Discussion
Despite being the rarest form of uveal melanoma, iris melanoma is a disease with which every ophthalmologist will be confronted at some point in his practice. This underlines the necessity of proper diagnosis and treatment, as the tumour can cause local and systemic complications or even death if left untreated.13
Using the AJCC classification system allows a more anatomically accurate description of iris melanomas and might help in prognosticating metastatic risk in the future.14 Unfortunately this classification system is not entirely appropriate when used on its own in determining the best therapeutic option. This is obvious in our series, since different patients with the same T category might require different irradiation strategies. In our series, 2 patients with T1b tumours underwent sectorial irradiation whereas another patient with the same T1b category had to undergo irradiation of the whole anterior segment to treat the entire tumour adequately. Future studies might be necessary to develop a revised classification system that incorporates treatment strategies.
PBRT is a game-changer in the treatment of tumours of the anterior uvea, due to the absence of invasiveness, which is leading progressively more physicians to consider it as the primary therapeutic option, especially in the case of diffuse iris melanoma.4–8 12 14–17 It achieves a high level of local tumour control and eye preservation rate, as no surgical tumour manipulation takes place, which could, at least theoretically, lead to iatrogenic tumour spread.14 The physical properties of protons (Bragg peak) allow for selective tumour treatment with minimal collateral damage to the surrounding tissues, that no other treatment modality offers.10 Because of that, critical structures for vision, such as the macula and optic nerve, are spared from irradiation, as they receive 0% of the irradiation dose. This explains why in our series no difference was found in BCVA before and after treatment. The usage of tantalum marker clips further increases the accuracy of PBRT, as it helps radiotherapists to define the target volume better. Tantalum marker placement is optional in the case of planned whole anterior segment irradiation, since anatomic landmarks such as the limbus and visual axis can be used to define target volume and eye position. In our series, all patients planned to receive sectorial PBRT underwent tantalum marker surgery. In the case of whole anterior segment irradiation, the decision on tantalum marker surgery was taken in a case per case manner, depending on the requirements of the radiotherapists and the ability to accurately model the eye in the irradiation planning software.
In our series, primary local tumour control could be achieved in 92% during a mean follow-up of 25 months, which is in coordinance with data from the literature.4 5 12 15 18 PBRT allows homogenous dosage distribution across the entire target volume, which further contributes to the extremely high local tumour control rate.10 There was only one case of local tumour recurrence due to tumour development in the non-irradiated area (out-of-field recurrence). This underlines the significance of thorough clinical examination to identify possible tumour seeding on the iris surface or the angle and adequate irradiation planning to cover all areas of tumour occurrence. After local recurrence, secondary PBRT of the whole anterior segment can be indicated and it is a beneficial therapeutic option, nevertheless, it may significantly increase complication rate.
Forty-six per cent of our patients showed no complications during follow-up. Irradiation of the entire anterior segment has been shown to be associated with a significant higher rate of complications.15 This finding could also be shown with our data although due to the low number of cases no statistical significance could be reached. Furthermore, this result could be the reason for the more than twice as long follow-up time in the whole anterior segment irradiation group compared with the sectorial irradiation group.
Glaucoma is possibly the most significant vision-threatening complication after PBRT for iris melanoma. Glaucoma at presentation or after PBRT is more common in tumours that are spreading more than three clock hours in size (previously called ‘diffuse’ melanomas) or that are extending into the angle and ciliary body in a circular manner (previously called ‘ring’ melanomas),7 due to the more extended angle infiltration and the scarring that occurs after irradiation of the complete anterior segment. In our series, patients that developed glaucoma had more advanced disease: 2 had stage T1c, 1 had T2c and 1 had T4a. In the case of uncontrolled IOP, surgery or cyclodestructive procedures are necessary. There is some concern about tumour seeding after filtrating procedures but taking into consideration the fact that excellent local control rates are achieved with PBRT, this risk seems not significant. Larger series with tubes have not shown any tube-related metastasis.18 19 Filtering procedures in the perilimbal conjunctiva and sclera, such as trabeculectomy, have the disadvantage that they involve previously irradiated and surgically manipulated (in the case of tantalum clip marking) tissue. This significantly increases the possibility of scarring and surgical failure. In our series, all patients with glaucoma (either pre-existing or after PBRT) required glaucoma shunt surgery or cyclodestruction to control IOP.
Postoperative hypotony is a known side effect after trabeculectomy and is more common after PBRT.20 Despite the sclera being relatively radiation tolerant, irradiated tissue on and around the tumour will be altered in a dose-dependent manner. Inflammation of the perilimbal conjunctiva and thinning of the sclera after PBRT, which can affect wound healing, has been reported.18 The degree to which PBRT affects wound healing after trabeculectomy is still unknown.21
Cataract development is common after PBRT for iris melanoma, especially in the case of complete anterior segment irradiation, since part or all the lens lies within the target volume. A retrospective study from Willerding et al showed that radiation cataract occurs over time in practically all patients after PBRT of the entire anterior segment.7
Madarosis is an uncommon complication of PBRT, as effort is being made to keep the eyelids outside the irradiation plane. In our series, the patient who developed madarosis had closely spaced palpebral fissures, which made it impossible to completely spare the eyelid margin.
Eye retention rate has been reported to be 80%–100% in different studies.4 5 12 15 16 In our series, eye retention rate was 100% at the mean follow-up time of 25 months. Despite the differences in the number of eyes, the initial eye status and the different tumour characteristics in the various studies, in most cases eye retention rates are excellent and in coordinance with our findings, which underlines the safety of PBRT for iris melanomas.
As already mentioned, there are also other therapy modalities apart from PBRT. Surgical resection was, and still is in the absence of other modalities, a valuable approach to treat localised iris or iridociliary uveal melanoma. Common postoperative complications after iridectomy, anterior irido-trabeculo-cyclectomy and Naumann block excision technique mentioned in the literature include hyphaema (21%), cataract (9%–32%), photophobia (85%), wound leakage (6%), vitreous haemorrhages (2%–35%), vitreous loss (2%), enucleation (2%–6%) and recurrence (3%–8%) with a median follow-up time up to 104 months.17 22–25
In comparison to surgical techniques, the patients treated with PBRT in our study had no photophobia, hyphaema, wound leakage, vitreous haemorrhage, vitreous loss and no patient had to be enucleated.
Local tumour relapse after surgical resection is comparable to that of radiation modalities.24
Metastatic disease is reported in up to 3% of patients at 5 years, 5% at 10 years, and 10% at 20 years of iris melanoma cases, independent of the method of management (resection, radiotherapy or enucleation).13 However, no patient of our study showed metastatic disease during follow-up after PBRT. The short follow-up time could be the reason for the low percentage of relapses and metastatic events which can occur very late in this setting as described above. In an analysis of 317 consecutive iris melanoma patients, the main factors found to be predictive for metastasis included extraocular extension and elevated IOP.24 In a previous report of 169 consecutive patients, Shields et al found increased age at diagnosis, elevated IOP, angle invasion, extraocular extension and previous surgical intervention before referral to be predictive for metastasis.13 In our analysis, only one patient had extrascleral extension (T4a) and glaucoma, but in a follow-up time of 5 years, there was no metastatic disease.
In conclusion, PBRT is a safe, effective and vision preserving therapeutic modality for the treatment of iris melanoma. Our study underlines the clinical significance of PBRT in iris melanoma treatment as the visual outcome and the eye retention rate is excellent and complications are manageable.