Increased Histological Tumor Pigmentation in Uveal Melanoma Is Related to Eye Color and Loss of Chromosome 3/BAP1.

Abstract

Heavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests. Retrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation. A total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and2021. Cox regression and log-rank tests were used for survival analysis; the chi-square test and Mann-Whitney U test were used for correlation analysis. Uveal melanoma-related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors. The 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n=54), 25% with lightly pigmented tumors (n=489), 41% with moderately pigmented tumors (n=333), and 33% with dark tumors (n=178) (P<0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P<0.001], and 19%, 43%, 61%, and 63% having 8q gain [P<0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1 (BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P=0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P=0.02) but not in dark tumors (P=0.85). Patients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P<0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor's genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.