 1986;21:276 – 83. 7. Gorin MB. Von Hippel-Lindau disease: clinical considerations and the use of fluorescein-potentiated argon laser therapy for treatment of retinal angiomas. Semin Ophthalmol 1992;7:182–91. 8. Whitson JT, Welch RB, Green WR. Von Hippel-Lindau disease: case report of a patient with spontaneous regression of a retinal angioma. Retina 1986;6:253–9. 9. Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol 1999;117: 371– 8. 10. Schindler RF, Sarin LK, MacDonald PR. Hemangiomas of the optic disc. Can J Ophthalmol 1975;10:305–18. 11. Chan CC, Vortmeyer AO, Chew EY, et al. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch Ophthalmol 1999;117:625–30. 12. Zbar B, Kaelin W, Maher E, Richard S. Third International Meeting on von Hippel-Lindau disease. Cancer Res 1999;59: 2251–3. 13. Maher ER, Kaelin WG Jr. von Hippel-Lindau disease [review]. Medicine (Baltimore) 1997;76:381–91. 14. Maher ER, Yates JRW, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77:1151– 63. 15. Moore AT, Maher ER, Rosen P, et al. Ophthalmological screening for von Hippel-Lindau disease. Eye 1991;5:723– 8. 16. Shields JA, Shields CL. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders, 1992;393– 407. 17. Jennings AM, Smith C, Cole DR, et al. Von Hippel-Lindau disease in a large British family: clinicopathological features and recommendations for screening and follow-up. Q J Med 1988;66:233– 49. 18. Zbar B, Kishida T, Chen F, et al. Germline mutations in the von Hippel-Lindau (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996;8:348 –57.
19. Martin RL, Goldblatt J, Walpole IR. Efficacy of gene testing for von Hippel-Lindau disease. Med J Aust 1998; 169:422– 4. 20. Eldem B, Abbasoglu OE, Sener EC. Capillary hemangioma of the optic disc. Ann Ophthalmol 1995;27:212– 6. 21. Garcia-Arumi J, Sararols LH, Cavero L, et al. Therapeutic options for capillary papillary hemangiomas. Ophthalmology 2000;107:48 –54. 22. Kremer I, Gilad E, Ben-Sira I. Juxtapapillary exophytic retinal capillary hemangioma treated by yellow krypton (568 nm) laser photocoagulation. Ophthalmic Surg 1988;19:743–7. 23. Kreusel KM, Bornfeld N, Lommatzsch A, et al. Ruthenium106 brachytherapy for peripheral retinal capillary hemangioma. Ophthalmology 1998;105:1386 –92. 24. Blodi CF, Russell SR, Pulido JS, Folk JC. Direct and feeder vessel photocoagulation of retinal angiomas with dye yellow laser. Ophthalmology 1990;97:791–7. 25. Johnson MW, Flynn HW Jr, Gass JM. Pars plana vitrectomy and direct diathermy for complications of multiple retinal angiomas. Ophthalmic Surg 1992;23:47–50. 26. Shields JA. Response of retinal capillary hemangioma to cryotherapy. Arch Ophthalmol 1993;111:551. 27. Rosa RH Jr, Goldberg MF, Green WR. Clinicopathologic correlation of argon laser photocoagulation of retinal angiomas in a patient with von Hippel-Lindau disease followed for more than 20 years. Retina 1996;16:145–56. 28. Raila FA, Zimmerman J, Azordegan P, et al. Successful surgical removal of an asymptomatic optic nerve hemangioblastoma in von Hippel-Lindau disease [review]. J Neuroimaging 1997;7:48 –50. 29. McDonald HR, Schatz H, Johnson RN, et al. Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment. Ophthalmology 1996;103:329 –35. 30. Chang SD, Meisel JA, Hancock SL, et al. Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery. Neurosurgery 1998;43: 28 –35.
Discussion by Steven A. Madreperla, MD, PhD The authors describe the collective experience of four ophthalmology centers and eight ophthalmologists with capillary hemangiomas on or near the optic disc. Although 72 such eyes were identified, 60 had more than 6 months follow-up. They catalogued clinical parameters, including tumor features, visual acuity at diagnosis and at last follow-up, treatment, and the presence or absence of an associated diagnosis of von Hippel-Landau (VHL) disease. Their conclusions were that in patients with a peripapillary capillary hemangioma, visual acuity generally worsens over time and that a concurrent diagnosis of (VHL) disease was associated with (1) greater incidence of bilateral ocular involvement, (2) greater incidence of multiple tumors, (3) presentation at a younger age, (4) greater incidence of endophytic growth pattern. VHL is diagnosed when (1) there are two or more central nervous system hemangiomas, or (2) when there is a central nervous system hemangioma and a visceral manifestation, or (3)
From Retina Associates of New Jersey, Teaneck, New Jersey. Address correspondence to Steven A. Madreperla, MD, PhD, Retina Associates of New Jersey, 678 Cedar Ln., Teaneck, NJ 07666.
