The eye is an intricate organ composed of many structures that function together to allow us to see images clearly. It can be divided into three main layers: (1) the sclera representing the white outer part visible to the eye, (2) the uvea, a heavily pigmented, vascular structure that provides nutrients to the retina and lens as well as assists in refractive function of the eye, and (3) the retina, which contains nerve fibers that sense light and create electrical impulses that are sent through the optic nerve to the brain (Figure 1).
The uveal tract is subdivided into three components:
Citations for this section are found in Reference (1).
Uveal melanoma is a rare malignant tumour that arises from melanocytes (melanin-producing cells) present in the choroid, ciliary body, or iris (Table 1). It is the most common primary intraocular malignancy in adults, accounting for over 95% of all ocular melanomas, but only 3-5% of all melanomas. Uveal melanoma is rare in children, and even more rare in congenital cases. It typically presents as a unilateral lesion. It is most prevalent in Caucasian non-Hispanic populations during the sixth to seventh decade of life, however studies including Asian, Hispanic and Black populations report diagnosis at the fourth to fifth decades. Iris melanoma typically presents earlier in life, which may explain its lower rate of metastases compared to choroidal and ciliary body melanomas that are more commonly present in older patients. Although the age-adjusted incidence of uveal melanoma varies amongst distant geographic populations, it has remained stable across the globe over the past few decades, with a higher prevalence in older males than females. A study of patients under the United States National Cancer Institute revealed an incidence rate of 5.1 cases per million per year, whereas a much lower rate has been reported in Africa and Asia of 0.2–0.3 cases per million per year. A European Cancer Registry study reported 1.3–8.6 cases per million per year, with varying incidence per region, from 2 per million per year in Spain and southern Italy to 8 per million per year in Norway and Denmark.
Citations for this section are found in Reference (2).
Several risk factors have been identified for the early detection of uveal melanoma.
Host factors include individuals with light-coloured irises, fair skin, ability to tan, northern European ancestry, oculodermal melanocytosis, previous ocular or cutaneous melanocytic lesions, BRCA1-associated protein 1 mutation, and at times a family history of uveal melanoma or atypical nevi.
Patients with oculodermal melanocytosis have a strong predisposition to uveal melanoma with a lifetime risk of 1 in 400. Those who do go on to develop melanoma have double the risk for metastasis when compared to those without the oculodermal melanocytosis.
Ultraviolet exposure has been investigated as a potential risk factor for uveal melanoma, with most studies revealing insignificant or mixed results. A meta-analysis by Shah et. al demonstrated that chronic ultraviolet light exposure, occupational sunlight exposure, outdoor leisure sun exposure, and geographic latitude of birth played minimally significant roles in the development of uveal melanoma. Some studies have shown that patients with light iris pigmentations are at an increased risk for melanoma when exposed to ultraviolet radiation, whereas other studies have suggested significant risk for arc welders with occupational exposure to ultraviolet light. Therefore, although its role in the development of ocular melanoma remains unclear, it does not appear to have the same significance as that for cutaneous melanoma.
Although development of most choroidal and ciliary body melanomas is thought to arise de novo due to sporadic events, they can occasionally arise from pre-existing ocular nevi with noticeable growth and suspicious clinical features (Table 2). Iris nevi on the other hand are relatively common and benign, with a low rate of transformation into melanoma (8% in 15 years). Certain risk factors may dispose pre-existing iris nevi into developing malignancy (Table 3). Referral to ophthalmology is required in the case of lesions that are large, vascular, invade surrounding structures, increase intraocular pressure or cause secondary glaucoma.
Citations for this section are found in Reference (2-5).
The clinical presentation of uveal melanoma ranges from incidental findings on ophthalmic examinations to various visual disturbances and vision loss, and may be asymptomatic in up to 30% of patients. Symptoms will vary based on location and size of the tumour, but patients typically present with flashes, floaters or visual field defects.
Choroidal melanomas in the posterior chamber may present with blurriness or decreased visual acuity, floaters, photopsia, visual field defects, and rarely pain. Vision loss is often due to tumour involvement at the macula or secondary to exudative retinal detachment. It can rarely be associated with intraocular hemorrhages and extraocular extension.
Symptoms from ciliary body melanoma develop later and similarly include decreased visual acuity, visual field defects, and secondary glaucoma in advanced cases. They can be associated with a wide dilated pupil, and depending on location, may cause lens displacement or localized cataracts with consequent refractive and accommodative disturbances.
