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Scleral Necrosis after Plaque Radiotherapy of Uveal Melanoma: A Case-Control Study
Scleral Necrosis after Plaque Radiotherapy of Uveal Melanoma: A Case-Control Study Swathi Kaliki, MD,1,2 Carol L. Shields, MD,1 Duangnate Rojanaporn, MD,1,3 Josep Badal, MD,1 Laxmi Devisetty, MD,1 Jacqueline Emrich, PhD,4 Lydia Komarnicky, MD,4 Jerry A. Shields, MD1 Purpose: To identify risk factors and outcome of scleral necrosis after plaque radiotherapy of uveal melanoma. Design: Case-control study. Participants: A total of 73 cases with scleral necrosis and 73 controls without necrosis after plaque radiotherapy. Controls were matched for anteroposterior tumor epicenter and follow-up duration. Intervention: Plaque radiotherapy with iodine-125, cobalt-60, iridium-192, or ruthenium-106. Main Outcome Measures: Scleral necrosis. Results: Of 5057 patients treated with plaque radiotherapy for uveal melanoma, 73 (1%) developed radiotherapy-induced scleral necrosis. Scleral necrosis occurred in ⬍1% of patients (3/1140) when plaque radiotherapy was used for tumors ⬍3 mm in thickness, 1% of patients (33/3155) with 3- to 8-mm tumor thickness, and 5% of patients (37/762) with ⬎8-mm-thick tumors. On the basis of tumor location, scleral necrosis was detected after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in ⬍1% of patients (6/4731). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23 months; range, 4 –126 months). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1–15 mm), equivalent to 29% of mean tumor base (median, 24%; range, 6%–100%) and 22% of mean plaque size (median, 19%; range, 5%–75%). Multivariate analysis of factors that predicted clinically evident scleral necrosis included ciliary body (P ⫽ 0.0001) and pars plana to ora serrata (P ⬍ 0.0001) locations of anterior tumor margin, tumor thickness ⱖ6 mm (P ⫽ 0.0001), and radiation dose ⱖ400 Gy to the outer sclera (P ⫽ 0.0455). Scleral necrosis remained stable in 48% of patients (35/73), increased in size/severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) over a mean follow-up of 79 months (median, 54 months; range, 5–351 months). Treatment of scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), and enucleation in 5% of patients (4/73). Conclusions: Scleral necrosis after plaque radiotherapy of uveal melanoma was detected in 1% of cases. Factors predictive of scleral necrosis included increasing tumor thickness, ciliary body and peripheral choroidal location, and higher radiation dose to sclera. Most patients (81%) did not require treatment, and 4% evolved to full-thickness perforation. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:1004 –1011 © 2013 by the American Academy of Ophthalmology.
The management of uveal melanoma depends on tumor size and location and includes focal transpupillary thermotherapy for small borderline melanoma; radiotherapy (charged particle irradiation or plaque radiotherapy) for small, medium, and large melanoma; resection for anterior tumors; and enucleation for large melanoma or those encircling the optic disc.1 Plaque radiotherapy is the most commonly used method because of the advantages of high local tumor control and preservation of the eye with some vision.1–3 The Collaborative Ocular Melanoma Study revealed no difference in survival outcomes and little difference in quality of life outcomes comparing patients treated with plaque radiotherapy with those treated with enucleation, further favoring the conservative use of plaque radiotherapy.4 –7 The first description of focal ocular radiotherapy for uveal melanoma was by Moore8 in 1930, when he directly
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© 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
inserted radon seeds into the thickest portion of uveal melanoma, which resulted in reduction of the mass to one quarter of the original tumor size. Since then, various radioactive isotopes have been used, including cobalt-60 (60Co), iridium-192 (192Ir), ruthenium-106 (106Ru), gold198 (198Au), palladium-103 (103Pd), and iodine-125 (125I).9 –15 125I plaque radiotherapy is the most commonly used radionuclide in the United States. We currently use only 125I radioisotope at the Ocular Oncology Service, Wills Eye Institute. Ocular complications after plaque radiotherapy include radiation-induced dry eye in 8% of patients,16 diplopia in 10% of patients,17 strabismus in 2% of patients,18 keratitis in 4% to 21% of patients,16,19 iris neovascularization in 4% to 23% of patients,20,21 neovascular glaucoma in 2% to 45% of patients,20,22 cataract in 8% to 68% of patients,20,23 vitreous hemorrhage in 4% to 18% of patients,24 ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.10.021
Kaliki et al 䡠 Post-Plaque Scleral Necrosis radiation retinopathy in 10% to 63% of patients,25,26 radiation maculopathy in 13% to 52% of patients,22,27 optic neuropathy in 4% to 46% of patients,19,22,28 and scleral necrosis in 7% to 33% of patients.29,30 In this report, we evaluate our 40-year experience with plaque radiotherapy for uveal melanoma in more than 5000 cases and identify features predictive of scleral necrosis.
Materials and Methods This retrospective case-control study included all cases of clinically evident plaque radiotherapy-induced scleral necrosis developing after treatment of uveal melanoma at the Ocular Oncology Service, Wills Eye Institute, between August 25, 1970, and July 31, 2011. Institutional review board approval was obtained for this study. Controls were chosen from patients with uveal melanoma managed with plaque radiotherapy who did not develop clinically evident scleral necrosis after radiotherapy. Controls were matched with cases for anteroposterior tumor location and follow-up duration (within 1 year). The cases were first matched for anteroposterior tumor location; subsequently, the patient with the closest follow-up duration was selected as the control in each case. The data extracted from the medical records included patient age at diagnosis (years); sex (male, female); race (Caucasian, African American, Hispanic, Asian, Native American, Middle Eastern, Asian Indian); medical history (diabetes mellitus, hypertension, rheumatoid arthritis, and other autoimmune diseases); intraocular pressure (millimeters of mercury); tumor laterality (unilateral, bilateral); location of tumor epicenter (iris, ciliary body, choroid); quadrant location of tumor epicenter (superior, nasal, inferior, temporal, macula); anteroposterior location of tumor epicenter (iris, ciliary body, pars plana to ora serrata, ora
serrata to equator, equator to macula, macula); distance of posterior tumor margin to optic disc margin and foveola (millimeters); largest tumor basal dimension and thickness (millimeters); tumor configuration (dome, mushroom, tapioca, plateau); color (pigmented, nonpigmented, mixed); Bruch’s membrane rupture; subretinal fluid; intraocular hemorrhage; and extraocular extension. Tumor basal diameter and tumor thickness were measured by indirect ophthalmoscopy and confirmed on ocular ultrasonography. All findings were documented with a large color-coded fundus drawing, fundus photography, fluorescein angiography, and ultrasonography. All patients were treated with plaque radiotherapy. Plaque radiotherapy was performed using 125I, 60Co, or 106Ru. The recorded plaque radiotherapy details included radionuclide (125I, 106 Ru, 60Co, 192Ir); plaque size (millimeters); plaque shape (round, notched, postage stamp); duration of radiation exposure (hours); radiation dose (centigray) and dose rate (centigray/hour) to the tumor apex, tumor base, optic disc, foveola, and lens. The data on extraocular muscle disinsertion to facilitate appropriate plaque placement at the time of surgery were recorded. All disinserted rectus muscles were reinserted at the time of plaque removal. The disinserted oblique muscles were not reinserted. The conjunctiva was sutured back in position over the irradiated sclera in all cases. Follow-up data on the presence or absence of scleral necrosis were noted. In cases with plaque radiotherapy–induced-scleral necrosis, the following data were recorded: severity of necrosis (mild to moderate with ⬍50% scleral thinning compared with the thickness of normal surrounding sclera; severe scleral thinning with ⬎50% scleral thinning causing visualization of uveal contents but covered with Tenon’s fascia or conjunctiva; full-thickness scleral perforation with globe hypotony) (Fig 1), largest dimension of scleral necrosis (millimeters), scleral necrosis diameter compared with tumor diameter and plaque diameter, distance to limbus (millimeters), and time interval between plaque radiotherapy and scleral necrosis (months). The status of scleral necrosis (stable,
Figure 1. Scleral necrosis after plaque radiotherapy of uveal melanoma in 4 cases. A, Mild scleral necrosis involving ⬍50% of scleral thickness. B, Mild to moderate scleral necrosis involving ⬍50% of scleral thickness seen as an avascular area. C, Severe scleral necrosis involving ⬎50% of scleral thickness with invasion of overlying Tenon’s fascia and conjunctiva. D, Severe scleral necrosis with scleral perforation, globe hypotony, and vitreous hemorrhage.