2248
when there is one visceral manifestation or hemangioma with a positive family history.1 The gene that when defective leads to VHL was identified in 19932 and seems to function as a tumor suppressor similar to the retinoblastoma gene. In the two-hit model first proposed by Knudson,3 loss of both copies of the gene in one cell leads to tumor formation. Therefore, VHL disease occurs when one abnormal gene is inherited and subsequent somatic mutations lead to tumor formation in several sites. Clinically, the presence of two or more tumors (including two or more retinal hemangiomas) indicates a germline mutation is present and the diagnosis of VHL is made. However, expressivity of the VHL gene is quite variable and the presence of a single retinal tumor with a negative workup for nonocular lesions does not rule out the presence of a germline mutation. It has been estimated that 25% to 40% of such patients will eventually develop clinical manifestations of VHL.4,5 The current study included patients with as little as 6 months follow-up, and, therefore, a significant fraction of those counted as non-VHL patients may actually have been gene carriers. Comparisons between VHL patients and a group of sodefined, non-VHL patients may not accurately reflect the differences between gene carriers and those without the VHL mutation. In this study, statistically significant differences in age at pre-
McCabe et al 䡠 Juxtapapillary Capillary Hemangiomas sentation and the presence of peripheral or bilateral tumors were noted between patients with VHL and those without the diagnosis of VHL. These findings are predicted by the two-hit hypothesis of Knudson,3 in which those with germline disease usually develop multiple tumors and do so at an earlier age than patients without a germline mutation. Also, because the presence of multiple retinal hemangiomas is diagnostic for VHL disease, the fact that there was a statistically significant difference in the fractions of patients with peripheral or bilateral tumors between the VHL and non-VHL groups would be expected. Endophytic tumors were found to be more common in VHL patients but, interestingly, multivariate analysis did not detect tumor growth type as a risk factor for VHL disease. Overall, vision decreased with time in both groups of patients. The authors noted worse initial and final visual acuities were associated with the diagnosis of VHL disease, but the differences between VHL and non-VHL groups were not statistically significant. Treatment of tumors included laser, vitrectomy, and scleral buckling, but because treatment was applied in a nonstandardized fashion, no conclusions could be drawn regarding the timing or efficacy of treatment. As noted by the authors, this study was limited by the retrospective accumulation of data and nonstandardized vision assess-
ment and treatment protocols. However, such limitations are common in studies of rare disease such as VHL, and the authors are to be commended on compiling a large series of patients with peripapillary hemangiomas and documenting their clinical features. References 1. Melmon KL, Rosen SW. Lindau’s disease. Review of the literature and study of a large kindred. Am J Med 1964;36:595– 617. 2. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260:1317–20. 3. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820 –23. 4. Watzke RC, Weingeist TA, Constantine JB. Diagnosis and management of von Hippel-Landau disease. In: Peyman GA, Apple DJ, Sanders DR. eds. Intraocular Tumors. New York: Appleton/Century/Crofts; 1977;199 –217. 5. Maher ER, Yates JR, Harries F, et al. Clinical features and natural history of von Hippel-Landau disease. Q J Med 1990; 77:1151– 63.
2249
19. Martin RL, Goldblatt J, Walpole IR. Efficacy of gene testing for von Hippel-Lindau disease. Med J Aust 1998; 169:422– 4. 20. Eldem B, Abbasoglu OE, Sener EC. Capillary hemangioma of the optic disc. Ann Ophthalmol 1995;27:212– 6. 21. Garcia-Arumi J, Sararols LH, Cavero L, et al. Therapeutic options for capillary papillary hemangiomas. Ophthalmology 2000;107:48 –54. 22. Kremer I, Gilad E, Ben-Sira I. Juxtapapillary exophytic retinal capillary hemangioma treated by yellow krypton (568 nm) laser photocoagulation. Ophthalmic Surg 1988;19:743–7. 23. Kreusel KM, Bornfeld N, Lommatzsch A, et al. Ruthenium106 brachytherapy for peripheral retinal capillary hemangioma. Ophthalmology 1998;105:1386 –92. 24. Blodi CF, Russell SR, Pulido JS, Folk JC. Direct and feeder vessel photocoagulation of retinal angiomas with dye yellow laser. Ophthalmology 1990;97:791–7. 25. Johnson MW, Flynn HW Jr, Gass JM. Pars plana vitrectomy and direct diathermy for complications of multiple retinal angiomas. Ophthalmic Surg 1992;23:47–50. 26. Shields JA. Response of retinal capillary hemangioma to cryotherapy. Arch Ophthalmol 1993;111:551. 27. Rosa RH Jr, Goldberg MF, Green WR. Clinicopathologic correlation of argon laser photocoagulation of retinal angiomas in a patient with von Hippel-Lindau disease followed for more than 20 years. Retina 1996;16:145–56. 28. Raila FA, Zimmerman J, Azordegan P, et al. Successful surgical removal of an asymptomatic optic nerve hemangioblastoma in von Hippel-Lindau disease [review]. J Neuroimaging 1997;7:48 –50. 29. McDonald HR, Schatz H, Johnson RN, et al. Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment. Ophthalmology 1996;103:329 –35. 30. Chang SD, Meisel JA, Hancock SL, et al. Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery. Neurosurgery 1998;43: 28 –35.
