INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR LEVEL IN THE SUBRETINAL FLUID OF EYE WITH VASOPROLIFERATIVE RETINAL TUMORS Akio Fujiya, MD,* Kousuke Noda, MD, PhD,*† Shiho Yoshida, BA,† Wataru Saito, MD, PhD,* Susumu Ishida, MD, PhD*†
Purpose: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). Methods: A 30-year-old male patient presented with VPRTs subsequent to longstanding rhegmatogenous retinal detachment. Results: The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL. Conclusion: The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs. RETINAL CASES & BRIEF REPORTS 9:154–156, 2015
From the *Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and †Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
the secondary type is reportedly associated with other vitreoretinal diseases, such as uveitis, retinitis pigmentosa, and long-standing rhegmatogenous retinal detachment (RRD).2 Although only observation is required in the majority of cases, therapeutic intervention is recommended when sight-threatening complications occur. Treatment for VPRTs includes laser photocoagulation, cryopexy, photodynamic therapy, and plaque radiotherapy to tumor lesion.3 In addition, anti-vascular endothelial growth factor (VEGF) therapy for VPRTs has been reported4,5; however, the intraocular levels of VEGF in patients with VPRTs have not been documented so far. Here, we report the VEGF level in the subretinal fluid in a case with VPRTs.
V
asoproliferative retinal tumors (VPRTs) are benign retinal tumors occurring most commonly on inferotemporal or inferior quadrant and characterized by yellow-pinkish lesions accompanied with retinal exudation, cystoid macular edema, epiretinal membrane, retinal hemorrhage, and retinal detachment.1 Vasoproliferative retinal tumors have been classified into two types: idiopathic and secondary, and None of the authors have any financial/conflicting interests to disclose. Reprint requests: Kousuke Noda, MD, PhD, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan; e-mail: [email protected]
Case Report A 30-year-old male patient with decreased vision in his right eye (uncertain onset) was referred to us for further evaluation. On initial examination, his best-corrected visual acuity was 20/60 in the right
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Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
VEGF LEVEL IN CASE WITH VPRTS
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Fig. 1. Preoperative fundus photograph (A) and fluorescein angiography (B) of the right eye of a 30-year-old man with VPRTs and subtotal retinal detachment at the first visit. Arrows, VPRTs; arrowheads, retinal breaks.
eye and intraocular pressure was within a normal range. Slit-lamp examination revealed the presence of pigmented cells in the anterior vitreous with no other remarkable findings. Fundus examination revealed subtotal retinal detachment and the presence of retinal tears, multiple subretinal strands, and irregular retinal pigmentation in the inferotemporal quadrant in his right eye (Figure 1A). Retinal tears were surrounded by 3 yellowish elevated lesions with retinal neovascularization, which caused remarkable leakage visualized by fluorescein angiography (Figure 1B). In the fellow eye, the anterior segment and retinal examination including peripheral retinal examination were all normal. The patient was diagnosed with VPRTs subsequent to long-standing RRD. The patient underwent cryopexy, encircling scleral buckling, and external drainage of the subretinal fluid for RRD. Also, for VPRTs, cryopexy (triple freeze and thaw procedure) and intravitreal bevacizumab were performed. Postoperatively, the retina was reattached, and VPRTs were regressed with fibrotic changes (Figure 2, A and B). No recurrence was found at the last recorded examination 15 months after the surgery, while bestcorrected visual acuity was not improved. Intraoperatively, the subretinal fluid was collected during its external drainage, and the VEGF level was measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). As a control, the subretinal fluid obtained from patients with RRD (n = 4) was also quantified. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with RRD was 2.1 ± 2.8 pg/mL.
