Uveal Melanoma: A Brief Overview

Rokaiba Afrin

Introduction

Despite being a rare cancer overall, uveal melanoma is the most common primary intraocular malignancy in adults. Split into different subtypes, the most common type of uveal melanoma is choroidal melanoma (90%), followed by ciliary body and iris melanoma (1,2). Despite being a melanoma, uveal melanomas differ greatly from the more common cutaneous melanomas in areas including physiology, genetics, and management. This article will provide a brief overview of uveal melanoma, as well as identify some key differences from cutaneous melanomas.

Aetiology and Epidemiology

The aetiology of uveal melanomas remains largely unknown, however there is evidence for a number of potential causes. Uveal melanoma occurs most commonly in Caucasians. In particular, the presence of blonde hair, light skin and blue eyes seem to be specific risk factors (3). This may be due to the increased susceptibility of Caucasians to the cancerous effects of UV radiation from the sun, which has already been demonstrated for cutaneous melanomas (4). It is worth noting, however, that whilst sun exposure has been identified as a potential risk factor, its specific mechanism of causing uveal melanoma remains under debate. Rates of uveal melanoma do not seem to vary by distance from the equator, and no significant correlation has been identified for occupational sun exposure or outdoor leisure activity (5,6). The median age of presentation for uveal melanoma is around 60 years old (7). Whether this is linked to the cumulative effects of sun exposure over time, or whether there are other specific age-related risk factors remains unclear (8).

Aside from sun exposure, uveal melanoma has also been linked to mutations in the GNAQ or GNA11 genes, unlike cutaneous melanomas which have been found to have associations with BRAF or NRAF mutations (2,9). There does not seem to be a specific hereditary aspect to uveal melanoma, however another common risk factor for uveal melanoma is the presence of a choroidal naevus which have been linked to these GNAQ and GNA11 gene mutations (10).

Clinical Presentation

Uveal melanoma often presents asymptomatically, especially in the case of smaller tumours. As such, they may only be identified incidentally during routine screening. Uveal melanoma may also present with different forms of visual disturbance. This includes blurred vision, loss of visual fields, metamorphopsia (distorted vision where straight lines may appear warped), or pain (11). Symptoms of retinal detachment such as photopsia (flashes of light) and floaters may also occur, particularly in the presence of larger tumours as they may cause the retina to become detached. For example, this can occur in choroidal melanoma as the tumour breaches Bruch’s membrane (the innermost layer of the choroid) causing a ‘mushroom’ appearance of the tumour. In the case of ciliary body tumours, the intraocular lens may become displaced, leading to increased or asymmetrical astigmatism. Tumours occurring in the anterior chamber such as iris melanoma, are also more likely to present visibly, and iris discolouration may also be noted. Tumours may also be completely amelanotic (12).

Diagnosis and Investigation

Diagnosis of uveal melanomas are primarily clinical. Smaller uveal melanomas are often hard to distinguish from naevi, and as such are monitored for growth prior to diagnosis. Clinical examination may also reveal orange coloured lipofuscin pigment on the tumour, as well as the presence of subretinal fluid. Additional investigations which may also be used to help distinguish uveal melanomas include ultrasound, with low internal reflectivity, thickness greater then 2mm, and collar stud shape more likely to represent malignant pathology (1, 11).

Histopathology is not used regularly for diagnosis, however it can provide valuable insight into the prognosis of patients with uveal melanoma. Specifically, uveal melanomas may be classified into spindle-cell type, and mixed cell type tumours containing epithelioid cells, with spindle cell types having the best prognosis and epithelioid the worst (13). Immunohistochemistry may also be used to identify mutations linked to metastasis, such as BAP1 mutations, and as such could be used for routine screening (14).

The difficulty in identifying uveal melanoma may lead to significant delays in diagnosis, which go on to impact prognosis.

Management

Historically uveal melanoma has been treated by enucleation (removal of the eye), however the advent of treatments aimed at preserving vision and the eye allows management to be more specific to the patient’s needs. Eye preserving management may include radiotherapy (with ruthenium plaque or proton beam radiotherapy), or phototherapy (such as transpupillary thermotherapy or photodynamic therapy) (11). Overall, management will still depend largely on tumour size, location, and extent based on TNM classifications (15). Surgical excision is still commonly used and may involve partial resection (exoresection or endoresection) or full enucleation. Other structures in the surrounding orbit may also have to be removed in extensive disease (exenteration) (12).

As mentioned previously, the lack of BRAF and NRAF mutations prevent uveal melanomas from being treated with systemic BRAF inhibitors which are commonly used to manage cutaneous melanoma. Current NICE guidance suggests the potential of immunotherapy such as ipilimumab, pembrolizumab, nivolumab for use against unresectable or metastatic uveal melanoma. Chemotherapy drugs such as dacarbazine are also available when immunotherapy is unsuitable (16).

Novel management therapies such as tebentafusp (a monoclonal antibody which targets (HLA)-A*02:01-positive uveal melanoma) may also represent a potential avenue for life extending treatment and are currently being researched further. NICE guidance, however, makes no official recommendation due to the uncertainty of clinical benefit and cost effectiveness (16).

Prognosis

Around 50% of patients with uveal melanoma go on to develop metastasis. The most common site of metastasis is the liver, occurring in over 85% of uveal melanoma metastasis. This is then followed by metastasis to the lungs and bone (17). Evidence has linked tumour size to the development of metastasis and highlights the importance of early intervention (18).

Unfortunately, the prognosis after metastasis is quite poor, with mean survival being less than 6 months. As such, patients with uveal melanoma will often require long-term follow up and screening for metastasis (17).

References:

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