Discussion by Steven A. Madreperla, MD, PhD The authors describe the collective experience of four ophthalmology centers and eight ophthalmologists with capillary hemangiomas on or near the optic disc. Although 72 such eyes were identified, 60 had more than 6 months follow-up. They catalogued clinical parameters, including tumor features, visual acuity at diagnosis and at last follow-up, treatment, and the presence or absence of an associated diagnosis of von Hippel-Landau (VHL) disease. Their conclusions were that in patients with a peripapillary capillary hemangioma, visual acuity generally worsens over time and that a concurrent diagnosis of (VHL) disease was associated with (1) greater incidence of bilateral ocular involvement, (2) greater incidence of multiple tumors, (3) presentation at a younger age, (4) greater incidence of endophytic growth pattern. VHL is diagnosed when (1) there are two or more central nervous system hemangiomas, or (2) when there is a central nervous system hemangioma and a visceral manifestation, or (3)
From Retina Associates of New Jersey, Teaneck, New Jersey. Address correspondence to Steven A. Madreperla, MD, PhD, Retina Associates of New Jersey, 678 Cedar Ln., Teaneck, NJ 07666.
2248
when there is one visceral manifestation or hemangioma with a positive family history.1 The gene that when defective leads to VHL was identified in 19932 and seems to function as a tumor suppressor similar to the retinoblastoma gene. In the two-hit model first proposed by Knudson,3 loss of both copies of the gene in one cell leads to tumor formation. Therefore, VHL disease occurs when one abnormal gene is inherited and subsequent somatic mutations lead to tumor formation in several sites. Clinically, the presence of two or more tumors (including two or more retinal hemangiomas) indicates a germline mutation is present and the diagnosis of VHL is made. However, expressivity of the VHL gene is quite variable and the presence of a single retinal tumor with a negative workup for nonocular lesions does not rule out the presence of a germline mutation. It has been estimated that 25% to 40% of such patients will eventually develop clinical manifestations of VHL.4,5 The current study included patients with as little as 6 months follow-up, and, therefore, a significant fraction of those counted as non-VHL patients may actually have been gene carriers. Comparisons between VHL patients and a group of sodefined, non-VHL patients may not accurately reflect the differences between gene carriers and those without the VHL mutation. In this study, statistically significant differences in age at pre-
McCabe et al 䡠 Juxtapapillary Capillary Hemangiomas sentation and the presence of peripheral or bilateral tumors were noted between patients with VHL and those without the diagnosis of VHL. These findings are predicted by the two-hit hypothesis of Knudson,3 in which those with germline disease usually develop multiple tumors and do so at an earlier age than patients without a germline mutation. Also, because the presence of multiple retinal hemangiomas is diagnostic for VHL disease, the fact that there was a statistically significant difference in the fractions of patients with peripheral or bilateral tumors between the VHL and non-VHL groups would be expected. Endophytic tumors were found to be more common in VHL patients but, interestingly, multivariate analysis did not detect tumor growth type as a risk factor for VHL disease. Overall, vision decreased with time in both groups of patients. The authors noted worse initial and final visual acuities were associated with the diagnosis of VHL disease, but the differences between VHL and non-VHL groups were not statistically significant. Treatment of tumors included laser, vitrectomy, and scleral buckling, but because treatment was applied in a nonstandardized fashion, no conclusions could be drawn regarding the timing or efficacy of treatment. As noted by the authors, this study was limited by the retrospective accumulation of data and nonstandardized vision assess-
ment and treatment protocols. However, such limitations are common in studies of rare disease such as VHL, and the authors are to be commended on compiling a large series of patients with peripapillary hemangiomas and documenting their clinical features. References 1. Melmon KL, Rosen SW. Lindau’s disease. Review of the literature and study of a large kindred. Am J Med 1964;36:595– 617. 2. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260:1317–20. 3. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820 –23. 4. Watzke RC, Weingeist TA, Constantine JB. Diagnosis and management of von Hippel-Landau disease. In: Peyman GA, Apple DJ, Sanders DR. eds. Intraocular Tumors. New York: Appleton/Century/Crofts; 1977;199 –217. 5. Maher ER, Yates JR, Harries F, et al. Clinical features and natural history of von Hippel-Landau disease. Q J Med 1990; 77:1151– 63.
2249