Update on uveal melanoma: Translational research from biology to clinical practice (Review)

Abstract

Uveal melanoma is the most common type of intraocular cancer with a low mean annual incidence of 5‑10 cases per million. Tumours are located in the choroid (90%), ciliary body (6%) or iris (4%) and of 85% are primary tumours. As in cutaneous melanoma, tumours arise in melanocytes; however, the characteristics of uveal melanoma differ, accounting for 3‑5% of melanocytic cancers. Among the numerous risk factors are age, sex, genetic and phenotypic predisposition, the work environment and dermatological conditions. Management is usually multidisciplinary, including several specialists such as ophthalmologists, oncologists and maxillofacial surgeons, who participate in the diagnosis, treatment and complex follow‑up of these patients, without excluding the management of the immense emotional burden. Clinically, uveal melanoma generates symptoms that depend as much on the affected ocular globe site as on the tumour size. The anatomopathological study of uveal melanoma has recently benefited from developments in molecular biology. In effect, disease classification or staging according to molecular profile is proving useful for the assessment of this type of tumour. Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control. In the present study, the main epidemiological, clinical, physiopathological and molecular features of this disease are reviewed, and the associations among all these factors are discussed.

Keywords: uveal melanoma; cell transduction pathways; epigenetics; miRNA; immunotherapy.

Figure 1

Diagram illustrating the diagnostic features of cutaneous melanoma and uveal melanoma. Although both melanomas arise from melanocytes, each one shows its own characteristics while sharing the feature of an altered MAP kinase signalling pathway. Presently, these abnormalities are one of the most promising targets of the treatment of these patients, such as the inhibition of B-RAF for cutaneous melanoma. Nevertheless, as illustrated in the diagram, the mutations that activate this pathway differ and are accompanied by another set of modifications that are also different. In the case of uveal melanoma, these mutations serve to classify tumours into subtypes according to their molecular profile. The four mutations described are mutually exclusive. This molecular classification is also associated with metastasis risk and disease prognosis. The spread of both tumours also differs as cutaneous melanomas usually spread via the lymph while uveal melanomas usually spread via the bloodstream. Uveal melanoma exhibits a high predisposition to spread to the liver, which occurs in 90% of cases. By contrast, cutaneous melanoma may metastasize to the lungs, brain, lymph nodes and soft tissues with almost equal probability. Cytogenetic aberrations are also common in both types of melanoma, although these also differ. GNA, G protein subunit alpha; EIF1AX, eukaryotic translation initiation factor 1A X-linked; SF3B1, splicing factor 3b subunit 1; SRSF2, serine and arginine rich splicing factor 2; BAP1, BRCA-associated protein 1.

Figure 2

Overall schematic diagram of some of the most significant factors involved in the biology of uveal melanoma. In different types of cancer, associations among the different components of the tumour process are complex explaining the non-success of therapies such as PD-1 inhibition. Some factors involved in uveal melanoma, such as the role of oxidative stress, have been well established. In a cancer as aggressive as uveal melanoma, knowledge of the mechanisms involved and their interactions is essential to develop more effective treatments, predict tumour behaviour and identify new more reliable and accurate biomarkers. BRCA-associated protein 1; PRAME, preferentially expressed antigen in melanoma; SF3B1, splicing factor 3b subunit 1; GNA, G protein subunit alpha; HIF-1α, hypoxia inducible factor α.