Management of Choroidal Melanoma and Ciliary Body Melanoma
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In recent years, there have been advancements in the management of posterior uveal melanoma of the cilary body and choroidal region. 1-11 Several options are now available. The selected management depends on factors like tumor size, location, and activity as well as the status of the opposite eye and the age, general health, and psychological status of the patient. Each patient should have a detailed ophthalmic evaluation and the size and extent of the tumor carefully documented with accurate drawings and photography. The known risk factors for growth and metastasis should be considered and the patient should be counseled as to the therapeutic options. 12
The management of uveal melanoma includes many options such as observation, laser photocoagulation, transpupillary thermotherapy, plaque radiotherapy, charged particle radiotherapy, local resection, enucleation, exenteration, immunotherapy, chemotherapy, or combinations of these therapies.
Historically, enucleation of the affected eye was once considered to be the only appropriate management for the patient with a posterior uveal melanoma. Several years ago, however, some authorities challenged the effectiveness of enucleation for preventing metastatic disease and even proposed that enucleation may somehow promote or accelerate metastasis. 5,6 The validity of these arguments was challenged by others, who believed that early enucleation offered the patient the best chance of cure. 7,8 This controversy over enucleation was responsible for initiating a trend away from enucleation and the increasing use of more conservative therapeutic methods. 9-11
Depending upon several clinical factors, management options today include observation, photocoagulation, TTT, radiotherapy, local resection, enucleation and various combinations of these methods. The two most frequently employed treatment methods today are enucleation and plaque radiotherapy. The Collaborative Ocular Melanoma Study (COMS) was organized and funded in 1985 to address several issues related to management of choroidal melanoma. 13 Much information has come from the COMS regarding demographics, treatments, and outcomes. Further specific data on the COMS is listed below under surgical management. More recently, choroidal melanoma has been detected at earlier stages using published risk factors designed to allow detection as early as possible. It has been shown that melanoma prognosis depends on many factors, and tumor thickness is one of the most important. Every millimeter of increasing thickness promotes and increasing 5% risk for metastasis by 10 years follow up. 14 Early intervention with therapy is advised for posterior uveal melanoma.
Currently there is no effective oral or intravenous medical therapy for ciliary body or choroidal melanoma. There are tumors that are amenable to therapy in the office setting without operating room intervention. These include periodic observation, laser photocoagulation, transpupilllary thermotherapy, and photodynamic therapy.
Approximately 6% of the Caucasian population manifests a choroidal nevus.15 Choroidal nevi are managed by periodic observation. Choroidal nevi often present with overlying retinal pigment epithelial atrophy and drusen signifying a chronic condition. It is estimated that 1 in 5000 to 1 in 8800 choroidal nevi evolve into choroidal melanoma.16,17
Most choroidal melanomas are greater than 3 mm in thickness. There remains a gray zone of borderline, possibly at-risk tumors measuring 3 mm or less in thickness. Controversy regarding whether these small lesions represent small melanoma versus nevi is a concern. Risk factors have been identified in a study of 1287 “borderline tumors” that were found predictive of growth of these small tumors into melanoma. 18-21 These risk factors can be remembered using the mnemonic TFSOM, indicating To Find Small Ocular Melanoma. The letters in this mnemonic represent T (thickness >2 mm), F (fluid subretinal), S (symptoms of flashes or floaters), O (orange pigment), and M (margin touching optic disc). (Table 1) Choroidal melanocytic tumors that display no factors have 3% chance for growth at 5 years and most likely represent choroidal nevi. Tumors that display one factor have a 38% chance for growth and those with two or more factors show growth in over 50% of cases at 5 years. Individual and combined impact of these risk factors is listed in Table 2.