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Ophthalmology Volume 120, Number 5, May 2013 Table 1. Demographic Features Feature Age (yrs), mean (median, range) Race Caucasian Others Sex Male Female Medical history Hypertension Diabetes mellitus Rheumatoid arthritis
Cases (n ⴝ 73)
Controls (n ⴝ 73)
P Value*
61 (64, 28–86)
62 (64, 18–89)
0.7694†
73 (100) 0
73 (100) 0
1.0000
38 (52) 35 (48)
22 (30) 51 (70)
0.0113
18 (25) 4 (5) 0
17 (23) 8 (11) 0
1.0000 0.3669 —
Values provided as n (%) unless otherwise indicated. *Fisher exact test. † Independent-samples t test.
treated with 125I. Scleral necrosis developed in 7% of patients (10/134) treated with 60Co, 0% of patients (0/28) treated with 192Ir, 2% of patients (1/64) treated with 106Ru, and 1% of patients (14/4831) treated with 125I. Overall, 73 patients (1%) developed radiotherapy-induced scleral necrosis (cases) over a mean follow-up period of 79 months (median, 54 months; range, 5–351 months). After matching for tumor epicenter and follow-up duration (within 1 year), 73 patients who did not develop scleral necrosis after plaque radiotherapy served as the controls. The mean follow-up duration among controls was 78 months (median, 54 months; range, 6 –340 months). The demographic and clinical features of cases and controls are listed in Tables 1 and 2, respectively. The anteroposterior tumor epicenter was located in the ciliary body (n ⫽ 67; 92%), pars plana to ora serrata (n ⫽ 2; 3%), and ora serrata to equator (n ⫽ 4; 5%). The significant features in cases compared with controls included Table 2. Tumor Features at Presentation Features
increase in size or severity, progression to scleral perforation) at date last seen and treatment of scleral necrosis (observation, scleral patch graft, enucleation) also were recorded. For scleral patch graft, homologous full-thickness donor sclera was used in all cases. The size and shape of the scleral patch graft were determined on the basis of the defect in the recipient sclera. The patch graft was then sutured with 10-0 nylon over the scleral defect covering an additional 2- to 3-mm margin beyond the area of necrosis. Other follow-up data included radiation-related nonproliferative retinopathy, maculopathy, proliferative retinopathy, papillopathy, cataract, iris neovascularization, neovascular glaucoma, and vitreous or subretinal hemorrhage. Other factors include long-term visual acuity, tumor recurrence, systemic metastases, and death.
Statistical Analysis The demographics and tumor characteristics were categorized by patients who developed scleral necrosis after plaque radiotherapy of uveal melanoma (cases) and those who did not develop scleral necrosis (controls). All proportions in each group were presented as numbers and percentages and compared between the groups using the Fisher exact test. The data collected on a continuous or ordinal scale were expressed as mean, median, minimum, and maximum. An independent-samples t test was performed to compare patient age, tumor base, thickness, and radiation dose between cases and controls. Wilcoxon rank-sum test was performed to compare the interval from radiotherapy to radiation-induced complication between cases and controls. The factors predictive of scleral necrosis were identified using the Cox proportional hazard model. The factors found significant on univariable analysis at a 5% level of significance were considered for multivariable analysis using a forward stepwise method. The factors significant at the 0.05 level on multivariable analysis were reported.
Results Of 8101 patients with uveal melanoma managed at the Ocular Oncology Service at Wills Eye Institute, 5057 (62%) were treated with plaque radiotherapy for uveal melanoma. Of the 5057 patients, 134 (3%) were treated with 60Co, 28 (1%) were treated with 192 Ir, 64 (1%) were treated with 106Ru, and 4831 (95%) were
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Anteroposterior tumor epicenter Iris Ciliary body Pars plana to ora serrata Ora serrata to equator Equator to macula Macula Anterior tumor margin Iris Ciliary body Ora serrata to pars plana Equator to ora serrata Posterior to equator Quadrantic location of tumor Superior Nasal Inferior Temporal Macula Proximity to optic disc (mm), mean (median, range) Proximity to foveola (mm), mean (median, range) Largest tumor basal diameter (mm), mean (median, range) Tumor thickness (mm), mean (median, range) Tumor shape Dome Mushroom Diffuse Associated fundus findings Subretinal fluid Rupture of Bruch’s membrane Retinal invasion Extraocular extension
Cases (n ⴝ 73)
Controls (n ⴝ 73)
P Value*
0 67 (92) 2 (3) 4 (5) 0 0
0 67 (92) 2 (3) 4 (5) 0 0
6 (8) 52 (71) 10 (14) 4 (6) 1 (1)
9 (12) 27 (37) 15 (21) 16 (22) 6 (8)
0.5870 ⬍0.0001 0.3799 0.0069 0.1160
22 (30) 8 (11) 31 (43) 12 (16) 0 (0) 11 (11, 0–23)
31 (42) 10 (14) 26 (36) 6 (8) 0 (0) 16 (16, 2–22)
0.1683 0.8020 0.4976 0.2073 — ⬍0.0001†
11 (10, 0–23)
17 (18, 5–22)
⬍0.0001†
13 (13, 5–20)
11 (10, 5–18)
⬍0.0001†
8 (8, 2–12)
6 (6, 1–13)
⬍0.0001†
1.0000 1.0000 1.0000
58 (79) 13 (18) 2 (3)
70 (96) 3 (4) 0 (0)
0.0044 0.0149 0.4966
37 (51) 0 (0)
8 (11) 0 (0)
⬍0.0001 —
5 (7) 2 (3)
1 (1) 6 (8)
Values provided as n (%) unless otherwise indicated. *Fisher exact test. † Independent-samples t test.
0.2090 0.2752
Kaliki et al 䡠 Post-Plaque Scleral Necrosis Table 5. Risk Factors Predictive of Scleral Necrosis: Cox Proportional Hazard Model
Features Multivariate analysis Anterior tumor margin Pars plana to ora serrata vs. ora serrata to equator* CB vs. ora serrata to equator* Tumor thickness ⱖ6 mm† Radiation dose ⱖ400 Gy‡ to outer sclera
Cases Controls (n ⴝ 73), (n ⴝ 73), n (%) n (%) P Value
10 (14) 52 (71) 57 (78) 19 (26)
2 (3) 27 (37) 34 (47) 9 (12)
HR
95% CI
⬍0.0001 14.36 (3.99–51.70) 0.0001 9.83 (3.10–31.16) 0.0001 1.21 (1.09–1.34) 0.0455 1.49 (1.09–2.03)
CB ⫽ ciliary body; CI ⫽ confidence interval; HR ⫽ hazard ratio. *Reference category. † Per 1-mm increase. ‡ Per 10-Gy increase.
ciliary body location of anterior tumor margin (71% vs. 37%; P ⬍ 0.0001), increasing tumor thickness (8 vs. 6 mm; P ⬍ 0.0001), larger tumor base (13 vs. 11 mm; P ⬍ 0.0001) with decreasing proximity to optic disc (11 vs. 16 mm; P ⬍ 0.0001) and foveola (11 vs. 17 mm; P ⬍ 0.0001), and associated subretinal fluid (51% vs. 11%; P ⬍ 0.0001). The plaque radiotherapy parameters are listed in Table 3 (available at http://aaojournal.org). Comparison of cases versus controls revealed larger plaque size (17 vs. 15 mm; P ⫽ 0.0003); higher radiation dose to the tumor base (360 Gy vs. 313 cGy; P ⫽ 0.0023), optic disc (25 Gy vs. 17 Gy; P ⫽ 0.0127), and foveola (24 Gy vs. 15 Gy; P ⫽ 0.0015); and higher incidence of postoperative inflammation (11% vs. 0%; P ⫽ 0.0064) and radiation maculopathy (33% vs. 5%; P ⬍ 0.0001) in cases. The univariate analysis of factors predicting scleral necrosis after plaque radiotherapy are listed in Table 4 (available at http:// aaojournal.org). The multivariate factors included ciliary body (P ⫽ 0.0001) and pars plana to ora serrata (P ⬍ 0.0001) locations of anterior tumor margin, tumor thickness ⱖ6 mm (P ⫽ 0.0001), and radiation dose ⱖ400 Gy to the outer sclera (P ⫽ 0.0455) (Table 5). The features and treatment of plaque radiotherapy induced scleral necrosis are listed in Table 6. None of the cases developed corneal necrosis or severe corneal degeneration. On the basis of tumor thickness, scleral necrosis occurred in ⬍1% of patients (3/1140) with tumors ⬍3 mm in thickness, 1% of patients (33/ 3155) with tumors 3 to 8 mm in thickness, and 5% of patients (37/762) with tumors ⬎8 mm in thickness. On the basis of tumor location, scleral necrosis developed after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in ⬍1% of patients (6/4731). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1–15 mm), which represented 29% of mean tumor base (median, 24%; range, 6%–100%) and 22% of mean plaque size (median, 19%; range, 5%–75%). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23; range, 4 –126 months). Scleral necrosis became evident within 1 year of treatment with plaque radiotherapy in 30% of patients (22/73), within 2 years in 55% of patients (40/73), within 5 years in 85% of patients (62/73), within 10 years in 99% of patients (72/73), and within 15 years in 100% of patients (73/73). Scleral necrosis remained stable in 48% of patients (35/73), increased in size or severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) (Fig 2). Treatment of radiotherapy-induced scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), or enucleation in 5% of patients (4/73). One patient developed endo-
phthalmitis after scleral patch graft required enucleation. Three eyes under observation for stable scleral necrosis were subsequently enucleated secondary to neovascular glaucoma in a blind painful eye.
