Uveal melanoma (UM) although relatively rare is the most common primary intraocular malignancy in adults representing approximately 3–5% of all melanoma and 80% of ocular melanoma cases [1, 2, 3]. The mean annual incidence is between five and seven cases per million in Europe and the United States, eight per million in Australia and has remained largely unchanged over the past 30 years [4, 5, 6, 7]. The majority of ocular melanoma cases originate in the choroid (90%) followed by the ciliary body (7%) and the iris (3%) [8]. Predisposing factors for UM are ethnicity with incidence recorded as relatively low in Africa and Asia, age, sex with higher incidence seen in males, light eye colour and fair skin with sensitivity to sunburn. A higher incidence is also evident in individuals with cutaneous, iris and choroidal nevus, ocular or oculodermal melanocytosis (Nevus of Ota), dysplastic nevus syndrome and mutation of breast cancer 1 (BRCA1) associated protein 1 (BAP1) [2, 4, 9, 10, 11, 12, 13, 14, 15, 16, 17].

Cutaneous (CM) and UM share the same embryologic origin, however their epidemiology, prognostic features, molecular characteristics, clinical and biological behaviour differ and as such treatment of these tumours require different approaches [1, 3, 18, 19]. Despite significant improvement in local treatment of the primary tumour, the 5-year survival rate of patients with UM is 50–70% and remains unchanged over the past decades [5, 8, 18, 19, 20]. Approximately 50% of the patients develop metastases within five years from initial diagnosis with median survival between 6 and 12 months due to the lack of efficient treatment options [9, 21, 22, 23, 24, 25]. In patients with liver metastases, irrespective of the treatment method used the mortality rate is still approximately 80% after one year and 92% two years after diagnosis with only 1% of patients surviving over 5 years [26]. Better survival is seen in patients with metastases outside the liver or when the liver is not the first site [19]. Risk factors for systemic development include: large tumour size, epithelioid cell type, extra-scleral extension, loss of chromosome 3 and chromosome 8q amplification [27]. To date there is no standard form of care for patients who develop metastasis. Potential treatment options are surgical resection or other liver directed therapy, chemotherapy, immunotherapy and targeted therapies [2, 9, 19, 20, 25, 26, 27, 28, 29].

Advancement in the understanding of UM biological behaviour, the molecular and immunobiological characteristics are central to the development of new therapeutic strategies which will enable new therapeutic goals and approaches to treatment bringing benefit to patients with metastatic UM.

Circulating tumour cells are cancer cells which after separating from the primary tumour spread throughout the body via the bloodstream [68]. The interaction between the liver immune system and cancer cells creates unique and complex TME. New immune treatment strategies, such as blockade of immune checkpoints have significantly improved the survival of patients with CM without liver metastases; however, the response to this form of therapy in patients with hepatic metastases is less pronounced. Similarly, UM patients with liver metastases failed to reap benefit from these forms of immunotherapy [65].

The liver as a frequent site of metastases creates an immune-protected site for tumour growth due to its ability to locally mediate in T-cell inactivation, immune tolerance and cell destruction. All this can provide additional protection and a stimulus for the growth of UM cells [69]. Immunosuppressive TME as found in the liver may limit immunotherapy activity in advanced UM. Due to the role of the liver in filtering toxins from the body it can be assumed that the liver increases tolerance to tumour antigens compared to other organs [70]. Recent research shows an association between metastatic site and progression-free survival (PFS), overall survival (OS) and response rate to immunosuppressive treatment of melanoma. The response to immunotherapy has been shown to be more favourable in the case of metastases in the lungs and skin compared to metastases in other organs, particularly in the liver [19, 36, 60, 70, 71, 72].

