Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Abstract

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

Keywords: biomarkers; metastases; molecular pathology; prognostic factors; survival; uveal melanoma.

Figure 1

Overview of key facts in uveal melanoma, the most common intraocular primary malignant tumour in adults. Different risk factors are associated with the development of uveal melanoma. The choroid is the most frequent intraocular site of uveal melanoma development, which is detected in routine ophthalmological exams in asymptomatic patients. However, the majority of uveal melanoma patients present with symptoms, such as blurred vision or photopsia. Metastases, especially to the liver, occur in nearly 50% of patients during the first 10 years after diagnosis, but constitute a presenting symptom in only a small fraction of patients (<2%). In the carcinogenic process of uveal melanoma, several tumour-initiating and tumour-promoting mutations have already been identified and characterized. Uveal melanoma patients with mutations in BAP1 (highlighted in red) have been demonstrated to have the worst outcome, while patients with EIF1AX (highlighted in green) have a better prognosis and patients with SF3B1/SRSF2 (highlighted in orange) have an intermediate prognosis. Diagram generated in line with previous literature [1,2,3,9,22,25,26,27,36,37,38,39,40] (Diagram created with BioRender.com, accessed on 15 December 2021).

Figure 2

Uveal melanoma is a primary malignant tumour of the eye with a potential dismal prognosis, since nearly 50% of the patients die because of metastases, preferentially to the liver, which are not curable due to the absence of meaningful therapeutic strategies. The morphological features of uveal melanoma are instrumental to predict the prognosis of patients. (A) Eye specimen containing a pigmented round tumour located in the choroid (posterior segment of the eye), the most frequent anatomic location of uveal melanomas. (B) Whole-slide representative microscopic view of the large-sized choroidal melanoma with evidence of associated exudative retinal detachment (H&E, 2× magnification). (C) Uveal melanomas composed by more than 90% of spindle cells are called spindle cell melanomas (G1; H&E, 400× magnification). (D) Uveal melanomas containing more than 10% of a spindle cell component and less than 90% of an epithelioid component are termed mixed cell melanomas (G2; H&E, 400× magnification). (E) Epithelioid cell melanomas (G3), which are associated with a worse patient prognosis, are composed by more than 90% of epithelioid malignant cells (H&E, 400× magnification). (F) Uveal melanoma disseminates systemically through a preferential haematogenous pathway. The presence of images of vascular invasion is correlated with a worse prognosis for patients (H&E, 200× magnification). (G) The presence of an increased number of mitosis (yellow circle) also hints a worse outcome for uveal melanoma patients (H&E, 200× magnification). (H) The presence of necrosis in non-treated uveal melanoma cases is an additional marker of bad prognosis for patients (H&E, 200× magnification). A summary of all currently well-established markers of bad prognosis in uveal melanoma is presented in Table 2.

Figure 3

New molecular prognostic classification for uveal melanoma based on the data generated by the TCGA project involving primary uveal melanoma cases [40]. The new model comprises four main prognostic classes: class A [D3/D8], class B (D3/partial extra 8q), class C (M3/8q gain) and class D (M3/multiple 8q gains). The risk of metastases development increases progressively from class A to class D. Uveal melanoma patients in class D have the least favourable prognosis, with nearly all patients dying within the first decade after diagnosis. Diagram generated in line with previous literature [3,36,39,40,73] (Diagram created with BioRender.com, accessed on 15 December 2021).