Discussion Plaque radiotherapy for uveal melanoma generally requires a dose of 80 to 100 Gy of 125I to the tumor apex and 350 to 400 Gy to the tumor base.13 According to the American Brachytherapy Society, a prescription dose of 85 Gy to the tumor apex of uveal melanoma at a dose rate of 0.60 to 1.05 Gy/hour should be delivered over 3 to 7 consecutive days.31 This often results in incidental irradiation of surrounding normal structures, resulting in anticipated radiation side effects. The gradient in radiosensitivity of the ocular structures varies depending on the tissue. The lens is the most radiosensitive structure and shows clinically visible damage with 0.5 Gy within 2 to 3 years, followed by cornea (30 –50 Gy), conjunctiva (55–75 Gy), lacrimal system (50 – 65 Gy), retina (50 Gy), optic nerve (55 Gy), and sclera (15–100 Gy).32–34 Thus, the sclera is considered one of the most tolerant ocular tissues for radiotherapy. Scleral necrosis is an uncommon radiation complication because of the radioresistant nature of this avascular, hypocellular, relatively inactive tissue.35 The incidence of scleral necrosis has ranged from 0% to 33% in various studies.30,35– 40 In our study, only 1% of eyes (73/5057) treated with plaque radiotherapy for uveal melanoma developed scleral necrosis over a mean follow-up period of approximately 7 years. Scleral necrosis after plaque radiotherapy can occur as the result of several mechanisms, including a direct necrotizing effect of radiation on sclera, an indirect effect secondary to local ischemic inflammation related to muscle disinsertion, inflammation related to tumor necrosis, regression of tumor with inapparent scleral invasion, or an occult systemic autoimmune phenomenom.38,39,41,42 In our study, no patients had a history of autoimmune disease and muscle disinsertion was not a significant factor compared with controls. There was clinical evidence of an avascular area in 5 cases before the onset of scleral necrosis, and 3 tumors exhibited extensive tumor necrosis on histopathol-
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Ophthalmology Volume 120, Number 5, May 2013 Table 6. Features of Scleral Necrosis (n ⫽ 73) Features At onset of scleral necrosis Severity of scleral necrosis Mild to moderate (⬍50% scleral thinning) Severe (⬎50% scleral thinning with visualization of sclera but covered by Tenon’s fascia or conjunctiva) Scleral perforation with globe hypotony Largest basal dimension of scleral necrosis (mm); mean (median, range) Proximity to limbus (mm); mean (median, range) Percentage of scleral necrosis compared with tumor base (%); mean (median, range) Percentage of scleral necrosis compared with plaque size (%); mean (median, range) Scleral necrosis at the site of muscle insertion Yes No Percentage of reduction of tumor thickness at onset of scleral necrosis (%); mean (median, range) Features of scleral necrosis at last visit Largest basal dimension of scleral necrosis (mm); mean (median, range) Percentage of scleral necrosis compared with tumor base (%); mean (median, range) Percentage of scleral necrosis compared with plaque size (%); mean (median, range) Percentage of reduction of tumor thickness at last visit (%); mean (median, range) Status of scleral necrosis at last visit Progression Increase in size/severity of scleral necrosis Progression to scleral perforation Stable Time interval (mos); mean (median, range) From radiotherapy to onset of scleral necrosis From radiotherapy to severe scleral necrosis From radiotherapy to scleral perforation From onset to severe scleral necrosis From onset to scleral perforation Treatment of scleral necrosisⴱ Observation Scleral patch graft Enucleation
n (%)
32 (44) 41 (56) 0 (0) 4 (3, 1–15) 3 (3, 0–8) 29 (24, 6–100) 22 (19, 5–75)
18 (25) 55 (75) 42 (44, 6–83)
5 (4, 1–15) 40 (33, 7–125) 30 (27, 5–83) 53 (53, 7–88)
38 (52) 35 (48) 3 (4) 35 (48) 32 (23, 4–126) 38 (36, 4–130) 16 (12, 5–30) 12 (11, 1–54) 2 (3, 1–3) 59 (81) 10 (14) 4 (5)
*One patient underwent 2 treatment modalities, scleral patch graft and subsequent enucleation, because of patch graft failure.
ogy, favoring a direct ischemic or inflammatory effect on the sclera or secondary to tumor-related necrosis. There was no evidence of scleral involvement of melanoma in 8 enucleated eyes. Radiation-induced focal scleral necrosis was first reported by Jones and Reese36 in 3 cases after application of concentrated localized gamma or beta radiation (15 Gy in 1 case and 100 Gy in 2 cases) over the sclera or limbus for the treatment of ocular surface squamous cell carcinomas. Subsequently, there have been reports of scleral necrosis after 60 Co, 192Ir, 106Ru, 198Au, 125I, and proton beam radiotherapy for uveal melanoma.35,37– 40 In our study, scleral necrosis occurred with the use of 60Co, 106Ru, and 125I plaque radiotherapy. There was no statistical significance among the 60Co, 125I, and 106Ru plaques. 60Co and 192Ir have higher
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energy gamma emission, require thicker shielding for radiation protection, and deliver large radiation doses to surrounding normal ocular structures. The incidence of scleral necrosis with 60Co plaque radiotherapy ranges from 2% to 9%.10,43 125I and 103Pd are low-energy gamma emitters, are easier to shield, and reduce the dose to the surrounding normal ocular structures. The incidence of scleral necrosis after 125I plaque radiotherapy for uveal melanoma ranges from 0% to 11%.37,38 106Ru is a beta emitter and has a rapid dose fall-off. 106Ru provides excellent focal radiotherapy with minimal dose to surrounding ocular structures, but requires a higher scleral dose to achieve the same prescription apex dose compared with 125I plaque applicators. Furthermore, 106Ru can sufficiently treat tumors up to 5 mm in thickness, but poor depth penetration disallows treatment of thicker tumors.31 Scleral necrosis after 106Ru plaque radiotherapy ranges from 0% to 9%.11,44 198Au is a beta and gamma-ray emitter, with a low-energy gamma-ray emitting component. The incidence of scleral necrosis with 198Au is 12%.40 The comparative incidence of scleral necrosis with each radionuclide is not clearly understood. Most studies have implied that a higher radiation dose of approximately 15 to 100 Gy is the most important factor for scleral necrosis.35,36 However, animal studies of rabbit eyes by Kunz and Lommatzsch45 revealed early disruption of the scleral lamellae at even a low dose of 1 Gy and loss of scleral cells at 5 Gy. In our study, the average radiation dose to the outer sclera was 372 Gy in cases versus 328 Gy in controls (P ⫽ 0.0551), suggesting slightly higher radiation dose to the sclera in the cases group. In a study of scleral necrosis in 15 eyes, Chaudhry et al40 found the mean time interval between plaque radiotherapy and scleral necrosis at 15 months (range, 4 – 60 months). Radin et al39 studied 23 cases of scleral necrosis and documented the mean time to onset of scleral necrosis at 70 months (range, 11–257 months). In our study, the mean time to detection of scleral necrosis was 32 months (range, 4 –126 months). Most cases of scleral necrosis (85%) developed within the first 5 years of plaque radiotherapy. In a study of 136 patients with plaque-irradiated ciliary body melanoma, Gündüz et al38 found that 15 patients (11%) developed scleral necrosis. Factors predictive of scleral necrosis in that series included intraocular pressure ⬎15 mmHg and tumor thickness ⬎7 mm. Chaudhry et al40 found tumor thickness ⬎6 mm, ciliary body involvement, and intraocular pressure ⬎21 mmHg as the risk factors for scleral necrosis in their series. In our study, factors for scleral necrosis included peripheral tumor location (ciliary body [P ⫽ 0.0001], pars plana to ora serrata [P ⬍ 0.0001]), tumor thickness ⱖ6 mm (P ⫽ 0.0001), and radiation dose ⱖ400 Gy to the sclera (P ⫽ 0.0455). In most patients (92%), the scleral necrosis resulted after radiotherapy of ciliary body melanoma. This could be related to generally thicker tumors involving the ciliary body necessitating more intense scleral radiation dose and partly related to the more apparent identification of scleral necrosis because of the anterior location. There were 3 cases of scleral necrosis after radiotherapy to macular melanoma, identified on B-scan ultrasonography. There is a possibility that scleral necrosis
Kaliki et al 䡠 Post-Plaque Scleral Necrosis
Figure 2. Evolution of scleral necrosis after plaque radiotherapy of uveal melanoma. A, A 53-year-old male patient with an area of avascularity 2 months after plaque radiotherapy subsequently developed scleral necrosis (B) adjacent to the avascular area 24 months after plaque radiotherapy. C, A 40-year-old female patient developed scleral necrosis 47 months after plaque radiotherapy (D), which remained stable for 48 months. E, A 75-year-old male patient with mild scleral necrosis 22 months after plaque radiotherapy (F) with progression to severe scleral necrosis at 29 months.