Circulating tumour cells can be found in UM patients before clinical signs of metastatic disease [29]. There is a correlation between metastatic risk and the size of the tumour, suggesting that metastatic seeding might occur throughout tumour growth [27, 88]. Analysis of a large group of patients stressed that early treatment of UM may prevent metastatic spread in some patients which is in accordance with this hypothesis [89]. In only 2% of patients metastatic disease is confirmed at the time of diagnosis implicating the presence of subclinical micro-metastases prior to actual diagnosis [90]. Eskelin et al. [91] estimated that micro-metastases from UM could develop as early as five years before the treatment of the primary tumour. The evidence indicates that limited immune surveillance in the immune-privileged eye environment enables the UM tumour to be dormant and may be the explanation for the appearance of metastasis or recurrence after more than five years of a recurrence-free period [92].

Up to 50% of patients with UM develop metastases within 15 years of diagnosis [2, 20, 21, 23, 25, 58]. Due to the lack of lymphatic drainage from the eye primary UM spreads predominately haematogenously [19, 93]. Approximately half of all patients with primary UM ultimately develop metastasis with spread of tumour cells to the liver (89%), lung (29%), bone (17%), skin (12%) and lymph nodes (11%) [94]. Despite successful treatment of the primary tumour using radiotherapy or surgical resection, survival has remained relatively unchanged [9, 21, 22, 23, 24, 25, 58]. The 10-year metastasis rate varies among UM patients depending on the tissue of origin: 33% for ciliary body melanoma, 25% for choroidal melanoma and 7% for iris melanoma [8, 92]. Hepatic metastasis is an important determinant of clinical course and survival rate. After their development, the median survival of patients is 6 to 12 months with a slightly better prognosis in patients receiving treatment for metastasis [9, 21, 22, 23, 24, 25, 95]. The latency period for the onset of metastatic disease could be even more than 25 years, as such the patients require thorough monitoring over a long period of time [21].

Numerous clinical and histopathological features have been investigated in order to predict prognosis of patients with UM. Clinical factors associated with poor outcome include advanced patient age at time of diagnosis, large tumour size measured in diameter and thickness, extrascleral extension of the tumour, involvement of the ciliary body and presence of subretinal fluid or intraocular haemorrhage. Some pathologic features including epithelioid cell type, increased mitotic activity, extracellular matrix patterns, immune cell infiltration, genetic background and incomplete local control after primary tumour treatment are also associated with unfavourable prognosis [2, 8, 18, 25, 30]. The genetic analysis of melanocyte lesions has identified that extraocular invasion is related to the inactivation of the tumour suppressor gene, BAP1 and monosomy 3, as the main risk factors for disease spread and strongly correlates with decreased survival [33, 96]. The three-year OS rate among patients with monosomy 3 is 60%, whereas patients with disomy 3 have a three-year OS rate of 95–100% [97, 98]. Classification of UM using the GEP system may estimate metastatic potential however it cannot determine the time of metastasis occurrence. Nonetheless it may help in planning patient follow-up strategies based on an individualized approach and the selection of patients who could benefit from intensive and long term follow up and potential adjuvant therapy [21, 55].

There is no established criteria regarding the type nor the time and frequency of screening for systemic metastasis in UM mostly due to the lack of randomized studies [99, 100, 101]. Recommendations for follow-up after primary tumour treatment is within three to six months for two years and subsequently extended to a 6–12 months interval including local and systemic surveillance [21, 25]. The aim of ophthalmological examinations is the early detection of treatment-related complications as well as possible local tumour recurrence. Every follow-up should include a full ocular examination and local tumour assessment [102].

The purpose of systemic surveillance is early detection of metastatic disease and particular attention should be taken in the presence of high-risk factors namely class 2 primary tumours, monosomy 3 or tumours greater than 8 mm in apical dimension [46, 102]. Since the most frequent site of metastasis is the liver, surveillance of UM patients should include liver function tests and specific liver imaging [2, 18, 23, 25]. Some studies imply that lactate dehydrogenase (LDH) and GGT are sensitive liver function tests for UM and are most often elevated with advanced hepatic involvement [103]. Imaging modalities used in the staging of UM at baseline and follow-up include liver ultrasound, computed tomography (CT) of the head, chest, abdomen and pelvis, whole body positron-emission tomography (PET)-CT or magnetic resonance imaging (MRI) [102]. CT and MRI represent more effective methods than ultrasound [104] where MRI shows the best sensitivity in detecting small liver lesions and is also useful for the detection of lesions in the lungs and retroperitoneal nodes, bones and the brain [99]. Although PET/CT is not currently used as a routine method for detection of metastasis, it can be used as an alternative for patients with contraindications to MRI [104].