Discussion We report here the VEGF level in the subretinal fluid obtained from a case of VPRTs subsequent to long-standing RRD. To date, although the efficacy of
anti-VEGF agent for VPRTs has been reported,4,5 the intraocular concentration of VEGF in VPRTs remains obscure. To our knowledge, this is the first report regarding the VEGF level in eyes with VPRTs. In this case, yellowish elevated tumor lesions were seen at the inferotemporal quadrant in the fundus, a characteristic tumor location of VPRTs.2 In addition, multiple subretinal fibrosis and irregular retinal pigmentation, both of which indicated the long-standing duration of RRD, were found in the detached retina. Therefore, this case was diagnosed as VPRTs secondary to long-standing RRD. It was reported that RRD with long duration was occasionally complicated with retinal neovascularization showing a sea-fan configuration.6 It is postulated that long-standing detachment of retinal tissues induced hypoxia resulting from decreased retinal blood flow in the detached retina.6 By contrast, the biologic mechanism(s) by which subsequent VPRT occurs in cases with RRD with long duration has been unknown. In this case, VEGF concentration in the subretinal fluid is remarkably higher in comparison with those in cases with RRD, suggesting that VPRTs’ growth secondary to RRD with long duration is also VEGFdriven. Previously, VEGF concentration in the subretinal fluid of RRD was reported within a range of 19.1 pg/mL to 355 pg/mL.7 In comparison with the previous data, the current data showed the lower VEGF level in the subretinal fluid of RRD (2.1 ± 2.8
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
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RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
Fig. 2. Postoperative fundus photograph (A) and fluorescein angiography (B) showing the complete regression of VPRTs and successful reattachment of the retina. Arrows, VPRTs; arrowheads, retinal breaks.
pg/mL). It may be due to the difference of measurement, enzyme-linked immunosorbent assay kit used in this study, contamination saline during sample collection, and others. By contrast, the serum level of VEGF was reported within a range of 138 pg/mL to 258.2 pg/ mL.8–10 Therefore, the higher concentration of VEGF in the subretinal fluid obtained from a case with VPRTs (12,997.9 pg/mL) is presumably due to the increased production of VEGF in eye with VPRTs, but not due to the contamination of serum VEGF. Our group also reported the expression of VEGF protein in VPRTs tissues.5 Therefore, our previous and current reports provide the evidence that VEGF production is increased in eyes with PVRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs. Further studies are required to investigate the role of VEGF in the pathogenesis of VPRTs. Key words: anti-VEGF therapy, rhegmatogenous retinal detachment, vascular endothelial growth factor, vasoproliferative retinal tumors.
3.
4.
5.
6.
7.
8.
9.
References 1. Shields CL, Shields JA, Barrett J, De Potter P. Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients. Arch Ophthalmol 1995;113:615– 623. PubMed PMID: 7748132. 2. Shields CL, Kaliki S, Al-Dahmash S, et al. Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary
10.
tumors in 334 cases. JAMA Ophthalmology 2013;131:328–334. PubMed PMID: 23494037. Epub 2013/03/16. eng. Smith J, Steel D. The surgical management of vasoproliferative tumours. Ophthalmologica 2011;226(suppl 1):42–45. PubMed PMID: 21778779. Epub 2011/08/04. eng. Kenawy N, Groenwald C, Damato B. Treatment of a vasoproliferative tumour with intravitreal bevacizumab (Avastin). Eye (Lond) 2007;21:893–894. PubMed PMID: 17347676. Epub 2007/03/10. eng. Saito W, Kase S, Fujiya A, et al. Expression of vascular endothelial growth factor and intravitreal anti-Vegf therapy with bevacizumab in vasoproliferative retinal tumors. Retina 2013;33:1959–1967. Bonnet M. Peripheral neovascularization complicating rhegmatogenous retinal detachments of long duration. Graefes Arch Clin Exp Ophthalmol 1987;225:59–62. PubMed PMID: 2436979. Su CY, Chen MT, Wu WS, Wu WC. Concentration of vascular endothelial growth factor in the subretinal fluid of retinal detachment. J Ocul Pharmacol Ther 2000;16:463–469. PubMed PMID: 11110038. Epub 2000/12/08. eng. Di Raimondo F, Azzaro MP, Palumbo GA, et al. Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis. Leukemia 2001;15:976–980. PubMed PMID: 11417486. Klubo-Gwiezdzinska J, Junik R, Kopczynska E, et al. The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter. Eur J Endocrinol 2007;157:521–527. PubMed PMID: 17893268. Larsson A, Skoldenberg E, Ericson H. Serum and plasma levels of FGF-2 and VEGF in healthy blood donors. Angiogenesis 2002;5:107–110. PubMed PMID: 12549867.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
Purpose: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). Methods: A 30-year-old male patient presented with VPRTs subsequent to longstanding rhegmatogenous retinal detachment. Results: The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL. Conclusion: The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs. RETINAL CASES & BRIEF REPORTS 9:154–156, 2015
From the *Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and †Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
the secondary type is reportedly associated with other vitreoretinal diseases, such as uveitis, retinitis pigmentosa, and long-standing rhegmatogenous retinal detachment (RRD).2 Although only observation is required in the majority of cases, therapeutic intervention is recommended when sight-threatening complications occur. Treatment for VPRTs includes laser photocoagulation, cryopexy, photodynamic therapy, and plaque radiotherapy to tumor lesion.3 In addition, anti-vascular endothelial growth factor (VEGF) therapy for VPRTs has been reported4,5; however, the intraocular levels of VEGF in patients with VPRTs have not been documented so far. Here, we report the VEGF level in the subretinal fluid in a case with VPRTs.