might remain undetected in eyes with posterior tumors due to unapparent findings. The main challenges of scleral necrosis rest in its recognition, differentiation from tumor recurrence, and management. The key features to differentiation from recurrence encompass the identification of scleral thinning and blue discoloration to Tenon’s fascia, along with overall reduction in intraocular melanoma thickness over time. Ultrasound biomicroscopy or anterior segment optical coherence tomography can confirm scleral thinning. In contrast, melanoma recurrence after plaque radiotherapy generally occurs within the globe with increase in basal diameter or thickness and, if extensive, can extend through the emissarial canals and form a blue sub-Tenon’s fascia nodule with intact, typically normal thickness sclera. Scleral necrosis in patients with regressed tumor is associated with increased transillumination, whereas tumor recurrence results in tumor shadow corresponding to the tumor size. There are instances in which scleral thinning after radiotherapy is combined with tumor recurrence. According to Shields et
al,46 melanoma recurrence is uncommon, found in approximately 2% of eyes after plaque radiotherapy. In most patients, scleral necrosis evolves through a progression from a small spot of scleral thinning to a mean 4-mm diameter of thinning over 4 to 8 months, but it typically remains stable thereafter with observation and without full-thickness perforation. In a study of 23 cases by Radin et al,39 scleral necrosis was stable in 74% of patients (n ⫽ 17), partial regression was observed in 13% of patients (n ⫽ 3), and progression to pre-perforation was observed in 9% of patients (n ⫽ 2). In our study, scleral necrosis was stable in 48% of patients, increased in size or severity in 48% of patients, and progressed to scleral perforation in 4% of patients. Scleral necrosis is not usually an eye-threatening complication, unless perforation occurs. Depending on the severity of scleral necrosis, various management options include observation; artificial lubrication with tears, gels, or ointments; tissue glue; conjunctival graft/flap; amniotic membrane transplantation; scleral patch graft; dermal patch graft; vital Tenon’s fascia transposition; hyperbaric oxygen
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Ophthalmology Volume 120, Number 5, May 2013 therapy; and enucleation.47– 49 All patients are advised to avoid rubbing the eye. In this study, 81% of patients did not require further treatment. Scleral patch graft was performed in 10 patients. Progressive scleral necrosis can ensue despite scleral patch graft, so our current approach is observation and lubrication. In this study, the complication of radiation-induced scleral necrosis was associated with a higher incidence of other radiation complications, such as cataract, retinopathy, and maculopathy. This could be a result of the higher radiation dose because eyes with scleral necrosis tended to have thicker tumors. Furthermore, the thickness factor could have contributed to a higher rate of metastasis and death because each millimeter increase in tumor thickness increases the risk of systemic metastasis by approximately 5%.50 In conclusion, clinically evident scleral necrosis after plaque radiotherapy of uveal melanoma was found in 1% of cases. Risk factors include ciliary body and pars plana to ora serrata location of anterior tumor margin, tumor thickness ⱖ6 mm, and radiation dose ⱖ400 Gy to the outer sclera. Exposure of irradiated sclera can contribute to scleral necrosis and perforation. Postoperatively, irradiated sclera should be covered by conjunctiva in all cases. Scleral necrosis should be differentiated from tumor recurrence with extraocular extension, and unnecessary enucleation can be avoided. Scleral necrosis can be followed conservatively with observation and lubrication in the majority of cases. Acknowledgment. Statistical analysis for the study was provided by Rishita Nutheti, PhD, Hyderabad, India.
References 1. Shields JA, Shields CL. Posterior uveal melanoma: management. In: Shields JA, Shields CL, eds. Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:140 – 65. 2. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 2000;118:1219 –28. 3. Khan N, Khan MK, Bena J, et al. Plaque brachytherapy for uveal melanoma: a vision prognostication model [report online]. Int J Radiat Oncol Biol Phys 2012;84:e285–90. 4. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS report no. 18. Arch Ophthalmol 2001;119:969 – 82. 5. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report no. 28. Arch Ophthalmol 2006;124: 1684 –93. 6. Collaborative Ocular Melanoma Study–Quality of Life Study Group. Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS report no. 3. Arch Ophthalmol 2006;124:226 –38. 7. Hawkins BS. Collaborative Ocular Melanoma Study randomized trial of I-125 brachytherapy. Clin Trials 2011;8:661–73. 8. Moore RF. Choroidal sarcoma treated by the intraocular insertion of radon seeds. Br J Ophthalmol 1930;14:145–52.
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9. Stallard HB. Malignant melanoma of the choroid treated with radioactive applicators. Trans Ophthalmol Soc U K 1959;79: 373–92. 10. Shields JA, Augsburger JJ, Brady LW, Day JL. Cobalt plaque therapy of posterior uveal melanomas. Ophthalmology 1982; 89:1201–7. 11. Messmer E, Bornfeld N, Foerster M, et al. Histopathologic findings in eyes treated with a ruthenium plaque for uveal melanoma. Graefes Arch Clin Exp Ophthalmol 1992;230: 391– 6. 12. Finger PT, Chin KJ, Duvall G, Palladium-103 for Choroidal Melanoma Study Group. Palladium-103 ophthalmic plaque radiation therapy for choroidal melanoma: 400 treated patients. Ophthalmology 2009;116:790 – 6. 13. Shields CL, Shields JA, Gündüz K, et al. Radiation therapy for uveal malignant melanoma. Ophthalmic Surg Lasers 1998;29: 397– 409. 14. Hungerford JL. Current trends in the treatment of ocular melanoma by radiotherapy. Clin Experiment Ophthalmol 2003; 31:8 –13. 15. Leonard KL, Gagne NL, Mignano JE, et al. A 17-year retrospective study of institutional results for eye plaque brachytherapy of uveal melanoma using (125)I, (103)Pd, and (131)Cs and historical perspective. Brachytherapy 2011;10: 331–9. 16. Quivey JM, Char DH, Phillips TL, et al. High intensity 125iodine (125I) plaque treatment of uveal melanoma. Int J Radiat Oncol Biol Phys 1993;26:613– 8. 17. Sener EC, Kiratli H, Gedik S, Sanac AS. Ocular motility disturbances after episcleral plaque brachytherapy for uveal melanoma. J AAPOS 2004;8:38 – 45. 18. Dawson E, Sagoo MS, Mehta JS, et al. Strabismus in adults with uveal melanoma following episcleral plaque brachytherapy. J AAPOS 2007;11:584 – 8. 19. Lumbroso-Le Rouic L, Charif Chefchaouni M, Levy C, et al. 125I plaque brachytherapy for anterior uveal melanomas. Eye (Lond) 2004;18:911– 6. 20. Mameghan H, Karolis C, Fisher R, et al. Iodine-125 irradiation of choroidal melanoma: clinical experience from the Prince of Wales and Sydney Eye Hospitals. Australas Radiol 1992;36:249 –52. 21. Detorakis ET, Engstrom RE Jr, Wallace R, Straatsma BR. Iris and anterior chamber angle neovascularization after iodine 125 brachytherapy for uveal melanoma. Ophthalmology 2005; 112:505–10. 22. Puusaari I, Heikkonen J, Kivela T. Ocular complications after iodine brachytherapy for large uveal melanomas. Ophthalmology 2004;111:1768 –77. 23. Collaborative Ocular Melanoma Study Group. Incidence of cataract and outcomes after cataract surgery in the first 5 years after iodine 125 brachytherapy in the Collaborative Ocular Melanoma Study: COMS report no. 27. Ophthalmology 2007; 117:1363–71. 24. Bianciotto C, Shields CL, Pirondini C, et al. Vitreous hemorrhage after plaque radiotherapy for uveal melanoma. Retina 2012;32:1156 – 64. 25. Bosworth JL, Packer S, Rotman M, et al. Choroidal melanoma: I-125 plaque therapy. Radiology 1988;169:249 –51. 26. Jones R, Gore E, Mieler W, et al. Posttreatment visual acuity in patients treated with episcleral plaque therapy for choroidal melanomas: dose and dose rate effects. Int J Radiat Oncol Biol Phys 2002;52:989 –95. 27. Jensen AW, Petersen IA, Kline RW, et al. Radiation complications and tumor control after 125I plaque brachytherapy for
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28. 29. 30. 31.
