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(1) Background: Uveal melanoma (UM) is a common malignant intraocular tumor that presents with significant genetic differences to cutaneous melanoma and has a high genetic burden in terms of prognosis. (2) Methods: A systematic literature search of several repositories on uveal melanoma diagnosis, prognosis, molecular analysis, and treatment was conducted. (3) Results: Recent genetic understanding of oncogene-initiation mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 and secondary progression drivers of BAP1 inactivation and SF3B1 and EIF1AX mutations offers an appealing explanation to the high prognostic impact of adding genetic profiling to clinical UM classification. Genetic information could help better explain peculiarities in uveal melanoma, such as the low long-term survival despite effective primary tumor treatment, the overwhelming propensity to metastasize to the liver, and possibly therapeutic behaviors. (4) Conclusions: Understanding of uveal melanoma has improved step-by-step from histopathology to clinical classification to more recent genetic understanding of oncogenic initiation and progression.

(1) Background: Uveal malignant melanoma is the most common adult eye cancer and presents metabolic reprogramming that affects the tumoral microenvironment by altering the redox balance and producing oncometabolites. (2) Methods: The study prospectively evaluated patients undergoing enucleation surgery or stereotactic radiotherapy for uveal melanoma by following systemic oxidative-stress redox markers serum lipid peroxides, total albumin groups and total antioxidant levels (3) Results: Serum antioxidants and lipid peroxides were elevated from pre-treatment to longer-term follow-up. Antioxidants inversely correlated to lipid peroxides: higher in stereotactic radiosurgery patients pre/6/12/18 months post-treatment ( p = 0.001-0.049) versus higher lipid peroxides in enucleation surgery patients pre/after/6 months post-treatment ( p = 0.004-0.010). An increased variance in serum antioxidants was observed for enucleation surgery patients ( p < 0.001), however enucleation did not increase mean serum antioxidants or albumin thiols; only lipid peroxides were increased post-enucleation ( p < 0.001) and at 6-month follow-up ( p = 0.029). Mean albumin thiols were increased for 18- and 24-month follow-ups ( p = 0.017-0.022). Males who had enucleation surgery presented higher variance in serum determinations and overall higher lipid peroxides values pre/post-treatment and at the 18-month follow-up. (4) Conclusions: Initial oxidative stress-inducing events of surgical enucleation or stereotactic radiotherapy for uveal melanoma are followed by a longer-term inflammatory cascade gradually subsiding at later follow-ups.