V
asoproliferative retinal tumors (VPRTs) are benign retinal tumors occurring most commonly on inferotemporal or inferior quadrant and characterized by yellow-pinkish lesions accompanied with retinal exudation, cystoid macular edema, epiretinal membrane, retinal hemorrhage, and retinal detachment.1 Vasoproliferative retinal tumors have been classified into two types: idiopathic and secondary, and None of the authors have any financial/conflicting interests to disclose. Reprint requests: Kousuke Noda, MD, PhD, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan; e-mail: [email protected]
Case Report A 30-year-old male patient with decreased vision in his right eye (uncertain onset) was referred to us for further evaluation. On initial examination, his best-corrected visual acuity was 20/60 in the right
154
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
VEGF LEVEL IN CASE WITH VPRTS
155
Fig. 1. Preoperative fundus photograph (A) and fluorescein angiography (B) of the right eye of a 30-year-old man with VPRTs and subtotal retinal detachment at the first visit. Arrows, VPRTs; arrowheads, retinal breaks.
eye and intraocular pressure was within a normal range. Slit-lamp examination revealed the presence of pigmented cells in the anterior vitreous with no other remarkable findings. Fundus examination revealed subtotal retinal detachment and the presence of retinal tears, multiple subretinal strands, and irregular retinal pigmentation in the inferotemporal quadrant in his right eye (Figure 1A). Retinal tears were surrounded by 3 yellowish elevated lesions with retinal neovascularization, which caused remarkable leakage visualized by fluorescein angiography (Figure 1B). In the fellow eye, the anterior segment and retinal examination including peripheral retinal examination were all normal. The patient was diagnosed with VPRTs subsequent to long-standing RRD. The patient underwent cryopexy, encircling scleral buckling, and external drainage of the subretinal fluid for RRD. Also, for VPRTs, cryopexy (triple freeze and thaw procedure) and intravitreal bevacizumab were performed. Postoperatively, the retina was reattached, and VPRTs were regressed with fibrotic changes (Figure 2, A and B). No recurrence was found at the last recorded examination 15 months after the surgery, while bestcorrected visual acuity was not improved. Intraoperatively, the subretinal fluid was collected during its external drainage, and the VEGF level was measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). As a control, the subretinal fluid obtained from patients with RRD (n = 4) was also quantified. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with RRD was 2.1 ± 2.8 pg/mL.
