Corresponding Author: Christopher Seungkyu Lee, MD, PhD. Institute of Vision Research, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Uveal melanoma (UM) is the most common primary intraocular malignancy in adults although it is rare. Its incidence varies across ethnicities and regions, ranging from <1 to >9 per million population per year [1]. In the United States, the mean age-adjusted incidence of UM is 5.1 per million; the majority of cases (97.8%) affect the white population [2]. The incidence is relatively low in Asian countries, such as South Korea (0.4-1.1 per million per year) [3,4] and Japan (0.6 per million per year) [5].
The coexistence of a full-thickness macular hole (MH) and UM has been rarely reported. Uffer and Zografos [6] reported the first case of MH coexisting with UM and rhegmatogenous retinal detachment in 1997. A PubMed search revealed 11 more cases of UM with MH detected at the same time or that developed after tumor treatment (radiotherapy and/or transpupillary thermotherapy [TTT] or local resection) [6-14]. This suggests that the development of a tumor or tumor regression after treatment is associated with the development of MH. The present study analyzed previously reported cases of UM coexistent with MH and five new cases encountered at our institution.
Materials and Methods
Ethics statement
This retrospective observational case series was approved by the Institutional Review Board of Severance Hospital, with a waiver of informed consent (No. 4-2021-1085). The study was conducted in accordance with the tenets of the Declaration of Helsinki.
Study design
For the retrospective case series, the medical records of consecutive patients who were diagnosed with UM at our institution between June 1997 and March 2021 were reviewed. Of the 505 patients diagnosed with UM, 5 (1.0%) were diagnosed with MH. The clinical data of the five patients, including age, sex, ocular history, best-corrected visual acuities (BCVAs), tumor dimensions (measured by A- and B-scan ultrasonography), tumor location (macular, juxtapapillary, from arcade to equator, or anterior to equator), tumor treatment method, duration from tumor treatment to MH diagnosis, MH management, MH treatment outcome, follow-up duration, tumor recurrence, and distant metastasis, were retrieved. Every patient underwent a comprehensive ophthalmic examination, including fundus photography and spectral-domain optical coherence tomography (SD-OCT).
For the data collection of previously reported cases, reports of MH coexisting with UM published before December 2022 were retrieved from the PubMed search using the keyword “macular hole and melanoma.” Additional articles were identified through a reference search.
Data from the present and previous cases were pooled and analyzed for the clinical features of MH coexisting with UM. Patients were categorized into two groups according to the order of MH diagnosis and tumor treatment. Group 1 included patients who presented with MH simultaneously or before UM treatment. Group 2 comprised patients who developed MH after UM treatment (TTT, radioactive plaque brachytherapy, and external beam radiotherapy). The demographic and clinical characteristics of the patients in the two groups were compared.
Statistical analysis
Results are presented as mean or median with standard deviation or interquartile range for quantitative variables and with absolute and relative frequencies for qualitative variables. The Snellen chart BCVA was converted to the logarithm of the minimum angle of resolution (logMAR). Fisher exact test was performed for discontinuous variables, and Mann-Whitney U-test was used for continuous variables. The Wilcoxon signed rank test was used to analyze the differences in VAs and tumor sizes before and after treatment. Spearman rank correlation analysis was performed to evaluate the association between tumor size and MH diameter. All data were analyzed using IBM SPSS ver. 25 (IBM Corp), and the level of statistical significance was set at the two-sided 5% level.
Results
Demographic and clinical characteristics
The present retrospective observational case series involved 12 patients from 10 previous case reports and series [6-15] and 5 new patients from our institution (Table 1). Table 2 presents the results of the combined analysis of the data from the present and previous cases. The mean age of the 17 included patients (5 men, 11 women, 1 not reported) at the time of MH diagnosis was 63.9 ± 14.4 years (range, 42-84 years). The tumor location was within the macular or juxtapapillary area in six patients (35.3%), from the arcade to the equator in seven (41.2%), within the area anterior to the equator in two (11.8%), and unknown in two patients (11.8%). The mean largest basal tumor dimension and height at the initial presentation were 9.6 mm (median, 9 mm; range, 5.9-16.0 mm) and 5.6 mm (median, 5 mm; range, 2.3-13.0 mm), respectively. For UM management, nine patients were treated with plaque brachytherapy (six plaque brachytherapy only, two with adjunctive TTT, one with vitrectomy and silicone oil tamponade). Three patients received external beam radiotherapy, and two patients were treated with TTT monotherapy. In one patient, MH was detected in the enucleated specimen.