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35. 36. 37. 38. 39.
ocular melanoma. Int J Radiat Oncol Biol Phys 2005;63: 101– 8. Wen JC, Oliver SC, McCannel TA. Ocular complications following I-125 brachytherapy for choroidal melanoma. Eye (Lond) 2009;23:1254 – 68. Shields CL, Shields JA, Karlsson U, et al. Enucleation after plaque radiotherapy for posterior uveal melanoma. Histopathologic findings. Ophthalmology 1990;97:1665–70. Petrovich Z, McDonnell JM, Palmer D, et al. Histopathologic changes following irradiation for uveal tract melanoma. Am J Clin Oncol 1994;17:298 –306. Nag S, Quivey JM, Earle JD, et al, American Brachytherapy Society. The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas. Int J Radiat Oncol Biol Phys 2003;56:544 –55. Parsons JT, Bova FJ, Mendenhall WM, et al. Response of the normal eye to high dose radiotherapy. Oncology (Williston Park) 1996;10:837– 47. Merriam GR Jr, Worgul BV. Experimental radiation cataract– its clinical relevance. Bull N Y Acad Med 1983;59:372–92. Sheils WC, Lee SY, Marcus DM. Radiation therapy for agerelated macular degeneration. In: Alberti WE, Richard G, Sagerman RH, eds. Age-Related Macular Degeneration: Current Treatment Concepts. New York: Springer; 2001:187–98. Macfaul PA, Bedford MA. Ocular complications after therapeutic irradiation. Br J Ophthalmol 1970;54:237– 47. Jones IS, Reese AB. Focal scleral necrosis; a late sequel of irradiation. AMA Arch Ophthalmol 1953;49:633– 6. Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for large posterior uveal melanomas (⬎ or ⫽ 8-mm thick) in 354 consecutive patients. Ophthalmology 2002;109:1838 – 49. Gündüz K, Shields CL, Shields JA, et al. Plaque radiotherapy of uveal melanoma with predominant ciliary body involvement. Arch Ophthalmol 1999;117:170 –7. Radin PP, Lumbroso-Le Rouic L, Levy-Gabriel C, et al. Scleral necrosis after radiation therapy for uveal melanomas:
40. 41. 42. 43. 44. 45.
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report of 23 cases. Graefes Arch Clin Exp Ophthalmol 2008; 246:1731– 6. Chaudhry IA, Liu M, Shamsi FA, et al. Corneoscleral necrosis after episcleral Au-198 brachytherapy of uveal melanoma. Retina 2009;29:73–9. Corrêa ZM, Augsburger JJ, Freire J, Eagle RC Jr. Early-onset scleral necrosis after iodine I 125 plaque radiotherapy for ciliochoroidal melanoma. Arch Ophthalmol 1999;117:259 – 61. Shields CL, Shields JA, Karlsson U, et al. Reasons for enucleation after plaque radiotherapy for posterior uveal melanoma. Clinical findings. Ophthalmology 1989;96:919 –23. MacFaul PA, Morgan G. Histopathological changes in malignant melanomas of the choroid after cobalt plaque therapy. Br J Ophthalmol 1977;61:221– 8. Lommatzsch PK. Results after beta-irradiation (106Ru/ 106Rh) of choroidal melanomas. Twenty years’ experience. Am J Clin Oncol 1987;10:146 –51. Kunz J, Lommatzsch P. Changes of the S35 sulfate incorporation into the sclera of rabbit eyes following high-dosed beta irradiation [in German]. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1966;171:68 –76. Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol 2002;120:933– 40. Kim BH. Surgical treatment of necrotic scleral calcification using combined conjunctival autografting and an amniotic membrane inlay filling technique. Eye (Lond) 2011;25:1484 –90. Sangwan VS, Jain V, Gupta P. Structural and functional outcome of scleral patch graft. Eye (Lond) 2007;21:930 –5. Bayer A, Mutlu FM, Sobaci G. Hyperbaric oxygen therapy for mitomycin C-induced scleral necrosis. Ophthalmic Surg Lasers 2002;33:58 – 61. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 2009;127:989 –98.
Footnotes and Financial Disclosures Originally received: August 3, 2012. Final revision: October 16, 2012. Accepted: October 16, 2012. Available online: January 21, 2013.
Manuscript no. 2012-1176.
1
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Ocular Oncology Service, L. V. Prasad Eye Institute, Hyderabad, India.
3
Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
4
Department of Radiation Oncology, Drexel University, College of Medicine, Philadelphia, Pennsylvania.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Support provided by a donation from Michael, Bruce, and Ellen Ratner, New York, New York (J.A.S., C.L.S.), and Eye Tumor Research Foundation, Philadelphia, Pennsylvania (C.L.S., J.A.S.). Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail carol.shields@ shieldsoncology.com.
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The management of uveal melanoma depends on tumor size and location and includes focal transpupillary thermotherapy for small borderline melanoma; radiotherapy (charged particle irradiation or plaque radiotherapy) for small, medium, and large melanoma; resection for anterior tumors; and enucleation for large melanoma or those encircling the optic disc.1 Plaque radiotherapy is the most commonly used method because of the advantages of high local tumor control and preservation of the eye with some vision.1–3 The Collaborative Ocular Melanoma Study revealed no difference in survival outcomes and little difference in quality of life outcomes comparing patients treated with plaque radiotherapy with those treated with enucleation, further favoring the conservative use of plaque radiotherapy.4 –7 The first description of focal ocular radiotherapy for uveal melanoma was by Moore8 in 1930, when he directly
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© 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
inserted radon seeds into the thickest portion of uveal melanoma, which resulted in reduction of the mass to one quarter of the original tumor size. Since then, various radioactive isotopes have been used, including cobalt-60 (60Co), iridium-192 (192Ir), ruthenium-106 (106Ru), gold198 (198Au), palladium-103 (103Pd), and iodine-125 (125I).9 –15 125I plaque radiotherapy is the most commonly used radionuclide in the United States. We currently use only 125I radioisotope at the Ocular Oncology Service, Wills Eye Institute. Ocular complications after plaque radiotherapy include radiation-induced dry eye in 8% of patients,16 diplopia in 10% of patients,17 strabismus in 2% of patients,18 keratitis in 4% to 21% of patients,16,19 iris neovascularization in 4% to 23% of patients,20,21 neovascular glaucoma in 2% to 45% of patients,20,22 cataract in 8% to 68% of patients,20,23 vitreous hemorrhage in 4% to 18% of patients,24 ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.10.021
Kaliki et al 䡠 Post-Plaque Scleral Necrosis radiation retinopathy in 10% to 63% of patients,25,26 radiation maculopathy in 13% to 52% of patients,22,27 optic neuropathy in 4% to 46% of patients,19,22,28 and scleral necrosis in 7% to 33% of patients.29,30 In this report, we evaluate our 40-year experience with plaque radiotherapy for uveal melanoma in more than 5000 cases and identify features predictive of scleral necrosis.