Local treatment depends on the size and location of the tumour, patient preferences and present comorbidities. The most effective treatment is enucleation, however it highly impacts patient’s quality of life. Other surgical options are tumour exoresection or endoresection which can be combined with local radiotherapy to prevent recurrence [2, 9, 18, 24, 25]. Currently, the most common local treatment for UM is plaque brachytherapy [18, 25]. Other treatment modalities frequently used are proton beam radiotherapy and gamma knife radiotherapy, both very useful since they offer an eye preserving option with good local control, especially in the posterior pole. Possible complications of these therapies include the risk of increased intraocular pressure, cataract formation and optic neuropathy [2, 9, 18, 24, 88]. Additional local treatment options that are usually combined with radiation techniques in order to reduce the risk of metastasis are transpupillary thermotherapy, photocoagulation and photodynamic therapy [9, 18, 25, 88, 89, 92].

Despite conducted research in which various treatment modalities of disseminated UM were evaluated definite systemic standard treatment for metastatic disease has not yet been established. A meta-analysis of 29 metastatic UM trials conducted between 2000 and 2016 showed the median PFS of 3.29 months and median OS of 10.2 months. In the same analysis the six-month PFS was recorded in 27% of patients and the one-year OS in 43% of patients [100]. Failure of metastatic UM treatment can be due to the specific gene expression profile, somatic mutations, the lack of effective treatment approaches and absence of clinical evidence-based guidelines [36].

Uveal melanoma is a rare but serious disease with a poor survival rate and a large number of patients developing metastasis. The OS of affected patients has remained unaltered and there is still no effective treatment for metastatic disease available. Recently, increasing attention has focused on the molecular mechanisms involved in UM carcinogenesis and progression which could allow for the identification of valuable diagnostic and prognostic biomarkers as well as novel therapeutic targets [33]. Immune-modulating agents and ICIs as new forms of therapy have significantly improved treatment of CM, however due to differences in molecular biology, molecular profiles and cytogenetic alterations these methods have not shown to be effective in UM treatment. A better insight into the biological behaviour and genomic alterations of the UM is essential for the identification of new therapeutic targets and developing new therapeutic strategies [39, 105].

Substantial obstacles in UM treatment are caused by the fact that histological, cytological, immunological and genetic analysis is rarely performed in treatment of primary tumours [19, 144]. In recent studies emphasis has been placed on genetic and epigenetic characteristics of tumours considering their role in carcinogenesis and the fact that they can clarify tumour behaviour [145]. Analysis of tumour tissue and determination of the immune and genetic profile at the time of diagnosis will help establish the potential risks and selection of the most effective systemic therapy. In this way planning treatment and follow up can be individualized [88, 145]. Additional problems associated with UM include limited published studies, insufficient knowledge, high risk for distant metastases, absence of effective systemic treatment and management outside expert centres. Further, in up to 30% of cases patients with UM can be asymptomatic particularly those with tumours located outside the macula where vision is not affected and this can result in misdiagnosis or late diagnosis of the primary tumour [146].

Inappropriate management at the early stage may result in increased risk of metastasis with possible fatal outcome [23]. Given that the occurrence of systemic disease is associated with increased mortality and adverse outcome it is important to identify high risk patients. Strong prognostic genetic biomarkers predicting the development of metastasis include chromosomal aberrations, DNA mutations and RNA profiles [38]. A possible direction for future research could be identifying biomarkers that enable the selection of patients who have a higher risk of developing metastasis as well as those who would respond best to treatment [19, 144, 145, 147, 148].

