Cytopathology and Prognostic Accuracy of 15-GEP/PRAME

Importance Gene expression profiling (GEP) reliably predicts metastatic uveal melanoma risk and is used to manage uveal melanoma (UM) in patients with this diagnosis. Efforts to refine molecular prognostication continue. Objective To determine if confirmatory cytopathology findings influence the prognostic accuracy of a commercially available GEP/Preferentially Expressed Antigen in Melanoma (PRAME) assay. Design, Setting, and Participants The Collaborative Ocular Oncology Group 2 study, a prospective cohort study, was conducted from 2017 to 2020 with follow-up recorded at 6-month intervals. This was a multicenter study that included patients with choroidal and/or ciliary body melanoma and results from a 15-GEP and PRAME RNA expression (15-GEP/PRAME) assay. Patients with iris tumors or less than 6 months’ follow-up were excluded. Study data were analyzed from April 2025 to July 2026. Exposures 15-GEP/PRAME, cytopathology, and next-generation sequencing (NGS). Main Outcomes and Measures Metastatic uveal melanoma rates in patients who had 15-GEP/PRAME and confirmatory cytopathology (CCP) results confirming or suspicious for UM (GEP+CCP) were compared with those who had 15-GEP/PRAME and no cytopathology performed, or unknown or nondiagnostic cytopathology results (GEP only). UM-associated variants identified by NGS were also evaluated. Results Of 1537 patients (mean [SD] age, 62.0 [13.4] years; 787 male [51.2%]), 727 (47.3%) had CCP results, and 810 (52.7%) had nondiagnostic cytopathology results or no cytopathology performed. Class 2/PRAME+ tumors were more common (136 of 727 [18.7%]) in the GEP+CCP group than in the GEP-only group (72 of 810 [8.9%]; 9.8% difference; 95% CI, 6.4-13.3; P <.001), whereas class 1/PRAME– tumors were less common (330 of 727 [45.4%] vs 495 of 810 [61.1%]; 15.7% difference; 95% CI, 10.8-20.6; P <.001). In patients with GEP+CCP, 22.7% (n = 165) developed metastasis vs 15.4% (n = 125) in patients with GEP only (7.3% difference, 95% CI, 3.3-11.2; P < .001). Adjusting for 15-GEP/PRAME status, there were no differences in metastasis rates between CCP groups. Of 1327 patients with successful NGS, 94.1% (605 of 643) in the GEP+CCP group and 71.9% (492 of 684) in the GEP-only group had a UM-associated variant (22.2% difference, 95% CI, 18.3-26.0; P < .001). Conclusions and Relevance Results of this cohort study reveal that no differences in metastasis outcomes were observed between patients with and without CCP within any GEP/PRAME categories. UM-associated variants were found less frequently in the GEP-only group than in the GEP+CCP group. In this cohort, 15-GEP/PRAME classification without CCP retained prognostic validity, supporting its clinical consideration in guiding metastatic surveillance in cases in which cytopathology is unavailable.