A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated WithBRAFMutations

Abstract

IMPORTANCE Large studies investigating clinical presentation and treatment in primary conjunctival melanoma (CM) are rare. Clinicopathological characteristics of BRAF-mutated CM have not been studied thoroughly.OBJECTIVES To determine the associations of clinicopathological tumor features and treatment with local recurrence, metastasis, and mortality and to determine the association of BRAF mutations with these features. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study at the Eye Pathology Institute, Copenhagen, Denmark. Participants included 139 patients with primary CM in Denmark from January 1, 1960, to December 31, 2012. For BRAF analysis, all patients with available formalin-fixed, paraffin-embedded tumor samples from January 1, 1994, to December 31, 2012, were included.MAIN OUTCOMES AND MEASURES BRAF mutations, local recurrence, regional and distant metastasis, melanoma-related mortality, and all-cause mortality were examined.RESULTS A poor prognosis of tumors involving the extrabulbar conjunctiva and adjacent tissue structures was confirmed in multivariable Cox proportional hazards regression models. Patients undergoing incisional biopsy more frequently developed metastasis (hazard ratio [HR], 2.46; 95% CI, 1.08-5.58; P = .03). Excision without adjuvant treatment was associated with local recurrence (HR, 1.97; 95% CI, 0.11-3.48; P = .02), metastatic disease (HR, 2.51; 95% CI, 1.07-5.91; P = .03), and all-cause mortality (HR, 1.80; 95% CI, 1.05-3.08; P = .03). BRAF mutations were identified in 19 of 47 primary CMs (40.4%) and were more frequent in younger patients (P = .005), less frequent in the extrabulbar conjunctiva (P = .05), more frequently classified as T1 tumors (P = .03), and rarely manifested with primary acquired melanosis (P = .001) or with a uniformly pigmented lesion (P = .006). Distant metastases developed in 6 of 19 BRAF-mutated CMs (31.6%) as opposed to 1 of 28 BRAF wild-type CMs (3.6%). No definitive association with distant metastasis was seen in multivariable Cox proportional hazards regression models.CONCLUSIONS AND RELEVANCE Incisional biopsy and excision without adjuvant therapy were associated with a poor outcome in patients with CM. Extrabulbar location was also associated with a poor outcome in multivariable analysis. BRAF-mutated CMs were frequent in younger patients and were rare in tumors involving the extrabulbar conjunctiva. Despite a more favorable location, BRAF-mutated tumors may be associated with more frequent distant metastasis.

MicroRNA Expression Profile in Conjunctival Melanoma

“…[2][3][4][5]13,14 Identification of diagnostic, prognostic, or therapeutic miRNAs has the potential to improve the prognosis for both cutaneous melanoma patients and UM patients. [15][16][17][18] However, to the best of our knowledge, no previous reports on miRNA expression in CM and head and neck MM have been published.…”

“…1,2 Recently, oncogenic mutations in BRAF, NRAS, and KIT have been identified in CM, emphasizing their close genetic resemblance to cutaneous and mucosal melanomas (MMs), and their difference from uveal melanomas (UMs). [2][3][4][5] Owing to the high mortality rate associated with CM and MM, 2,6 there is a need to further identify molecular pathways that drive development and progression. MicroRNAs (miRNAs) are small noncoding RNA molecules that epigenetically regulate gene expression at the posttranscriptional level by either degradation of or translational blockage of target messenger RNAs.…”

“…Information on patient and tumor characteristics, clinical presentation, local recurrence, regional and distant metastases, and cause of death was obtained from clinical patient records, from pathology reports, and by searching the Danish Registry of Pathology and the Danish Register of Causes of Death, as previously described. 2,10 The proliferative index (mitotic rate) was evaluated in slides stained with anti-Ki-67 (Dako Denmark, Glostrup, Denmark) and the percentage of Ki-67-positive cells was assessed. All of the CMs were divided into two groups ( 15% and >15%).…”

Sentinel Lymph Node Biopsy in the Setting of Conjunctival Melanoma: Report of Two Cases and Literature Review

“…Approximately 1% of all CM cases occur in Hispanics. The mean age at diagnosis is 67.2 years and doesn't have a gender predilection [5,7]. CM typically presents as a pigmented nodular or flat conjunctival lesion [6,8].…”

Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma

“…Evidence suggests that mutated BRAF is associated with younger age at diagnosis, a sun-exposed location (caruncle or epibulbar conjunctiva), intermittent but not chronic sun damage, development from benign nevi instead of PAM with atypia, T1 stage, and male gender [16,21,52,53,54]. This is in accordance with skin melanoma, where BRAF-mutated tumors have been associated with a distinct, more aggressive phenotype, intermittent sun exposure, and lower age at diagnosis [17,55,56].…”