Current research has given useful insights into the biological behaviour of UM enabling the development of targeted therapies [33, 36, 145, 148]. Understanding the mechanisms involved in resistance and adverse drug reactions would greatly improve therapeutic strategies for metastatic UM and the setting of guidelines for new treatments [36, 149]. Achieving improvement should involve intensive biomarker research, exploring tumour immunogenicity and studying the mechanisms involved in immune escape. To achieve this goal, future UM investigations should anticipate biological analyses by collecting samples and sharing the obtained data. In addition, we need to improve our understanding of the aetiology and tumorigenesis of UM in order to have the opportunity to develop therapeutic strategies that alter clinical outcomes. The observation regarding the biological, clinical and genetic differences emphasises the need for therapy specifically designed and adopted for UM patients. Specific efforts are required to accelerate fundamental and clinical research, expand access to clinical trials and raise awareness about UM particularly its metastatic form [38]. Current data suggest that several immunological mechanisms partake in the development, growth and spread of UM and thus may be potential targets for immunotherapy [33, 57, 58, 72, 98]. It is crucial to identify the presence of metastasis in the early phase in order to initiate timely treatment. Intensive research and understanding of UM behaviour will enable the advancement of treatment methods that will affect specific stages of tumour development with an individual approach applied for every specific case [21, 32, 33, 44, 76, 114].

New drug discovery and innovative surgical methods such as IHP or PHP provide a localized approach to treatment. Current treatment of metastatic disease should focus on live directed therapy due to the lack of success of systemic chemotherapy and immunotherapy. Despite the relative improvement in survival with hepatic perfusion, novel therapy is required to improve outcome in these patients. Newer approaches are focused on studying the success of combined therapies including targeted and immunotherapies together with local liver-directed therapy. Future research should evaluate how the tumour cells evade the immune system with the aim of developing new therapies directed at these pathways. Novel therapies also include dendritic cell vaccination and biospecific molecules. Molecular therapies with RNA vaccines focusing on the genomic mutations are currently being investigated in cases of CM and have shown objective response in small studies [56, 57, 60, 98]. These results may be extrapolated to cases of UM offering personalized treatment based on the patient’s genetic mutations [60].

Advancement in treating UM patients may also be achieved with the knowledge of whether systemic adjuvant therapy at the time of primary tumour management improves prognosis and prolongs survival outcome. To date this form of treatment has not proven to be effective in reducing the risk of metastasis [150]. Further, the benefit and potential side effects of monotherapy versus combined therapies to obtain the optimal treatment outcome should also be clarified. In order to explain a number of issues related to the treatment of UM patients, it is necessary to conduct well-planned prospective studies [19].

Uveal melanoma is a rare and life threatening disease which shows notably different biological behaviour compared to other forms of melanoma and as such requires specific treatment strategies. Regardless of improvements in local treatment OS has not increased and therefore new treatment options in patients with metastatic disease are essential. Uveal melanoma has a predisposition to metastasize to the liver and many different loco regional techniques have been developed however with modest results. Even though there has been significant progress in understanding the biology of this type of melanoma leading to new targeted therapies and approaches to immunotherapy, standardized treatment for metastatic UM still does not exist. Available treatment options for metastatic UM have not been able to prolong the survival rate of affected patients. Additional studies are essential to comprehend and enhance the efficacy of targeted therapy and immunotherapy as well as liver directed therapies. Decisions regarding treatment options and the best clinical approach are crucial in providing individualized patient care.

SK conceived the idea and made the outline of the manuscript, sorted and compiled the relevant information and prepared the manuscript for final publication. SK and DMZ wrote the manuscript, MI, IM and AGA participated in literature research, AGA prepared the tables. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Not applicable.

We acknowledge Angela Budimir, University Hospital Dubrava, for her proofreading of the manuscript.

This research received no external funding.

The authors declare no conflict of interest.