A later analysis of choroidal nevus transformation into melanoma in 2514 cases revealed similar risk factors but 3 new factors were identified including ultrasound hollowness, absence of drusen, and absence of surrounding halo. 22 This updated risk factor list is remembered by the mnemonic To Find Small Ocular Melanoma Using Helpful Hints Daily (TFSOMUHHD), similar to the last mnemonic but the addition of UH for ultrasound hollow, D for drusent absent, and H for halo absent. (Table 3)
Documented growth of a melanocytic choroidal tumor is suggestive that the lesion is a choroidal melanoma. Growth over a short time (< 2years) is strongly suggestive of melanoma whereas growth over a long period (>10 years) could suggest a nevus. 23 Since documented growth may be associated with worse systemic prognosis, some patients with small tumors that show three or more risk factors are treated promptly, without waiting for documentation of growth. 18-22 Increasing tumor size both in base and thickness lead to increased risk for metastasis. (Table 4) 14 Based on the few patients with medium size choroidal melanoma who refuse treatment and are followed, natural history studies have found that there is greater mortality and higher risk of death.24
Photocoagulation is an acceptable method for treating selected small choroidal melanomas. 25,26 It was originally performed with xenon photocoagulation and later with argon laser photocoagulation. Studies have shown that xenon achieved better tumor control but argon was associated with fewer complications. 26 Low energy long-exposure laser therapy has been advocated by some authorities. 25 Recently TTT has largely replaced argon laser for treating selected small melanomas, paarticularly those that are less than 3 mm in thickness and located more than 3 mm from the foveola.
TTT is a recently popularized method of treating selected small choroidal melanomas.27-30 With this technique, infrared radiation, using a modified diode laser system, delivers heat to the tumor, causing tumor necrosis. TTT is typically delivered in 3 sessions and, at completion, leaves an atrophic chorioretinal scar at the site of the previous tumor. Tumor control is found in over 90% of properly selected cases. 30 The tumors most suitable for TTT are small, heavily pigmented melanoma less than 3 mm in thickness, with minimal or no suberetinal fluid, and located in the extramacular region, not touching the optic disc. Tumors at the optic disc show greater recurrence and are best managed with plaque radiotherapy combined with thermotherapy. Choroidal melanoma treated with TTT should be followed long-term as delayed recurrence, even with extrascleral extension, can occur. Currently, TTT is used most frequently as a supplement to plaque radiotherapy. 30-34 A alternative technique using a transscleral thermotherapy probe has been found effective for choroidal melanoma and intrascleral tumor.35
The popularity of TTT for small choroidal melanoma has waxed and waned as tumor control and complications were better understood. In 2002, Shields and associates analyzed the clinical factors predictive of tumor recurrence and poor visual outcome following 3 consecutive sessions of primary TTT for choroidal melanoma in 256 patients.30 In this series, 91% of tumors showed regression without recurrence, and 9% showed recurrence, but one-half of those with recurrence were controlled with further TTT. Using Kaplan Meier estimates, recurrence was found in 4% by 1 year, 12% by 2 years, and 22% by 3 years. Overall, 96% were controlled with TTT. Factors predictive of recurrence were optic disc overhung by tumor and increasing number of TTT sessions (implying poor response). If these factors were not present then tumor recurrence was reduced to 10% at 3 years.
In 2007, Pan et al. reported on 20 patients with small choroidal melanoma treated with a mean of 2 sessions of primary TTT and followed for a mean of 4 years. 33 Only 11 (55%) achieved initial control and 9 (45%) showed recurrence, of which 5 were controlled with additional TTT. Overall, 16 (80%) showed complete control with TTT alone. No tumor-related metastasis were found and 75% of patients had post-TTT visual acuity within one line of pretreatment acuity. In 2008, Aaberg et al. published on 135 patients with choroidal melanoma treated with TTT, but that analysis was less refined and 12% of tumors were classified as medium size with thickness up to 6.6 mm. 34. These tumors were mostly treated with one session initially, and further treatments were applied as necessary. In this report, 102 patients (76%) had successful tumor regression, but by Kaplan Meier analysis, 19% showed failure at 5 years and 33% at 10 years. Features that predicted treatment failure included tumor base >10 mm, thickness >3 mm, high-risk characteristics (subretinal fluid, orange pigmentation and tumor thickness ≥2 mm), and tumors touching the optic disc. A particularly bothersome finding was the presence of extraocular extension in 11 cases.