Nine patients underwent MH repair surgery, and MH closure was achieved in seven eyes following surgery; closure was not achieved in one eye [13], and postoperative data were unavailable for another [7]. The MH remained closed for a mean follow-up of 12.2 months (n = 5; median, 12 months; range, 1-24 months) with no reported cases of intraocular or extraocular tumor dissemination. Overall, the mean VA showed a tendency of improvement after surgery; the initial and final mean logMAR VAs were 1.34 ± 0.87 and 0.72 ± 0.49, respectively (p = 0.285). Of the six eyes that did not undergo MH surgery, MH remained stable in five (patients 2, 4, 5, 13, and 14) during a mean follow- up duration of 23.6 months (median, 19 months; range, 5-52 months).
Local recurrence or distant metastasis of UM accompanying MH was not identified, except in a single patient (patient 17) with systemic metastasis to the liver. None of the five patients in our institute developed intraocular tumor dissemination or systemic metastasis during follow-up with a mean duration of 22.4 months (range, 5-52 months). Furthermore, surgery-related intraocular or extraocular tumor dissemination was not observed.
There were 5 patients in group 1 (patients 1-5), 10 patients in group 2 (patients 6-15), and 2 patients who were not included in either group due to lack of data (patients 16 and 17). There were no differences between groups 1 and 2 related to patient demographic and clinical data, including tumor size, VA at the time of MH diagnosis, and follow-up duration after MH diagnosis (Table 3).
In group 2, the duration from tumor treatment to MH diagnosis ranged from 3 to 56 months (median, 8.5 months; n = 8). The mean tumor height at the time of MH diagnosis was significantly lower than the mean height before treatment (3.59 ± 1.58 mm vs. 5.33 ± 2.61 mm, p = 0.043).
The analysis conducted on the subset of cases with available data on tumor size and MH diameter (seven eyes) revealed no significant correlation between the largest basal diameter of the tumor and the MH size (p = 0.589), or between tumor height and the MH size (p = 0.645). This suggests that tumor size, either in terms of basal diameter or height, does not appear to influence the development or size of the MH. However, the analysis was limited by the small sample size, and therefore, further studies with larger cohorts are needed to validate these findings and better understand the potential relationship between tumor size and MH development or size.
Group 1 (simultaneous UM and MH): case 1 (patient 5)
A 74-year-old woman presented with a large choroidal melanoma in her right eye. Her ocular history included cataract surgery 10 years earlier and a failed MH surgery 3 years earlier. There was no history of a choroidal mass in the records obtained from the previous hospital where she underwent MH surgery (Fig. 1A, 1B). At presentation, an elevated pigmented mass in the inferior fundus with surrounding serous retinal detachment was noted with a large, chronic MH (Fig. 1C). Ultrasonography revealed a mushroom-shaped choroidal mass with medium internal reflectivity; the largest basal diameter was 6.50 mm and the maximum tumor height was 9.21 mm. The mass was hypointense on T2-weighted magnetic resonance imaging and showed moderate 18F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography. CyberKnife radiotherapy (total dose to the tumor, 60 Gy) was delivered in four equal fractions.
Group 2 (MH after plaque brachytherapy or external beam irradiation of UM)
1) Case 2 (patient 12)
A 47-year-old woman presented with a mushroom-shaped choroidal melanoma just below the inferior arcade in her left eye with 20/20 vision. Ophthalmic findings of the fellow eye were unremarkable. The height and largest basal diameter of the tumor were 4.99 and 7.50 mm, respectively, and SD-OCT revealed a normal contour of the macula. She underwent ruthenium-106 plaque brachytherapy delivering 85 Gy to the tumor apex and 509.4 Gy to the sclera. One month after brachytherapy, TTT was performed twice at a 3-month interval as an adjunctive treatment. The tumor regressed well and was stable after treatment. Fifty-six months after brachytherapy, her VA decreased to 20/400. Fundus examination and OCT revealed a full-thickness MH (Fig. 1D, 1E). She subsequently underwent pars plana vitrectomy with internal limiting membrane peeling and pneumatic tamponade with 14% perfluoropropane (C3F8). The MH remained closed for 24 months after surgery, and her BCVA was 20/22 at the final visit (Fig. 1F). There has been no tumor recurrence or metastasis 24 months after MH repair.
