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Original Investigation |

A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated With BRAF Mutations

Ann-Cathrine Larsen, MD1; Christina M. Dahmcke, MSc2; Christina Dahl, PhD2; Volkert D. Siersma, PhD3; Peter B. Toft, MD, DMSc4; Sarah E. Coupland, MBBS, PhD5; Jan U. Prause, MD, DMSc1; Per Guldberg, PhD2; Steffen Heegaard, MD, DMSc1,4
[+] Author Affiliations
1Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark
2Research Center, Danish Cancer Society, Copenhagen, Denmark
3Research Unit, Section of General Practice, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark
4Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
5Division of Pathology, Department of Molecular and Clinical Medicine, Royal Liverpool University Hospital, Liverpool, England
JAMA Ophthalmol. 2015;133(11):1295-1303. doi:10.1001/jamaophthalmol.2015.3200.
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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.

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Figure.
BRAF Mutation Status and Clinical Presentation in Conjunctival Melanoma

A, Location in the palpebral conjunctiva. B, Location in the bulbar conjunctiva. C, Shown are examples of BRAF wild-type (WT) and mutated (MUT) tumors. Cutoff lines (at 6336 for BRAF V600E and 4103 for BRAF V600K) were determined using the mutation-positive control (MUT CTRL) and mutation-negative control (WT CTRL) DNA samples. The top axes of the graphs show examples of BRAF-mutated conjunctival melanoma samples (28 and 41) and BRAF wild-type conjunctival melanoma samples (19 and 42) compared with MUT CTRL and WT CTRL DNA samples. FAM indicates 1.1 µL of mutation primer or probe mix.

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