Most clinicians prefer TTT only for small and not medium-sized melanoma and most patients receive 3 sessions, even if the tumor appears regressed. Currently most treated tumors are <3.0 mm or even <2.5 mm thickness. The most common side effects of TTT for small melanoma include branch retinal vein occlusion, retinal traction, and retinal hemorrhage. When considering this treatment, it is important to evaluate whether the patient will be able to sustain careful, long-term follow-up to monitor for recurrences. The ideal tumor characteristics for primary TTT include a tumor with dark pigmentation for best diode absorption, a tumor of small size (thickness less than 3.0 mm and not of diffuse variety), and a tumor with minimal or no contact with the optic disc as heat absorption lessens at the disc. The greatest advantage of TTT over plaque radiotherapy is the preservation of vision, and this treatment is particularly beneficial for tumors near but not under the fovea. However, when the tumor is subfoveal or immediately adjacent to the fovea, we most often employ plaque radiotherapy combined with 3 sessions of extrafoveal TTT in order to adequately treat the tumor but retain useful vision as long as possible. Primary TTT can also be useful for elderly patients, particularly those with diabetes mellitus so that macular edema might be avoided.
Photodynamic therapy using verrteporfin has been considered for uveal melanoma but little has been published. One report on 4 patients showed tumor regression for 18 months in one patient, but lack of response or continued growth in 3 patients.36 Others have emphasized that this is best used with amelanotic choroidal melanoma. 37
Medical follow up
Patients with uveal melanoma should have regular systemic follow up examinations by both an ocular oncologist as well as a medical oncologist. The ocular oncologist should monitor the uveal scar for tumor regression and complications of therapy. The medical oncologist should survey for metastatic disease. Particular evaluation of the liver, lung, and skin should be made as this malignancy most often mestatsizes to these sites. It is recommended that physical examination and liver function testing twice yearly, as well as liver magnetic resonance imaging and chest radiograph annually be performed for monitoring.
There are several available methods for surgical management of posterior uveal melanoma including plaque radiotherapy, charged particle radiotherapy, local resection, enucleation, and exenteration.
Radiotherapy is still the most widely employed treatment for posterior uveal melanoma. The most commonly employed form of radiotherapy is brachytherapy, using a radioactive plaque.3,38-51 Several years ago, Cobalt 60 plaque was popular. 38 More recently, Iodine-125 and Ruthenium-106 plaques have largely replaced Cobalt-60 at most institutions. Originally, plaque radiotherapy was used for small and medium-sized melanomas located outside the macular region and posterior to the ora serrata. Later, with innovations in radiotherapeutic plan, plaque radiotherapy can be custom designed to treat uveal melanoma at any site within the eye including macular melanoma using a round or notched plaque, juxtapapillary melanoma using a notched plaque, ciliary body melanoma using a round or curvilinear plaque, iris melanoma using a curvilinear plaque, and even extrascleral extension of uveal melanoma. 40-47 Plaque radiotherapy can also be custom fit to treat small, medium, and even large uveal melanoma up to approximately 12 mm in thickness. 47 Shields and associates found that plaque radiotherapy for large melanoma was effective with satisfactory tumor control, but complications of radiation maculopathy and papillopathy often lead to poor long term vision. 47
Another method of radiotherapy is charged particle irradiation. 48-51 This technique provides a focused beam of radiotherapy to the region of the tumor from an external source. A recent report showed that the 5- and 10-year rates of regrowth were 3% and 4%.4? Among the 45 documented recurrences, about one half occurred at the margin, presumably due to treatment planning errors. Recurrence of the tumor was independently related to risk of tumor-related death. Similar to plaque radiotherapy, radiation complications in the eye and adnexa can occur.43 Tumor control with charged particle and plaque radiotherapy are similar. Plaque radiotherapy combined with thermotherapy has provided tumor control in 97% with only 3% recurrence at 8 years. 39 The high control rate was maintained for eyes with juxtapapillary choroidal melanoma, despite the fact that this location is difficult for plaque placement. Studies have shown that between 5% and 10% of patients treated with radiotherapy ultimately require enucleation of the affected eye because of tumor recurrence or radiation complications. 52-53