2) Case 3 (patient 13)
A 42-year-old woman presented with a large mushroom-shaped juxtapapillary choroidal melanoma obscuring the optic disc and macula in her left eye (Fig. 1G). The height and largest basal diameter of the tumor were 9.63 and 11.30 mm, respectively, with a VA of hand motion. Transretinal biopsy (TRB) using a 25-gauge ocutome was performed, and CyberKnife radiotherapy with a total dose of 64 Gy was performed in four equal fractions. The tumor markedly decreased in size, with the largest basal diameter at 7.41 mm and height at 3.38 mm at 7 months after radiotherapy. At 11 months after radiotherapy, MH developed, but the VA persisted at hand motion (Fig. 1H, 1I). Due to the limited potential of visual gain, MH repair surgery was not recommended. Her most recent visit at 31 months after radiotherapy revealed no definite changes in the MH status and VA of hand motion, along with a stable tumor without metastasis.
3) Case 4 (patient 14)
A 65-year-old man presented with a large choroidal melanoma with the largest basal diameter of 10 mm and a height of 7.09 mm associated with mild vitreous hemorrhage in his right eye fundus (Fig. 1J). His ocular history included superior branch retinal vein occlusion treated with sector panretinal photocoagulation 10 years earlier. SD-OCT revealed a relatively normal foveal contour. Ruthenium-106 plaque brachytherapy delivering 53.18 Gy to the tumor apex and 1,062 Gy to the sclera and adjunctive TTT (one session) were performed. After 2 months, the patient underwent pars plana vitrectomy with lensectomy due to a nonclearing vitreous hemorrhage and worsening cataract obscuring fundus details with VA of no light perception. The postoperative VA remained at light perception negative, presumably due to radiation optic neuropathy. Tumor regression was observed approximately 1 year later, but the patient developed exudative retinal detachment with proliferative vitreoretinopathy and underwent additional vitrectomy with retinectomy and silicone oil tamponade. MH was observed under a surgical microscope. After surgery, the retina was attached, but the MH remained open (Fig. 1K, 1L). Because the tumor was stable and there was no vision potential, MH repair surgery was not attempted. For 5 years, there was no tumor recurrence or metastasis.
4) Case 5 (patient 15)
A 46-year-old woman presented with choroidal melanoma just temporally inferior to the macula in her right eye with 20/25 vision (Fig. 1M). The height and largest basal diameter were 3.58 and 6.63 mm, respectively. SD-OCT revealed a lamellar hole with temporal cystoid macular edema. TRB was performed using a 25-gauge ocutome, and ruthenium-106 plaque brachytherapy delivering 92 Gy to the tumor apex and 319 Gy to the sclera was performed. Radiation retinopathy developed at 9 months after radiotherapy with a stable tumor. The patient received two intravitreal injections of bevacizumab (1.25 mg/0.05 mL) at an 8-week interval. At 12 months after radiotherapy, the patient complained of metamorphopsia with the development of MH (Fig. 1N, 1O). Subsequent vitrectomy with internal limiting membrane peeling and pneumatic tamponade with 20% sulfur hexafluoride (SF6) resulted in hole closure (Fig. 1P). No local recurrence or distant metastasis occurred 24 months after brachytherapy and 12 months after MH surgery.
Discussion
There are limited reports in the literature on the diagnosis and management of UM with coexisting MH [7-15]. In this study, we analyzed the data of 5 new and 12 previously reported cases to identify the clinical characteristics and possible mechanisms of MH in eyes with UM. The prevalence of MH in eyes with UM in our cohort was 1.0%, which is higher than the prevalence of idiopathic MH, approximately 0.17% [16]. However, since this study evaluated the proportion of MH among UM patients within a single institution, and the data were not age- or sex-standardized to the general population, direct comparisons with prevalence rates are limited.
Two most relevant systemic risk factors of idiopathic MH include age of ≥65 years and female sex, accounting for 67% to 72% of cases [17-19]. In this study, among UM patients, the mean age at the time of MH diagnosis was 63.9 ± 14.4 years, and the female to male ratio was 2.2:1, similar to those observed in idiopathic MH. Although these two entities may coincidentally occur in the same eye, the observation that MH was found in 1% of eyes among 505 UM patients in this study suggests a potential association between the development of MH and UM. However, since female predilection is not prominent in UM, further studies are needed to investigate the risk of developing MH in female patients with UM. Moreover, UM tends to be larger and more posterior in men than in women [20], which can place more stress on the macular area and might lead to MH development in men rather than women.
Several mechanisms may account for the co-occurrence or development of MH in patients with untreated UM (group 1). The presumed pathogeneses include tangential retinal traction from the enlargement of the tumor, changes secondary to cystoid changes of the macula, or coincidence. Gold et al. [10] hypothesized that the MH may have developed as a result of the combination of tangential retinal traction from an enlarging mass, dehiscence of associated cystic macular changes, and lipid exudation in UM. In our case series, 13 of the 17 UM cases (76.5%) were located posterior to the equator. The proximity of the tumor and the macula may influence the retinal tractional forces as the tumor enlarges. Cystoid macular edema can occur in eyes with UM due to several factors, including the undetermined “toxic” effect of the tumor on the macula [6], increased capillary permeability secondary to inflammation [6,8], and microvascular abnormalities and damage to the external limiting membrane [8]. Foveal cysts may be the initial changes in the foveal structure that predisposes to MH progression [21].