Iris melanomas often present incidentally on ophthalmic examination. Majority are located in the inferior quadrant, with the most common findings being heterochromia (change in iris colour) and corectopia (pupil distortion / displacement). As the tumour advances, they can present with secondary glaucoma due to tumour extension into the angle causing blockage of the trabecular meshwork or neovascularization.
Citations for this section are found in Reference (2,6).
The diagnosis of uveal melanoma is done using careful funduscopic examination and slit-lamp biomicroscopy, along with specialized noninvasive testing techniques to characterize the tumour. These include B-scan ultrasonography (Figure 2), optical coherence tomography (OCT), and fluorescein angiography. Other techniques such as gonioscopy and anterior segment optical coherence tomography (AS-OCT) are used to assess tumour involvement in the anterior chamber and surrounding angle. Fine-needle aspiration for cytological studies may be sometimes required for molecular prognostic testing to customize metastatic surveillance testing, tumour management and stratify high-risk patients into clinical trials.
Despite advancements in diagnostic techniques, 23% of patients with ocular tumours are missed or misdiagnosed, resulting in more advanced staging at diagnosis and higher rates of primary enucleation.
Most patients are offered baseline imaging to assess for extraocular metastases prior to treatment. Given the propensity of developing hepatic metastases, the liver is commonly imaged using MRI, or alternatively ultrasound and computed tomography (CT). Patients without evidence of liver metastases are unlikely to develop extrahepatic disease. Therefore, initial staging for metastatic disease using CT of the chest, abdomen, and pelvis may be omitted unless hepatic metastases are confirmed or the patient experiences suspicious systemic symptoms.
Citations for this section are found in Reference (2,6).
Staging of uveal melanoma follows the tumour, node, metastasis (TNM) system by the American Joint Committee for Cancer (AJCC) that is used to guide treatment and prognosis (Tables 4 and 5). TNM refers to the three primary features used to stage the cancer: the size of the tumour (T), the presence or absence of lymph node metastases (N) and the presence or absence of distant metastases (M). More specifically for posterior uveal melanoma, T is organized based on the tumour’s largest basal diameter and thickness into increasing size categories and then subclassified according to ciliary body involvement and extraocular extension. Numbers or letters appearing after the TNM categories provide additional details, with higher numbers or letters indicating more advanced cancer. These features are then combined to generate a prognostic stage based on TNM status. Stages are assigned from I through IV, with a higher risk for metastasis and mortality with each stage. At present, no staging system is available for prognostication of iris melanomas. In cases following enucleation, histologic grading should be assessed (Table 4E). At the moment, histologic grade is not used in prognostic staging, although it may be incorporated in the future.
Citations for this section are found in Reference (7).
Management of uveal melanoma aims to preserve the eye and the visual function by achieving local tumour control and reducing the risk of metastatic dissemination. It entails a comprehensive review of the patient and requires the efforts of a multidisciplinary team. Treatment is individualized with many factors considered including tumour location, size, extension, visual function, systemic status, as well as patient age and goals of care. Therapeutic options are discussed on a case by case basis, and range from observation to globe-preserving therapies (radiation, laser therapy, surgical resection) and enucleation (Table 6). Globe-sparing radiotherapy techniques are widely preferred to enucleation. Overall, surgical resection and plaque brachytherapy (Figure 3) are the mainstay of treatment for iris melanoma and posterior uveal melanoma, respectively. The main concern with radiation therapy is damage to surrounding healthy tissue that causes blurry vision, dry eye, cataracts, retinal detachment, glaucoma, loss of eye lashes, problems with tear ducts, bleeding, and in some cases partial or complete loss of vision that may worsen with time. The risk depends on the size and location of the tumour. Details of the management decision are beyond the scope of this module, however, general approaches and treatment options are reviewed below.
