Uveal melanoma (UM), the most frequently occurring non-cutaneous melanoma and most common primary intraocular malignancy in adults, arises from the melanocytes of the choroid in approximately 95% of cases. Prompt diagnosis and treatment is vital as primary tumor size is one of the key factors associated with survival. Despite recent advances in management, more than half of the patients develop metastatic disease which portends poor survival. Currently, treatment options for UM include local resection, enucleation, plaque brachytherapy, and/or particle beam radiotherapy (RT). Enucleation was initially the standard of care in the management of UM, but a shift towards eye-preserving therapeutic choices such as RT and local resection has been noted in recent decades. Plaque brachytherapy, a form of localized RT, is the most popular option and is now the preferred treatment modality for a majority of UM cases. In this review we discuss the etiopathogenesis, clinical presentation and diagnosis of UM and place a special emphasis on its therapeutic options. Furthermore, we review the current literature on UM management and propose a functional treatment algorithm for non-metastatic disease.
Melanoma is a malignancy that originates from the neoplastic proliferation of melanin-producing cells known as melanocytes, which can be primarily found in the skin, ocular region and mucous membranes. Uveal melanoma (UM) is the most frequently occurring non-cutaneous melanoma and is the most common primary intraocular malignancy in adults [
The worldwide incidence of UM is estimated to be close to 4 to 5 cases per million per year and varies with gender, race and geographical location. Even though most studies reveal no apparent gender preponderance, some European studies have seen a slightly increased incidence in males [
As with many other types of malignancies, the precise causative elements for this rare cancer have yet to be clearly established. Both genetic and environmental risk factors have been implicated in the etiology of developing UM. Genetic factors previously associated include fair skin, inability to tan and light eye color [
Although sunlight exposure is an independent risk factor in the development of cutaneous melanoma, epidemiological attempts to analyze the association between exposure to ultraviolet (UV) light and UM have led to contradicting results. Some studies suggest that UV light exposure is a synergistic risk factor for developing UM in individuals with light iris color [
Nearly half of the patients at the time of diagnosis are asymptomatic and UM is only identified after routine eye examination. Symptomatic patients present with ophthalmological features such as floaters, photopsia, visual field defects, metamorphopsia, visible tumor, and/or painless loss of vision [
There are a significant differential diagnoses of UM that include choroidal nevus, retinal pigment epithelium hypertrophy and disciform degeneration, making it is integral to obtain an accurate diagnosis as soon as possible. A fundoscopic examination is the first step in obtaining this goal. Presence of orange pigment, subretinal fluid, and documentation of tumor growth all aid in obtaining an appropriate diagnosis [
Despite advances in UM therapies, almost half of the patients are ultimately at risk for developing metastatic disease, primarily due to the inability to identify a unique feature of UM which is early micro-metastases [
Given this constantly evolving treatment paradigm, herein, we evaluate the published data on local therapeutic options for non-metastatic UM and propose a functional treatment algorithm (
Most common treatment options for non-metastatic UM include surgery, plaque brachytherapy, and/or particle beam radiotherapy (RT). Surgical options include local resection, enucleation and orbital exenteration. Local resection can be achieved either by exoresection, which involves en bloc tumor removal via a scleral approach, or by endoresection, which is piecemeal removal via a vitreoretinal approach. These eye-conserving treatment approaches, in recent years, are now preferred over enucleation [
Plaque brachytherapy or plaque radiotherapy is the most widely used treatment modality in the management of UM and involves administration of a fixed dose of RT to the tumor. This is achieved by insertion of a radioactive implant into the episcleral tissue that delivers an apex RT dose of 80–100 Gy [
Particle beam therapy (PBT) or charged-particle radiotherapy (CPRT) is the second most frequently used form of RT in the treatment of UM. Protons, helium ions and carbon ions are delivered as highly precise external RT beams with a pre-specified dose. When PBT is utilized, a RT dose of 50–70 cobalt gray equivalent (CGyE) is usually delivered in 4 to 5 fractions. When carbon ions are used, a dose of 60–85 CGyE is delivered in 4 to 5 fractions. Owing to their physical properties, charged particles provide increased targeting, especially at the end of the beam range [
The overall tumor size for UM is assessed based on both the apical height as well as the largest basal diameter of the tumor and is classified based on guidelines from the Collaborative Ocular Melanoma Study (COMS) group [
A landmark COMS study elucidated that tumors measuring <3 mm in apical height along with having a basal diameter measuring <5 mm should be primarily managed with observation [
Medium tumors are defined as an apical height of 3–8 mm and a basal diameter of <16 mm. Treatment options for these patients range from plaque brachytherapy to PBT to enucleation. Another landmark COMS study, conducted over a span of 10 years, evaluated the quality of life after 125I plaque brachytherapy (IBT) or enucleation in 209 patients with choroidal melanoma. They concluded that there was no significant difference in survival between the two groups, but revealed that there was better visual function, defined as peripheral vision, for up to 2 years after treatment in patients who underwent IBT when compared to enucleation [
Several other studies have been conducted with an aim to explore the use of different radioisotopes in plaque brachytherapy for UM [
Finally, more recent data is emerging looking at additional treatment options in conjunction with IBT. Use of intravitreal bevacizumab at the time of plaque removal and at 4-month intervals for a period of 2 years in 292 patients with UM showed significantly decreased macular edema and vision loss in these patients [
Stereotactic photon beam radiosurgery (SRS) is another option that can be employed in the treatment of UM in the medium-sized tumor group. Gamma knife, CyberKnife or linear accelerator platforms are some of modalities utilized [
Several studies have been performed to compare the effectiveness of surgical procedures to brachytherapy in the management of large UM, defined as an apical height >8 mm or a basal diameter of >16 mm [
Regarding CPRT, there are many studies detailing the use of PBT in comparison with other treatment modalities for UM [
Finally, Bechrakis and Foerster [
In summary, surgical intervention such as enucleation is the preferred approach in large tumors which cannot be effectively managed with RT, especially if they are well-circumscribed or juxtapapillary in location. The use of neoadjuvant RT prior to performing surgery has been shown to produce improved results and a decrease in the potential risk of tumor seeding. Further evaluation of this combined modality approach is required but may be appropriate patients presenting with neovascular glaucoma, tumor replacing more than half of the globe, orbital invasion or optic nerve involvement.
