title: A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated With BRAF Mutations.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ann-Cathrine
authors.initials: AC
authors.lastname: Larsen
authors.affiliation: Research Center, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dahmcke
authors.affiliation: Research Center, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Dahl
authors.affiliation: Research Unit, Section of General Practice, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Volkert D
authors.initials: VD
authors.lastname: Siersma
authors.affiliation: Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Toft
authors.affiliation: Division of Pathology, Department of Molecular and Clinical Medicine, Royal Liverpool University Hospital, Liverpool, England.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Coupland
authors.affiliation: Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan U
authors.initials: JU
authors.lastname: Prause
authors.affiliation: Research Center, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.affiliation: Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark4Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heegaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D003230:Conjunctival Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy; D004252:DNA Mutational Analysis; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf