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

Maria Chiara Gelmi; Annemijn P A Wierenga; Wilma G M Kroes; Sjoerd G van Duinen; Jessica S Karuntu; Marina Marinkovic; Jaco C Bleeker; Gregorius P M Luyten; T H Khanh Vu; Robert M Verdijk; Martine J Jager

doi:10.1016/j.xops.2023.100297

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

Ophthalmol Sci. 2023 Mar 11;3(3):100297. doi: 10.1016/j.xops.2023.100297. eCollection 2023 Sep.

Affiliations

¹ Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Section Ophthalmic Pathology, Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Abstract

Purpose: 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.

Design: Retrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation.

Participants: A total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021.

Methods: 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.

Main outcome measures: Uveal melanoma-related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors.

Results: 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).

Conclusions: 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.

Keywords: Eye; Melanoma; Oncology; Pigmentation; Prognosis.