The Collaborative Ocular Melanoma Study (COMS) was designed to evaluate management of choroidal melanoma in a prospective fashion. The COMS conducted three multicenter trials including: the large choroidal melanoma trial comparing enucleation versus enucleation preceded by external beam radiotherapy, the medium choroidal melanoma trial comparing enucleation versus plaque radiotherapy, and the small choroidal melanoma trial evaluating the natural history of these tumors. 54-63 In the large tumor trial (>10 mm thickness or >2 mm thickness and >16 mm basal diameter), eyes were randomized to enucleation or external beam radiotherapy preceding enucleation. In that trial, melanoma-related mortality at 5 and 10 years was 28% and 40%, respectively, for patients in the enucleation treatment arm and 26% and 45% in the external beam radiotherapy preceding enucleation treatment arm. 60,61 The results of the large tumor trial showed no difference in patient survival between enucleation and pre-enucleation radiation groups. In the medium-sized tumor trial (2.5-10mm thickness and basal diameter <16 mm), eyes were randomized to iodine I 125 brachytherapy or enucleation. In this trial, melanoma-related mortality at 5, 10, and 12 years was 10%, 18%, and 21%, respectively, for patients in the brachytherapy treatment arm and 11%, 17%, and 17%, respectively, for those in the enucleation treatment arm.58,59 The medium tumor trial showed no difference in patient survival between enucleation and plaque radiotherapy. The small tumor trial showed that small choroidal melanomas managed by observation showed tumor growth in 21% by 2 years and 31% by 5 years. 62 The results of the COMS confirmed numerous previous publications regarding management of choroidal melanoma.
Local resection of melanomas involving the ciliary body and choroid can be performed using a partial lamellar sclerouvectomy technique. 51 This surgical technique is a modification of the one popularized by Foulds, and later Shields and Damato, in which the tumor is removed with the aim of leaving the retina and vitreous intact. 51-53
Local resection of a posterior uveal melanoma offers several theoretical advantages over enucleation and radiotherapy. 4,64-66 In contrast to enucleation, it is designed to preserve vision and to maintain a cosmetically normal eye. In contrast to radiotherapy it has fewer long-term complications if the initial surgery is successful. However, it does have more potential immediate complications, such as vitreous hemorrhage, retinal detachment and cataract, while radiotherapy is almost uncommonly associated with such immediate complications. However, raditotherapy carries the risk for long-term complications of of radiation retinopathy, papillopathy, glaucoma, and cataract. There is no current evidence that local resection of posterior uveal melanoma is different from enucleation or radiotherapy with regard to patient survival. There are fewer complications and better visual results for smaller, more anteriorly located tumors. More complications can be expected when larger post-equatorial tumors are managed in this manner.
The traditional method of treating uveal melanomas by enucleation was challenged several years ago. 5,6 Others continued to believe that enucleation was an appropriate method of management.7,8 Enucleation is generally indicated for advanced melanomas that occupy most of the intraocular structures and for those that have produced secondary glaucoma. Another relative indication for enucleation is melanoma overhanging the optic disc or with optic nerve invasion. Enucleation with a long section of the optic nerve is appropriate in such cases. However, many juxtapapillary melanomas that abut the optic nerve and show no evidence of invasion can be managed by custom-designed notched radioactive plaques rather than enucleation. 42-45
The "no touch enucleation" was introduced to minimize the amount of surgical trauma and theoretically to lessen the chance of tumor dissemination at the time of surgery. 68 An essential aspect of this technique was to freeze the venous drainage from the tumor prior to cutting the optic nerve. The "no touch " technique has recently fallen into disuse at most centers because it is cumbersome and its benefits are only theoretical. However a gentle standard technique of enucleation should be employed, without clamping the optic nerve prior to cutting it.
There have been recent advances in the types of orbital implants used following enucleation. The hydroxyapatite implant, designed to improve the ocular motility in patients undergoing enucleation, is used widely. 69-71 Other implants include polyethylene and polymer coated hydroxyapatite. 71,72
The subject of orbital exenteration for uveal melanomas with extrascleral extension is also controversial. 73-74 It seems that complete orbital exenteration should not be done in cases of mild degrees of extrascleral extension. However, in the rare instance of massive orbital extension in a blind, uncomfortable eye, primary orbital exenteration is probably justified. In most instances of orbital extension for uveal melanoma, it is not necessary to sacrifice the skin of the eyelid. The eyelid-sparing exenteration provides a better cosmetic appearance. 74
Surgical follow up
Patients with uveal melanoma who have had surgical therapy should have regular systemic follow up examinations by both an ocular oncologist as well as a medical oncologist. The ocular oncologist should monitor the uveal scar for tumor regression and complications of therapy. Following radiotherapy there are complications of radiation retinopathy, papillopathy, cataract, glaucoma, scleral necrosis, and pain.