Observation is preferred for small iris melanomas that are asymptomatic, whereas surgical resection is the treatment of choice for larger, symptomatic iris lesions. Small and medium-sized (≤1.5cm diameter) choroidal tumours are mainly radiated, with plaque brachytherapy being the mainstay of treatment. Small asymptomatic uveal melanomas are managed by observation and treated accordingly with progression of tumour or symptoms. Large non-resectable tumours (>1.5cm diameter) may be treated by plaque radiotherapy or enucleation, depending on certain factors. Many studies have shown equivalent survival outcomes for patients with medium- to large-sized choroidal melanomas randomized to iodine-125 brachytherapy versus enucleation, thereby shifting the trend to globe-preserving management therapies whenever possible. Enucleation is restricted to cases with recurrent malignancy, cases where vision cannot be salvaged, or cases where the tumour has spread to the optic nerve or caused complications (increased intraocular pressure, neovascular glaucoma, chronic inflammation, pain etc.). Orbital exenteration is indicated in advanced tumours with extra-bulbar spread or in relapsed tumours after previous enucleation. The patient may then be fitted with a custom-made ocular prosthesis to match their other eye, giving a more natural appearance (without restoring vision). Observation may be considered in cases where a tumour is present in the only eye with useful vision. Terminal patients with advanced metastatic disease are observed and treated palliatively as needed.
New and targeted therapies are on the horizon for the management of uveal melanoma. Novel treatments including immunotherapy, anti-angiogenic agents and light-activated targeted therapy using viral-like nanoparticles administered by intravitreal injection for early-stage treatment are being investigated.
Citations for this section are found in Reference (2,6,8).
Iris melanomas have the best prognosis compared to ciliary body and choroidal melanoma, with a 5-10 times lower reported mortality rate. This is likely due to its more obvious location and thus earlier presentation at diagnosis, thereby preventing hematologic spread and distant metastasis. On the contrary, ciliary body melanomas carry the worst prognosis given their hidden location behind the iris, and asymptomatic progression until substantial growth that prompts clinical symptoms and a late diagnosis. In general, the earlier a melanoma is detected the better the prognosis.
Despite excellent local control, uveal melanoma is associated with a relatively high mortality secondary to metastasis, with melanomas involving the ciliary body conferring the highest risk of metastasis. Even with early diagnosis, appropriate treatment, and close follow-up, it is estimated that 50% of patients with primary uveal melanoma will eventually die of metastatic disease. Up to 90% of individuals with distant metastasis develop liver involvement, with remaining sites of metastasis that include the lung, bone, and skin. The median rate of survival for individuals with disseminated disease is reported to be less than 1 year. Unfortunately, patients with metastatic liver involvement have a much worse prognosis, with a median survival of 4–5 months. Aggressive management of patients with disseminated metastatic disease includes: systemic chemotherapy regimens, chemoembolization, intra-arterial chemotherapy, and surgery. Unfortunately, there has been no chemotherapeutic, immunotherapeutic or targeted therapy to date that has achieved a reproducible response rate of >10% in metastatic uveal melanoma.
Several clinical features have been associated with poorer prognostic outcomes, including older age at presentation, male gender, large tumour size (thickness and diameter), location involving the ciliary body, diffuse tumour configuration, association with ocular or oculodermal melanocytosis, epithelial cell type on histology, extraocular tumour extension, and advanced tumour staging by American Joint Committee on Cancer classification.
Recent discoveries in tumour cytology, gene expression profiling, and identification of circulating tumours cells may allow for improved prognostication of uveal melanoma for early detection and treatment before extension of metastasis.
Citations for this section are found in Reference (2,9-11).
Monitoring for metastasis in patients with uveal melanoma should be regularly performed with emphasis on patient compliance with ongoing follow-up. This includes but is not limited to regular dilated fundus examination, liver function tests, tumour markers, and CT or right upper quadrant abdominal ultrasound to assess for liver metastasis. Serial fundus photography is imperative in the screening and follow-up of suspicious melanocytic lesions. Patients with oculodermal melanocytosis should undergo periodic ophthalmic examination to rule out uveal melanoma. The frequency of follow-up depends on risk of the tumour, with visits every 3 to 4 months recommended for patients with the highest risk tumours.
As mentioned in Table 2, choroidal nevi with suspicious features should be monitored regularly. Lesions with any one factor listed have a 38% chance for transformation into melanoma, and those with two or more factors have over 50% chance at 5 years. The combination of tumour thickness >2 mm, symptoms, and tumour margin near the optic disc pose the most dangerous risk with a 69% chance for growth.
Citations for this section are found in Reference (2).
Use your mouse to click through the slides and answer each question in the text box provided.
Note: This case can be completed on an iPad. To do this download the (free) Articulate Mobile Player for the iPad by clicking here.