Genetic Profiling of Primary Orbital Melanoma

Abstract

Purpose: To analyze the genetic profile of 6 cases of primary orbital melanoma with clinicopathologic correlation. Design: Retrospective noninterventional study to analyze the genetic profile of 6 cases of primary orbital melanoma and to correlate the genetic findings with prognosis and clinicopathologic features. Inclusion criteria were patients with primary orbital melanoma with no evidence of primary eyelid skin, conjunctival, uveal, or remote melanoma at extraocular sites. Participants: The study involved 6 primary orbital melanomas from 6 patients. Four patients were exenterated and 2 had incisional biopsies performed. Methods: Clinical notes and radiologic records were assessed to ascertain clinical tumor behavior. Sections were stained with hematoxylineeosin and exposed to immunohistochemistry for S100, MelA, HMB45, Sox10, and BAP1. Melanoma DNA was exposed to array comparative genomic hybridization to assess gross chromosomal copy number changes. Point mutation assessment and Sanger sequencing were performed for GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX. Main Outcome Measures: These were the presence of gross chromosomal copy number changes and the presence of mutations in GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX; the presence of metastases and time period between diagnosis and death from melanoma; and correlation between the tumor genetic profile and the clinical behavior of the tumor. Results: One of the 6 cases was clinically associated with oculodermal melanocytosis. Of the 6 patients, 3 died of melanoma metastases and 1 of unrelated causes; 2 remain alive at last review. Three of the 6 cases were histologically associated with a benign precursor lesion. All melanomas expressed S100, MelA, HMB45, and Sox10. One patient showed loss of BAP1 nuclear staining. The most frequent chromosomal gains across the 6 cases, in order of frequency, were 6p, 8q, 17q, 6q, and 20p. The most frequently lost regions were 1p, 9p, 16q, and 17p. One patient showed monsomy 3 and gain of 8q (and showed the BAP1 loss). Mutations were found in GNAQ (1 case), GNA11 (1 case), SF3B1 (2 cases), NRAS (2 cases), and pTERT (2 cases). Conclusions: The data point to 2 genetic groups for primary orbital conjunctiva melanoma-like and a uveal melanomaelike group. A larger study would help confirm this suggestion. Ophthalmology 2019;126:1045-1052 ª 2019 by the American Academy of Ophthalmology Primary orbital melanoma accounts for less than 1% of all primary orbital neoplasms. 1 In the largest clinicopathologic series on this subject to date, all 21 cases occurred in white patients, with a mean age at diagnosis of 42 years. Of these cases, 19 (90%) were associated with an orbital blue nevus. Of these 19 cases, 10 cases also showed some form of congenital melanosis (nevus of Ota or ocular melanocytosis). 2 Death from metastatic tumor occurred in 38% of cases, after a mean of 4.5 years follow-up, with liver (88%) and brain (12%) being main targets of metastases. 2 A recent clinical study of 13 cases showed mortality from the ...

Primary Orbital Melanoma: An Investigation of a Rare Malignancy Using the National Cancer Database

“…However, for large tumors, there is a presumption of micrometastatic disease at the time of diagnosis and previous estimates of metastatic spread describe a 5-year incidence of 38% with a propensity for the liver followed by the lung. 2,9,17 Previous case studies emphasize a variety of treatment recommendations including the importance of removing the lesion with the capsule undisturbed, the use of the total orbital exenteration, and removal of all conjunctival tissue or dural tissue, while others suggest the value of adjuvant radiotherapy. 3,9,13,16 The efficacy of orbital exenteration was assessed in a population of 95 uveal melanoma patients, which suggested there was no difference in mortality between those who received orbital exenteration first or secondarily after alternative treatment failure.…”

“…POM has been diagnosed in all ages from the pediatric population to the elderly, with or without congenital anomalies, and with both indolent as well as extremely aggressive disease courses. [12][13][14][15][16][17][18] The treatment approaches include some combination of surgery, such as orbital exenteration or debulking, radiation, and chemotherapy. However, the choice of orbital exenteration for POM is grounded in observation from uveal melanoma and survival benefits between possible treatment sequences has only recently been explored.…”

Identifying biomarkers and novel therapeutic targets in uveal melanoma

“…19 In UM, SOX10 was expressed in a panel of ocular primary tumors where its assessment may help to differentiate it from other neoplasms and benign choroidal nevi. [20][21][22] However, it is widely unknown whether SOX10 or other neural crest factors in UM also exert functions similar to those in cutaneous melanoma. To address this question, we will analyze the expression of SOX10 and other neural crest transcription factors in patient-derived bio-specimens and UM cell lines.…”

“…In particular, the transcription factor SOX10 is highly expressed in congenital nevi and melanoma and is functionally important for cell proliferation and tumor initiation in interaction with other oncogenic factors such as NRAS 19 . In UM, SOX10 was expressed in a panel of ocular primary tumors where its assessment may help to differentiate it from other neoplasms and benign choroidal nevi 20–22 . However, it is widely unknown whether SOX10 or other neural crest factors in UM also exert functions similar to those in cutaneous melanoma.…”

The Vitreous Body and Its Role in the Diagnosis of Eye Pathologies

“…GNAQ/GNA11 mutations are also found in benign precursor lesions such as congenital ocular melanocytosis and are believed to be initiating events in the pathogenesis of uveal melanoma. 91 The combination of chromosome 3 loss and biallelic inactivation mutations in the BAP1 gene (which encodes BRCA1associated protein 1) on chromosome 3p21 are strongly prognostic for aggressiveness and metastasis. Given the cost of BAP1 mutation analysis, immunohistochemical staining to evaluate BAP1 expression is a more economical practical alternative and gives faster results.…”