Materials and Methods This retrospective case-control study included all cases of clinically evident plaque radiotherapy-induced scleral necrosis developing after treatment of uveal melanoma at the Ocular Oncology Service, Wills Eye Institute, between August 25, 1970, and July 31, 2011. Institutional review board approval was obtained for this study. Controls were chosen from patients with uveal melanoma managed with plaque radiotherapy who did not develop clinically evident scleral necrosis after radiotherapy. Controls were matched with cases for anteroposterior tumor location and follow-up duration (within 1 year). The cases were first matched for anteroposterior tumor location; subsequently, the patient with the closest follow-up duration was selected as the control in each case. The data extracted from the medical records included patient age at diagnosis (years); sex (male, female); race (Caucasian, African American, Hispanic, Asian, Native American, Middle Eastern, Asian Indian); medical history (diabetes mellitus, hypertension, rheumatoid arthritis, and other autoimmune diseases); intraocular pressure (millimeters of mercury); tumor laterality (unilateral, bilateral); location of tumor epicenter (iris, ciliary body, choroid); quadrant location of tumor epicenter (superior, nasal, inferior, temporal, macula); anteroposterior location of tumor epicenter (iris, ciliary body, pars plana to ora serrata, ora
serrata to equator, equator to macula, macula); distance of posterior tumor margin to optic disc margin and foveola (millimeters); largest tumor basal dimension and thickness (millimeters); tumor configuration (dome, mushroom, tapioca, plateau); color (pigmented, nonpigmented, mixed); Bruch’s membrane rupture; subretinal fluid; intraocular hemorrhage; and extraocular extension. Tumor basal diameter and tumor thickness were measured by indirect ophthalmoscopy and confirmed on ocular ultrasonography. All findings were documented with a large color-coded fundus drawing, fundus photography, fluorescein angiography, and ultrasonography. All patients were treated with plaque radiotherapy. Plaque radiotherapy was performed using 125I, 60Co, or 106Ru. The recorded plaque radiotherapy details included radionuclide (125I, 106 Ru, 60Co, 192Ir); plaque size (millimeters); plaque shape (round, notched, postage stamp); duration of radiation exposure (hours); radiation dose (centigray) and dose rate (centigray/hour) to the tumor apex, tumor base, optic disc, foveola, and lens. The data on extraocular muscle disinsertion to facilitate appropriate plaque placement at the time of surgery were recorded. All disinserted rectus muscles were reinserted at the time of plaque removal. The disinserted oblique muscles were not reinserted. The conjunctiva was sutured back in position over the irradiated sclera in all cases. Follow-up data on the presence or absence of scleral necrosis were noted. In cases with plaque radiotherapy–induced-scleral necrosis, the following data were recorded: severity of necrosis (mild to moderate with ⬍50% scleral thinning compared with the thickness of normal surrounding sclera; severe scleral thinning with ⬎50% scleral thinning causing visualization of uveal contents but covered with Tenon’s fascia or conjunctiva; full-thickness scleral perforation with globe hypotony) (Fig 1), largest dimension of scleral necrosis (millimeters), scleral necrosis diameter compared with tumor diameter and plaque diameter, distance to limbus (millimeters), and time interval between plaque radiotherapy and scleral necrosis (months). The status of scleral necrosis (stable,
Figure 1. Scleral necrosis after plaque radiotherapy of uveal melanoma in 4 cases. A, Mild scleral necrosis involving ⬍50% of scleral thickness. B, Mild to moderate scleral necrosis involving ⬍50% of scleral thickness seen as an avascular area. C, Severe scleral necrosis involving ⬎50% of scleral thickness with invasion of overlying Tenon’s fascia and conjunctiva. D, Severe scleral necrosis with scleral perforation, globe hypotony, and vitreous hemorrhage.
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Ophthalmology Volume 120, Number 5, May 2013 Table 1. Demographic Features Feature Age (yrs), mean (median, range) Race Caucasian Others Sex Male Female Medical history Hypertension Diabetes mellitus Rheumatoid arthritis
Cases (n ⴝ 73)
Controls (n ⴝ 73)
P Value*
61 (64, 28–86)
62 (64, 18–89)
0.7694†
73 (100) 0
73 (100) 0
1.0000
38 (52) 35 (48)
22 (30) 51 (70)
0.0113
18 (25) 4 (5) 0
17 (23) 8 (11) 0
1.0000 0.3669 —
Values provided as n (%) unless otherwise indicated. *Fisher exact test. † Independent-samples t test.
treated with 125I. Scleral necrosis developed in 7% of patients (10/134) treated with 60Co, 0% of patients (0/28) treated with 192Ir, 2% of patients (1/64) treated with 106Ru, and 1% of patients (14/4831) treated with 125I. Overall, 73 patients (1%) developed radiotherapy-induced scleral necrosis (cases) over a mean follow-up period of 79 months (median, 54 months; range, 5–351 months). After matching for tumor epicenter and follow-up duration (within 1 year), 73 patients who did not develop scleral necrosis after plaque radiotherapy served as the controls. The mean follow-up duration among controls was 78 months (median, 54 months; range, 6 –340 months). The demographic and clinical features of cases and controls are listed in Tables 1 and 2, respectively. The anteroposterior tumor epicenter was located in the ciliary body (n ⫽ 67; 92%), pars plana to ora serrata (n ⫽ 2; 3%), and ora serrata to equator (n ⫽ 4; 5%). The significant features in cases compared with controls included Table 2. Tumor Features at Presentation Features
increase in size or severity, progression to scleral perforation) at date last seen and treatment of scleral necrosis (observation, scleral patch graft, enucleation) also were recorded. For scleral patch graft, homologous full-thickness donor sclera was used in all cases. The size and shape of the scleral patch graft were determined on the basis of the defect in the recipient sclera. The patch graft was then sutured with 10-0 nylon over the scleral defect covering an additional 2- to 3-mm margin beyond the area of necrosis. Other follow-up data included radiation-related nonproliferative retinopathy, maculopathy, proliferative retinopathy, papillopathy, cataract, iris neovascularization, neovascular glaucoma, and vitreous or subretinal hemorrhage. Other factors include long-term visual acuity, tumor recurrence, systemic metastases, and death.
Statistical Analysis The demographics and tumor characteristics were categorized by patients who developed scleral necrosis after plaque radiotherapy of uveal melanoma (cases) and those who did not develop scleral necrosis (controls). All proportions in each group were presented as numbers and percentages and compared between the groups using the Fisher exact test. The data collected on a continuous or ordinal scale were expressed as mean, median, minimum, and maximum. An independent-samples t test was performed to compare patient age, tumor base, thickness, and radiation dose between cases and controls. Wilcoxon rank-sum test was performed to compare the interval from radiotherapy to radiation-induced complication between cases and controls. The factors predictive of scleral necrosis were identified using the Cox proportional hazard model. The factors found significant on univariable analysis at a 5% level of significance were considered for multivariable analysis using a forward stepwise method. The factors significant at the 0.05 level on multivariable analysis were reported.
Results Of 8101 patients with uveal melanoma managed at the Ocular Oncology Service at Wills Eye Institute, 5057 (62%) were treated with plaque radiotherapy for uveal melanoma. Of the 5057 patients, 134 (3%) were treated with 60Co, 28 (1%) were treated with 192 Ir, 64 (1%) were treated with 106Ru, and 4831 (95%) were
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Anteroposterior tumor epicenter Iris Ciliary body Pars plana to ora serrata Ora serrata to equator Equator to macula Macula Anterior tumor margin Iris Ciliary body Ora serrata to pars plana Equator to ora serrata Posterior to equator Quadrantic location of tumor Superior Nasal Inferior Temporal Macula Proximity to optic disc (mm), mean (median, range) Proximity to foveola (mm), mean (median, range) Largest tumor basal diameter (mm), mean (median, range) Tumor thickness (mm), mean (median, range) Tumor shape Dome Mushroom Diffuse Associated fundus findings Subretinal fluid Rupture of Bruch’s membrane Retinal invasion Extraocular extension
Cases (n ⴝ 73)
Controls (n ⴝ 73)
P Value*
0 67 (92) 2 (3) 4 (5) 0 0
0 67 (92) 2 (3) 4 (5) 0 0
6 (8) 52 (71) 10 (14) 4 (6) 1 (1)
9 (12) 27 (37) 15 (21) 16 (22) 6 (8)
0.5870 ⬍0.0001 0.3799 0.0069 0.1160
22 (30) 8 (11) 31 (43) 12 (16) 0 (0) 11 (11, 0–23)
31 (42) 10 (14) 26 (36) 6 (8) 0 (0) 16 (16, 2–22)
0.1683 0.8020 0.4976 0.2073 — ⬍0.0001†
11 (10, 0–23)
17 (18, 5–22)
⬍0.0001†
13 (13, 5–20)
11 (10, 5–18)
⬍0.0001†
8 (8, 2–12)
6 (6, 1–13)
⬍0.0001†
1.0000 1.0000 1.0000
58 (79) 13 (18) 2 (3)
70 (96) 3 (4) 0 (0)
0.0044 0.0149 0.4966
37 (51) 0 (0)
8 (11) 0 (0)
⬍0.0001 —
5 (7) 2 (3)
1 (1) 6 (8)
Values provided as n (%) unless otherwise indicated. *Fisher exact test. † Independent-samples t test.