Discussion We report here the VEGF level in the subretinal fluid obtained from a case of VPRTs subsequent to long-standing RRD. To date, although the efficacy of
anti-VEGF agent for VPRTs has been reported,4,5 the intraocular concentration of VEGF in VPRTs remains obscure. To our knowledge, this is the first report regarding the VEGF level in eyes with VPRTs. In this case, yellowish elevated tumor lesions were seen at the inferotemporal quadrant in the fundus, a characteristic tumor location of VPRTs.2 In addition, multiple subretinal fibrosis and irregular retinal pigmentation, both of which indicated the long-standing duration of RRD, were found in the detached retina. Therefore, this case was diagnosed as VPRTs secondary to long-standing RRD. It was reported that RRD with long duration was occasionally complicated with retinal neovascularization showing a sea-fan configuration.6 It is postulated that long-standing detachment of retinal tissues induced hypoxia resulting from decreased retinal blood flow in the detached retina.6 By contrast, the biologic mechanism(s) by which subsequent VPRT occurs in cases with RRD with long duration has been unknown. In this case, VEGF concentration in the subretinal fluid is remarkably higher in comparison with those in cases with RRD, suggesting that VPRTs’ growth secondary to RRD with long duration is also VEGFdriven. Previously, VEGF concentration in the subretinal fluid of RRD was reported within a range of 19.1 pg/mL to 355 pg/mL.7 In comparison with the previous data, the current data showed the lower VEGF level in the subretinal fluid of RRD (2.1 ± 2.8
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
156
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
Fig. 2. Postoperative fundus photograph (A) and fluorescein angiography (B) showing the complete regression of VPRTs and successful reattachment of the retina. Arrows, VPRTs; arrowheads, retinal breaks.
pg/mL). It may be due to the difference of measurement, enzyme-linked immunosorbent assay kit used in this study, contamination saline during sample collection, and others. By contrast, the serum level of VEGF was reported within a range of 138 pg/mL to 258.2 pg/ mL.8–10 Therefore, the higher concentration of VEGF in the subretinal fluid obtained from a case with VPRTs (12,997.9 pg/mL) is presumably due to the increased production of VEGF in eye with VPRTs, but not due to the contamination of serum VEGF. Our group also reported the expression of VEGF protein in VPRTs tissues.5 Therefore, our previous and current reports provide the evidence that VEGF production is increased in eyes with PVRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs. Further studies are required to investigate the role of VEGF in the pathogenesis of VPRTs. Key words: anti-VEGF therapy, rhegmatogenous retinal detachment, vascular endothelial growth factor, vasoproliferative retinal tumors.
3.
4.
5.
6.
7.
8.
9.
References 1. Shields CL, Shields JA, Barrett J, De Potter P. Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients. Arch Ophthalmol 1995;113:615– 623. PubMed PMID: 7748132. 2. Shields CL, Kaliki S, Al-Dahmash S, et al. Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary
10.
tumors in 334 cases. JAMA Ophthalmology 2013;131:328–334. PubMed PMID: 23494037. Epub 2013/03/16. eng. Smith J, Steel D. The surgical management of vasoproliferative tumours. Ophthalmologica 2011;226(suppl 1):42–45. PubMed PMID: 21778779. Epub 2011/08/04. eng. Kenawy N, Groenwald C, Damato B. Treatment of a vasoproliferative tumour with intravitreal bevacizumab (Avastin). Eye (Lond) 2007;21:893–894. PubMed PMID: 17347676. Epub 2007/03/10. eng. Saito W, Kase S, Fujiya A, et al. Expression of vascular endothelial growth factor and intravitreal anti-Vegf therapy with bevacizumab in vasoproliferative retinal tumors. Retina 2013;33:1959–1967. Bonnet M. Peripheral neovascularization complicating rhegmatogenous retinal detachments of long duration. Graefes Arch Clin Exp Ophthalmol 1987;225:59–62. PubMed PMID: 2436979. Su CY, Chen MT, Wu WS, Wu WC. Concentration of vascular endothelial growth factor in the subretinal fluid of retinal detachment. J Ocul Pharmacol Ther 2000;16:463–469. PubMed PMID: 11110038. Epub 2000/12/08. eng. Di Raimondo F, Azzaro MP, Palumbo GA, et al. Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis. Leukemia 2001;15:976–980. PubMed PMID: 11417486. Klubo-Gwiezdzinska J, Junik R, Kopczynska E, et al. The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter. Eur J Endocrinol 2007;157:521–527. PubMed PMID: 17893268. Larsson A, Skoldenberg E, Ericson H. Serum and plasma levels of FGF-2 and VEGF in healthy blood donors. Angiogenesis 2002;5:107–110. PubMed PMID: 12549867.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
