Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Research Center, Danish Cancer Society, Copenhagen, Denmark.
JAMA Ophthalmol. 2015 Nov;133(11):1295-303. doi: 10.1001/jamaophthalmol.2015.3200.
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.
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.
BRAF mutations, local recurrence, regional and distant metastasis, melanoma-related mortality, and all-cause mortality were examined.
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.
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.
大规模研究原发性结膜黑色素瘤（CM）的临床表现和治疗方法很少见。BRAF 突变型 CM 的临床病理特征尚未得到深入研究。
确定临床病理肿瘤特征和治疗方法与局部复发、转移和死亡率的关系，并确定 BRAF 突变与这些特征的关系。
设计、地点和参与者：丹麦哥本哈根眼病理研究所的基于人群的队列研究。参与者包括 1960 年 1 月 1 日至 2012 年 12 月 31 日期间丹麦的 139 例原发性 CM 患者。对于 BRAF 分析，纳入了所有 1994 年 1 月 1 日至 2012 年 12 月 31 日有可用福尔马林固定、石蜡包埋肿瘤样本的患者。
检查了 BRAF 突变、局部复发、区域和远处转移、黑色素瘤相关死亡率和全因死亡率。
多变量 Cox 比例风险回归模型证实，涉及球外结膜和相邻组织结构的肿瘤预后较差。接受切取活检的患者更常发生转移（风险比 [HR]，2.46；95%CI，1.08-5.58；P = .03）。无辅助治疗的切除术与局部复发（HR，1.97；95%CI，0.11-3.48；P = .02）、转移性疾病（HR，2.51；95%CI，1.07-5.91；P = .03）和全因死亡率（HR，1.80；95%CI，1.05-3.08；P = .03）相关。在 47 例原发性 CM 中有 19 例（40.4%）发现了 BRAF 突变，这些突变在年轻患者中更为常见（P = .005），在球外结膜中较为少见（P = .05），更常被归类为 T1 肿瘤（P = .03），且很少表现为原发性获得性黑色素沉着（P = .001）或色素均匀的病变（P = .006）。在 19 例 BRAF 突变型 CM 中有 6 例（31.6%）发生远处转移，而在 28 例 BRAF 野生型 CM 中仅有 1 例（3.6%）发生远处转移。多变量 Cox 比例风险回归模型未发现与远处转移有明确的关联。
切取活检和无辅助治疗的切除术与 CM 患者的不良预后相关。球外位置在多变量分析中也与不良预后相关。BRAF 突变型 CM 多见于年轻患者，而发生于球外结膜的肿瘤则较为罕见。尽管位置更有利，但 BRAF 突变型肿瘤可能与更频繁的远处转移有关。