UM, the most common primary intraocular malignancy, continues to provide daunting challenges in its treatment management. With more than half the patients developing metastatic disease after initial non-metastatic presentation, prompt diagnosis and treatment play a crucial role in alleviating the morbidity and mortality of this disease. Currently, RT is the most common treatment approach in the management of UM, especially for small and intermediate-sized tumors. IBT is the most frequently employed type of RT, followed by CPRT. The most common surgical approaches remain enucleation and local resection. In recent years, enucleation is considered as an option only in patients with large tumors or in those with optic nerve involvement where RT does not result in a favorable outcome. The popularity of local resection has also diminished of late, as RT provides a superior alternative; however, when local resection is performed as a primary treatment modality, it is often coupled with neoadjuvant or adjuvant RT to further decrease chances of local recurrence. Additional clinical trials and targeted therapies aimed at the molecular pathogenesis of UM may offer novel avenues in managing this disease in the future.
No potential conflict of interest relevant to this article was reported.
Treatment algorithm for the management of nonmetastatic uveal melanoma.
Studies of plaque brachytherapy in uveal melanoma
Study | Radioisotope | n | Tumor thickness |
Tumor diameter |
Follow-up |
Local control (%) |
---|---|---|---|---|---|---|
Shields et al. [ |
125I (TTT) | 272 | 4.0 | 11.0 | 5 | 97.0 |
Verschueren et al. [ |
106Ru | 425 | 4.2 | 10.9 | 5 | 96.0 |
Takiar et al. [ |
106Ru | 40 | 3.1 | 9.6 | 5 | 97.0 |
Tarmann et al. [ |
106Ru | 143 | 4.5 | 11.0 | 4 | 85.3 |
Finger et al. [ |
103Pd | 400 | N/A | NA | 4.2 | 96.7 |
I, iodine; Ru, ruthenium; Pd, palladium; TTT, transpupillary thermotherapy; NA, not available.
Mean values.
Studies of TSR vs. IBT in uveal melanoma
Study | n | Tumor height |
Tumor diameter |
VA in TSR and IBT | Risk of LR in TSR and IBT |
---|---|---|---|---|---|
Bechrakis et al. [ |
237 | 9.4 | 14.5 | VA > 2/200 in 61.1% TSR vs. 5.6% IBT (p < 0.0009) | NA |
Kivela et al. [ |
98 | 7.9 | NA | VA < 20/200 after IBT (HR = 2.38; 95% CI, 1.48–3.83; p < 0.001) | LR in IBT vs. TSR (HR = 0.02; 95% CI, 0.01–0.11; p < 0.001) |
Caminal et al. [ |
72 | 10.0 | 15.0 | VA < 20/200 in 46.7% TSR vs. 68.8 % IBT (p < 0.121) | LR in TSR 10.5% vs. IBT 5.7% (p < 0.602) |
Puusaari et al. [ |
87 | 10.8 | 13.3 | VA < 20/400 in 60% TSR (95% CI, 35–75) vs. 75% IBT (95% CI, 59–86) | 5-year LR 41% in TSR (95% CI, 17–63) vs. 7% in IBT (95% CI, 2–17) |
TSR, transscleral resection; IBT, Iodine-125 brachytherapy; VA, visual acuity; LR, local recurrence; HR, hazard ratio; CI, confidence interval; NA, not available.
Mean values.
Studies of external beam radiotherapy in uveal melanoma
Study | Radiation | n | Mean follow-up (yr) | Local control (%) |
---|---|---|---|---|
Mishra et al. [ |
Helium ions | 86 | 14.6 | 100 (5 yr) |
125I plaque | 98 | 12.3 | 84 (5 yr) | |
Sikuade et al. [ |
Protons | 106 | 2.8 | 97 |
SRS | 85 | 3.3 | 100 | |
Caujolle et al. [ |
Protons | 886 | 5.3 | 94 (5 yr) |
Egger et al. [ |
Protons | 2,645 | 3.6 | 99 (5 yr) |
Bensoussan et al. [ |
Protons | 492 | 5.1 | 94 (5 yr) |
I, iodine; SRS, stereotactic radiosurgery.