The medical oncologist should survey for metastatic disease. Particular evaluation of the liver, lung, and skin should be made as this malignancy most often mestatsizes to these sites. It is recommended that physical examination and liver function testing twice yearly, as well as liver magnetic resonance imaging and chest radiograph annually be performed for monitoring.
Ideally, the best management of uveal melanoma would be to use methods of preventing metastasis in the early stages of the intraocular disease. 75-77 Unfortunately, there is no current method of achieving this. Once a uveal melanoma has metastasized to distant organs, the patient's prognosis is poor. If the metastasis occurs as a solitary lesion, local resection of the metastatic focus can prolong life. 75 Several chemotherapy and immunotherapy trials have been performed with little positive results.
Likewise, the role of chemotherapy and immunotherapy is unproven in the treatment of patients with systemic metastasis from uveal melanomas. There have been reports of tumor regression after hepatic arterial chemoembolization or immunoembolization. 76.77 There is a possibility that such treatment may prolong survival for a few months but it is unlikely that it will be curative. The role of monoclonal antibodies in the detection and management of metastatic uveal melanoma is currently being investigated.
Complications of each therapy is detailed in the literature. In general, the main ocular complication following radiotherapy is retinopathy with resultant decreased visual acuity. 78-81 Gunduz and associates studied retinopathy following plaque radiotherapy and noted nonproliferative retinopathy in 42% at 5 years and proliferative retinopathy in 8% at 5 years. 79 Other radiation complications included cataract (39%), papillopathy (8%), vitreous hemorrhage (7%), neovascular glaucoma (1%), and scleral necrosis (1%). The treatment of these complications involves laser photocoagulation, anti vascular endothelial growth factor medications, and anti-inflammatory medications. 80,81
The prognosis for uveal melanoma should be considered in terms of life, the globe, and visual acuity. With regards to life prognosis, uveal melanoma prognosis has been shown to be dependent on several clinical factors including tumor location in the ciliary body, large tumor size, diffuse (flat) configuration, and extraocular extension as well as histopathologic and cytogenetic factors including epithelioid cell type, increased mitotic activity, infiltrating lymphocytes, tumor vascular networks, and chromosomal mutations including monosomy 3 and 8q addition. 14,82-85 In several articles, tumor size has been identified as one of the key clinical features predictive of metastasis. In one large analysis on 8033 eyes with uveal melanoma, metastasis occurred at 5, 10, and 20 years in 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and 37% for medium melanoma (3.1-8.0 mm), and 35%, 49%, and 67% for large melanoma (>8.0 mm). 14 More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0mmthickness), 12% (1.1-2.0 mm), 12% (2.1- 3.0 mm), 16% (3.1-4.0 mm), 27% (4.1-5.0 mm), 28% (5.1- 6.0 mm), 29% (6.1-7.0 mm), 41% (7.1-8.0 mm), 50% (8.1- 9.0 mm), 44% (9.1-10.0 mm), and 51% (>10.0 mm). 14 The authors concluded that increasing millimeter thickness of uveal melanoma was associated with increasing risk for metastasis. Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, tumor pigmentation, and subretinal fluid, intraocular hemorrhage, and extraocular extension.
With regards to the globe, nearly 95% of patients treated with conservative measures such as radiotherapy or resection, maintain their globe on follow up. The greater the tumor thickness, the greater the risk for enucleation.52,53,57
With regards to visual acuity, a study on 1106 consecutive plaque-irradiated patients with uveal melanoma poor visual acuity (20/200 or worse) in 34% at 5 years and 68% at 10 years of follow-up. 86 Factors related to poor visual acuity included increasing tumor thickness, proximity of tumor to foveola of less than 5 mm, evidence of tumor recurrence, patient age 60 years or older, subretinal fluid, cobalt isotope, tumor posterior to equator, and worse initial visual acuity.
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