The pathogenesis of MH formation after tumor treatment (group 2) can be explained at several levels. First, MH may occur as a complication of the diagnostic procedures for UM. Transretinal or transscleral biopsy may be performed in UM to confirm the diagnosis or to obtain cytogenetic information. TRB has agreeable complication rates, but MH can occur as a postoperative complication [22]. Two patients (patients 13 and 15) in group 2 underwent TRB using an ocutome, and MH was diagnosed after 13 and 14 months, respectively. In some cases, vitrectomy and silicone oil tamponade were performed before or with radiation therapy in anticipation of the radiation-attenuating effect (patient 8) [9]. Although secondary MH formation after vitrectomy is a rare surgical complication (incidence rate, 0.24%-1.9%) [23], MH occurrence as a complication of vitrectomy cannot be ruled out.
Second, MH may occur as a complication of UM treatment. Radiation maculopathy can occur in 19.6% to 50% of patients after ruthenium-106 plaque [24-26] and in 85% of patients after external beam radiotherapy [27]. Macular cystic changes after radiation maculopathy may result in MH formation. In patient 15 in group 2, MH was diagnosed 3 months after the onset of radiation retinopathy. However, it remains whether the MH resulted from cystic changes related to radiation retinopathy. TTT using an infrared diode 810-nm laser is sometimes used to treat smaller UM or as an adjunctive therapy, which can cause retinal holes or tears if severe retinal atrophy or abnormal vitreoretinal adhesion develops in the laser-ablated area [28,29]. Balestrazzi et al. [11] reported the occurrence of MH and rhegmatogenous retinal detachment 3 months after TTT for choroidal melanoma, although it is uncertain whether MH occurred as a complication of TTT because the treated area was distant from the macula. In group 2, three patients (patients 6, 12, and 14) underwent TTT with or without plaque brachytherapy; however, the treated tumor was distant from the macula in all patients.
Third, MH may develop in association with tumor regression after treatment. The majority of UMs exhibit tumor regression after radiotherapy, usually during the first 2 years or so, before becoming stable [30]. In group 2 of this study, all patients with available data showed significant tumor regression after treatment (radioactive plaque brachytherapy or external beam radiotherapy and/or TTT) (p = 0.043). Significant tumor regression may induce changes in vitreoretinal traction forces, leading to MH formation. Six tumors (46.2%) were located in the juxtapapillary area close to the macula or macular area.
Moreover, MH formation may be associated with reduced choroidal thickness after tumor treatment. Lee et al. [31] reported that subfoveal choroidal thickness significantly decreased after ruthenium-106 brachytherapy in choroidal melanoma. The thinner choroid is implicated in the pathogenesis of idiopathic MH [32,33]. Thus, reduced choroidal thickness in treated UM may be associated with posttreatment MH formation, although the exact mechanism has yet to be determined.
The safety and effectiveness of the surgical repair of MH and the optimal duration of surgery remain to be elucidated. In this review, vitrectomy was performed in nine cases (52.9%), including seven previous cases [7,9-14] and two cases from our institute. The anatomical outcomes were favorable, with all patients with available data achieving successful hole closure after surgery. Among the six patients with available data, the mean VA showed a tendency to improve after surgery. Vitrectomy may rarely lead to intraocular or extrascleral tumor dissemination in UM [7], and MH surgery in stable tumors appears to be safe. No patient in the present study developed local tumor progression or extension after MH surgery. However, the benefits and risks of surgical management of MH should be carefully evaluated for patients with minimal visual potential.
This study has several limitations. First, its retrospective design and small sample size limit the statistical significance of our findings. Second, the proportion of MH among UM patients was derived from a single institution and was not standardized by age or sex to the general population, limiting direct comparisons with the prevalence of idiopathic MH. Third, the small sample size and the lack of comprehensive data on variables that could potentially influence MH development prevented statistical analyses aimed at identifying risk factors. These limitations underscore the need for future studies with larger cohorts and more detailed datasets to better understand MH development and to identify associated risk factors in the context of UM.
In conclusion, MH was observed in approximately 1% of UM patients both before and after tumor treatment, showing a higher prevalence compared to idiopathic MH in the general population. MH surgery appears to be safe and effective in selected patients. Therefore, in cases with stable tumors and visual potential, MH surgery could be carefully considered.
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