0.2090 0.2752
Kaliki et al 䡠 Post-Plaque Scleral Necrosis Table 5. Risk Factors Predictive of Scleral Necrosis: Cox Proportional Hazard Model
Features Multivariate analysis Anterior tumor margin Pars plana to ora serrata vs. ora serrata to equator* CB vs. ora serrata to equator* Tumor thickness ⱖ6 mm† Radiation dose ⱖ400 Gy‡ to outer sclera
Cases Controls (n ⴝ 73), (n ⴝ 73), n (%) n (%) P Value
10 (14) 52 (71) 57 (78) 19 (26)
2 (3) 27 (37) 34 (47) 9 (12)
HR
95% CI
⬍0.0001 14.36 (3.99–51.70) 0.0001 9.83 (3.10–31.16) 0.0001 1.21 (1.09–1.34) 0.0455 1.49 (1.09–2.03)
CB ⫽ ciliary body; CI ⫽ confidence interval; HR ⫽ hazard ratio. *Reference category. † Per 1-mm increase. ‡ Per 10-Gy increase.
ciliary body location of anterior tumor margin (71% vs. 37%; P ⬍ 0.0001), increasing tumor thickness (8 vs. 6 mm; P ⬍ 0.0001), larger tumor base (13 vs. 11 mm; P ⬍ 0.0001) with decreasing proximity to optic disc (11 vs. 16 mm; P ⬍ 0.0001) and foveola (11 vs. 17 mm; P ⬍ 0.0001), and associated subretinal fluid (51% vs. 11%; P ⬍ 0.0001). The plaque radiotherapy parameters are listed in Table 3 (available at http://aaojournal.org). Comparison of cases versus controls revealed larger plaque size (17 vs. 15 mm; P ⫽ 0.0003); higher radiation dose to the tumor base (360 Gy vs. 313 cGy; P ⫽ 0.0023), optic disc (25 Gy vs. 17 Gy; P ⫽ 0.0127), and foveola (24 Gy vs. 15 Gy; P ⫽ 0.0015); and higher incidence of postoperative inflammation (11% vs. 0%; P ⫽ 0.0064) and radiation maculopathy (33% vs. 5%; P ⬍ 0.0001) in cases. The univariate analysis of factors predicting scleral necrosis after plaque radiotherapy are listed in Table 4 (available at http:// aaojournal.org). The multivariate factors included ciliary body (P ⫽ 0.0001) and pars plana to ora serrata (P ⬍ 0.0001) locations of anterior tumor margin, tumor thickness ⱖ6 mm (P ⫽ 0.0001), and radiation dose ⱖ400 Gy to the outer sclera (P ⫽ 0.0455) (Table 5). The features and treatment of plaque radiotherapy induced scleral necrosis are listed in Table 6. None of the cases developed corneal necrosis or severe corneal degeneration. On the basis of tumor thickness, scleral necrosis occurred in ⬍1% of patients (3/1140) with tumors ⬍3 mm in thickness, 1% of patients (33/ 3155) with tumors 3 to 8 mm in thickness, and 5% of patients (37/762) with tumors ⬎8 mm in thickness. On the basis of tumor location, scleral necrosis developed after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in ⬍1% of patients (6/4731). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1–15 mm), which represented 29% of mean tumor base (median, 24%; range, 6%–100%) and 22% of mean plaque size (median, 19%; range, 5%–75%). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23; range, 4 –126 months). Scleral necrosis became evident within 1 year of treatment with plaque radiotherapy in 30% of patients (22/73), within 2 years in 55% of patients (40/73), within 5 years in 85% of patients (62/73), within 10 years in 99% of patients (72/73), and within 15 years in 100% of patients (73/73). Scleral necrosis remained stable in 48% of patients (35/73), increased in size or severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) (Fig 2). Treatment of radiotherapy-induced scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), or enucleation in 5% of patients (4/73). One patient developed endo-
phthalmitis after scleral patch graft required enucleation. Three eyes under observation for stable scleral necrosis were subsequently enucleated secondary to neovascular glaucoma in a blind painful eye.
Discussion Plaque radiotherapy for uveal melanoma generally requires a dose of 80 to 100 Gy of 125I to the tumor apex and 350 to 400 Gy to the tumor base.13 According to the American Brachytherapy Society, a prescription dose of 85 Gy to the tumor apex of uveal melanoma at a dose rate of 0.60 to 1.05 Gy/hour should be delivered over 3 to 7 consecutive days.31 This often results in incidental irradiation of surrounding normal structures, resulting in anticipated radiation side effects. The gradient in radiosensitivity of the ocular structures varies depending on the tissue. The lens is the most radiosensitive structure and shows clinically visible damage with 0.5 Gy within 2 to 3 years, followed by cornea (30 –50 Gy), conjunctiva (55–75 Gy), lacrimal system (50 – 65 Gy), retina (50 Gy), optic nerve (55 Gy), and sclera (15–100 Gy).32–34 Thus, the sclera is considered one of the most tolerant ocular tissues for radiotherapy. Scleral necrosis is an uncommon radiation complication because of the radioresistant nature of this avascular, hypocellular, relatively inactive tissue.35 The incidence of scleral necrosis has ranged from 0% to 33% in various studies.30,35– 40 In our study, only 1% of eyes (73/5057) treated with plaque radiotherapy for uveal melanoma developed scleral necrosis over a mean follow-up period of approximately 7 years. Scleral necrosis after plaque radiotherapy can occur as the result of several mechanisms, including a direct necrotizing effect of radiation on sclera, an indirect effect secondary to local ischemic inflammation related to muscle disinsertion, inflammation related to tumor necrosis, regression of tumor with inapparent scleral invasion, or an occult systemic autoimmune phenomenom.38,39,41,42 In our study, no patients had a history of autoimmune disease and muscle disinsertion was not a significant factor compared with controls. There was clinical evidence of an avascular area in 5 cases before the onset of scleral necrosis, and 3 tumors exhibited extensive tumor necrosis on histopathol-
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Ophthalmology Volume 120, Number 5, May 2013 Table 6. Features of Scleral Necrosis (n ⫽ 73) Features At onset of scleral necrosis Severity of scleral necrosis Mild to moderate (⬍50% scleral thinning) Severe (⬎50% scleral thinning with visualization of sclera but covered by Tenon’s fascia or conjunctiva) Scleral perforation with globe hypotony Largest basal dimension of scleral necrosis (mm); mean (median, range) Proximity to limbus (mm); mean (median, range) Percentage of scleral necrosis compared with tumor base (%); mean (median, range) Percentage of scleral necrosis compared with plaque size (%); mean (median, range) Scleral necrosis at the site of muscle insertion Yes No Percentage of reduction of tumor thickness at onset of scleral necrosis (%); mean (median, range) Features of scleral necrosis at last visit Largest basal dimension of scleral necrosis (mm); mean (median, range) Percentage of scleral necrosis compared with tumor base (%); mean (median, range) Percentage of scleral necrosis compared with plaque size (%); mean (median, range) Percentage of reduction of tumor thickness at last visit (%); mean (median, range) Status of scleral necrosis at last visit Progression Increase in size/severity of scleral necrosis Progression to scleral perforation Stable Time interval (mos); mean (median, range) From radiotherapy to onset of scleral necrosis From radiotherapy to severe scleral necrosis From radiotherapy to scleral perforation From onset to severe scleral necrosis From onset to scleral perforation Treatment of scleral necrosisⴱ Observation Scleral patch graft Enucleation
n (%)
32 (44) 41 (56) 0 (0) 4 (3, 1–15) 3 (3, 0–8) 29 (24, 6–100) 22 (19, 5–75)
18 (25) 55 (75) 42 (44, 6–83)
5 (4, 1–15) 40 (33, 7–125) 30 (27, 5–83) 53 (53, 7–88)
38 (52) 35 (48) 3 (4) 35 (48) 32 (23, 4–126) 38 (36, 4–130) 16 (12, 5–30) 12 (11, 1–54) 2 (3, 1–3) 59 (81) 10 (14) 4 (5)
*One patient underwent 2 treatment modalities, scleral patch graft and subsequent enucleation, because of patch graft failure.
ogy, favoring a direct ischemic or inflammatory effect on the sclera or secondary to tumor-related necrosis. There was no evidence of scleral involvement of melanoma in 8 enucleated eyes. Radiation-induced focal scleral necrosis was first reported by Jones and Reese36 in 3 cases after application of concentrated localized gamma or beta radiation (15 Gy in 1 case and 100 Gy in 2 cases) over the sclera or limbus for the treatment of ocular surface squamous cell carcinomas. Subsequently, there have been reports of scleral necrosis after 60 Co, 192Ir, 106Ru, 198Au, 125I, and proton beam radiotherapy for uveal melanoma.35,37– 40 In our study, scleral necrosis occurred with the use of 60Co, 106Ru, and 125I plaque radiotherapy. There was no statistical significance among the 60Co, 125I, and 106Ru plaques. 60Co and 192Ir have higher
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energy gamma emission, require thicker shielding for radiation protection, and deliver large radiation doses to surrounding normal ocular structures. The incidence of scleral necrosis with 60Co plaque radiotherapy ranges from 2% to 9%.10,43 125I and 103Pd are low-energy gamma emitters, are easier to shield, and reduce the dose to the surrounding normal ocular structures. The incidence of scleral necrosis after 125I plaque radiotherapy for uveal melanoma ranges from 0% to 11%.37,38 106Ru is a beta emitter and has a rapid dose fall-off. 106Ru provides excellent focal radiotherapy with minimal dose to surrounding ocular structures, but requires a higher scleral dose to achieve the same prescription apex dose compared with 125I plaque applicators. Furthermore, 106Ru can sufficiently treat tumors up to 5 mm in thickness, but poor depth penetration disallows treatment of thicker tumors.31 Scleral necrosis after 106Ru plaque radiotherapy ranges from 0% to 9%.11,44 198Au is a beta and gamma-ray emitter, with a low-energy gamma-ray emitting component. The incidence of scleral necrosis with 198Au is 12%.40 The comparative incidence of scleral necrosis with each radionuclide is not clearly understood. Most studies have implied that a higher radiation dose of approximately 15 to 100 Gy is the most important factor for scleral necrosis.35,36 However, animal studies of rabbit eyes by Kunz and Lommatzsch45 revealed early disruption of the scleral lamellae at even a low dose of 1 Gy and loss of scleral cells at 5 Gy. In our study, the average radiation dose to the outer sclera was 372 Gy in cases versus 328 Gy in controls (P ⫽ 0.0551), suggesting slightly higher radiation dose to the sclera in the cases group. In a study of scleral necrosis in 15 eyes, Chaudhry et al40 found the mean time interval between plaque radiotherapy and scleral necrosis at 15 months (range, 4 – 60 months). Radin et al39 studied 23 cases of scleral necrosis and documented the mean time to onset of scleral necrosis at 70 months (range, 11–257 months). In our study, the mean time to detection of scleral necrosis was 32 months (range, 4 –126 months). Most cases of scleral necrosis (85%) developed within the first 5 years of plaque radiotherapy. In a study of 136 patients with plaque-irradiated ciliary body melanoma, Gündüz et al38 found that 15 patients (11%) developed scleral necrosis. Factors predictive of scleral necrosis in that series included intraocular pressure ⬎15 mmHg and tumor thickness ⬎7 mm. Chaudhry et al40 found tumor thickness ⬎6 mm, ciliary body involvement, and intraocular pressure ⬎21 mmHg as the risk factors for scleral necrosis in their series. In our study, factors for scleral necrosis included peripheral tumor location (ciliary body [P ⫽ 0.0001], pars plana to ora serrata [P ⬍ 0.0001]), tumor thickness ⱖ6 mm (P ⫽ 0.0001), and radiation dose ⱖ400 Gy to the sclera (P ⫽ 0.0455). In most patients (92%), the scleral necrosis resulted after radiotherapy of ciliary body melanoma. This could be related to generally thicker tumors involving the ciliary body necessitating more intense scleral radiation dose and partly related to the more apparent identification of scleral necrosis because of the anterior location. There were 3 cases of scleral necrosis after radiotherapy to macular melanoma, identified on B-scan ultrasonography. There is a possibility that scleral necrosis
Kaliki et al 䡠 Post-Plaque Scleral Necrosis
Figure 2. Evolution of scleral necrosis after plaque radiotherapy of uveal melanoma. A, A 53-year-old male patient with an area of avascularity 2 months after plaque radiotherapy subsequently developed scleral necrosis (B) adjacent to the avascular area 24 months after plaque radiotherapy. C, A 40-year-old female patient developed scleral necrosis 47 months after plaque radiotherapy (D), which remained stable for 48 months. E, A 75-year-old male patient with mild scleral necrosis 22 months after plaque radiotherapy (F) with progression to severe scleral necrosis at 29 months.
might remain undetected in eyes with posterior tumors due to unapparent findings. The main challenges of scleral necrosis rest in its recognition, differentiation from tumor recurrence, and management. The key features to differentiation from recurrence encompass the identification of scleral thinning and blue discoloration to Tenon’s fascia, along with overall reduction in intraocular melanoma thickness over time. Ultrasound biomicroscopy or anterior segment optical coherence tomography can confirm scleral thinning. In contrast, melanoma recurrence after plaque radiotherapy generally occurs within the globe with increase in basal diameter or thickness and, if extensive, can extend through the emissarial canals and form a blue sub-Tenon’s fascia nodule with intact, typically normal thickness sclera. Scleral necrosis in patients with regressed tumor is associated with increased transillumination, whereas tumor recurrence results in tumor shadow corresponding to the tumor size. There are instances in which scleral thinning after radiotherapy is combined with tumor recurrence. According to Shields et
al,46 melanoma recurrence is uncommon, found in approximately 2% of eyes after plaque radiotherapy. In most patients, scleral necrosis evolves through a progression from a small spot of scleral thinning to a mean 4-mm diameter of thinning over 4 to 8 months, but it typically remains stable thereafter with observation and without full-thickness perforation. In a study of 23 cases by Radin et al,39 scleral necrosis was stable in 74% of patients (n ⫽ 17), partial regression was observed in 13% of patients (n ⫽ 3), and progression to pre-perforation was observed in 9% of patients (n ⫽ 2). In our study, scleral necrosis was stable in 48% of patients, increased in size or severity in 48% of patients, and progressed to scleral perforation in 4% of patients. Scleral necrosis is not usually an eye-threatening complication, unless perforation occurs. Depending on the severity of scleral necrosis, various management options include observation; artificial lubrication with tears, gels, or ointments; tissue glue; conjunctival graft/flap; amniotic membrane transplantation; scleral patch graft; dermal patch graft; vital Tenon’s fascia transposition; hyperbaric oxygen
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Ophthalmology Volume 120, Number 5, May 2013 therapy; and enucleation.47– 49 All patients are advised to avoid rubbing the eye. In this study, 81% of patients did not require further treatment. Scleral patch graft was performed in 10 patients. Progressive scleral necrosis can ensue despite scleral patch graft, so our current approach is observation and lubrication. In this study, the complication of radiation-induced scleral necrosis was associated with a higher incidence of other radiation complications, such as cataract, retinopathy, and maculopathy. This could be a result of the higher radiation dose because eyes with scleral necrosis tended to have thicker tumors. Furthermore, the thickness factor could have contributed to a higher rate of metastasis and death because each millimeter increase in tumor thickness increases the risk of systemic metastasis by approximately 5%.50 In conclusion, clinically evident scleral necrosis after plaque radiotherapy of uveal melanoma was found in 1% of cases. Risk factors include ciliary body and pars plana to ora serrata location of anterior tumor margin, tumor thickness ⱖ6 mm, and radiation dose ⱖ400 Gy to the outer sclera. Exposure of irradiated sclera can contribute to scleral necrosis and perforation. Postoperatively, irradiated sclera should be covered by conjunctiva in all cases. Scleral necrosis should be differentiated from tumor recurrence with extraocular extension, and unnecessary enucleation can be avoided. Scleral necrosis can be followed conservatively with observation and lubrication in the majority of cases. Acknowledgment. Statistical analysis for the study was provided by Rishita Nutheti, PhD, Hyderabad, India.
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Footnotes and Financial Disclosures Originally received: August 3, 2012. Final revision: October 16, 2012. Accepted: October 16, 2012. Available online: January 21, 2013.
Manuscript no. 2012-1176.
1
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Ocular Oncology Service, L. V. Prasad Eye Institute, Hyderabad, India.
3
Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
4
Department of Radiation Oncology, Drexel University, College of Medicine, Philadelphia, Pennsylvania.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Support provided by a donation from Michael, Bruce, and Ellen Ratner, New York, New York (J.A.S., C.L.S.), and Eye Tumor Research Foundation, Philadelphia, Pennsylvania (C.L.S., J.A.S.). Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail carol.shields@ shieldsoncology.com.
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