儿童朗格罕细胞组织细胞增生症BRAFV600E突变对预后的影响

目的 探讨BRAFV600E突变在儿童朗格罕细胞组织细胞增生症（LCH）中的预后意义以及影响儿童LCH的预后因素。方法 回顾性纳入首都医科大学附属北京儿童医院2016年1月1日至2017年12月31日收治的初治LCH患儿，采用数字PCR方法检测患儿病灶组织中的BRAFV600E突变，分析突变与临床特征和预后的相关性，影响预后的因素。结果 140例LCH患儿纳入研究，诊断时中位年龄为2.2（0.1~15.7）岁，男89例（63.6%），女51例。临床分型为单系统（SS）60例（42.9%），多系统无危险器官受累（MS RO－）47例（33.6%），多系统有危险器官受累（MS RO+）33例（23.6%）。中位随访时间34.1（0.9~50.7）月，随访期内70例（50.0%）出现进展或复发，12例（9.6%）出现持续性后遗症，死亡3例（2.1%）。总体3年无进展生存率（PFS）、无事件生存率（EFS）和总生存率（OS）分别为（48.9±4.5）%、（46.6±4.4）%和（97.8±1.2）%。①儿童LCH中BRAFV600E突变阳性率67.1%（94/140）。②BRAFV600E突变与患儿临床分型明显相关，突变阳性率MS RO+患儿（90.9%）高于MS RO－患儿（53.2%）或SS患儿（65.0%）（P=0.001）；皮肤受累患儿中突变阳性率（77.8%）高于非皮肤受累的患儿（P=0.042）；③BRAFV600E突变阳性患儿进展/复发率（57.4%）高于突变阴性患儿（34.8%），P=0.019。3种临床分型中突变阳性和阴性患儿的预后差异均无统计学意义。④多因素分析结果表明，危险器官受累是影响LCH患儿PFS的独立预后因素（HR=2.702，P=0.003），垂体受累（HR=3.582，P<0.001）、危险器官（HR=2.321，P=0.008）和耳部受累（HR=2.093，P=0.013）是EFS的独立预后因素。结论 LCH患儿BRAFV600E突变与危险器官受累密切相关，突变阳性患儿的进展/复发率高于突变阴性患儿，BRAFV600E不是儿童LCH的独立预后因素。

Prognostic significance of BRAFV600E mutation in children with Langerhans cell histiocytosis

Objective To investigate the prognostic significance of BRAFV600E mutation in children with Langerhans cell histiocytosis (LCH), and to determine the prognostic factors of childhood LCH. Methods Children with newly diagnosed LCH were retrospectively included in this study who were enrolled in Beijing Children's Hospital affiliated to Capital Medical University between January 1, 2016 and December 31, 2017. BRAFV600E mutation in lesion tissues was detected by digital PCR method. Prognostic factors and the correlation of BRAFV600E mutation with clinical characteristics and prognosis were analyzed. Results A total of 140 patients with LCH were enrolled in this study, including 89 (63.6%) males and 51 females. The median age at diagnosis was 2.2 (0.1-15.7) years. For clinical classifications, there were 60 cases (42.9%) with single-system (SS) involvement, 47 cases (33.6%) with multi-system non-risk organ involvement (MS RO－), and 33 cases (23.6%) with risk organ involvement (MS RO+). The median follow-up time was 34.1 (0.9-50.7) months. During the follow-up, 70 patients (50.0%) developed progression or relapse; 12 patients (9.6%) had permanent sequelae; 3 patients (2.1%) died. The rate of 3-year progression free survival (PFS), event free survival (EFS) and overall survival (OS) was 48.9%±4.5%, 46.6%±4.4%, and 97.8%±1.2% respectively. BRAFV600E mutation was positive in 67.1% of 140 patients with LCH. There was a significant relationship between BRAFV600E mutation and clinical classifications. BRAFV600E was identified in 90.9% of patients with MS RO+ LCH, 53.2% of patients with MS RO－ LCH, and 65.0% of patients with SS LCH (P=0.001). Of patients with skin involvement, 77.8% was BRAFV600E positive, which was significantly higher than that of those without involvement (P=0.042). Of mutation positive patients, 57.4%had progression or relapse, which was significantly higher than that of negative patients (34.8%，P=0.019). However, there was no significant difference in the prognosis of patients with and without BRAFV600E mutation in the three clinical classifications. The multivariate analysis showed that only the RO+ was an independent prognostic factor of PFS in children with LCH (hazard ratio, HR=2.702, P=0.003), and pituitary involvement (HR=3.582，P<0.001), RO+ (HR=2.321, P=0.008) and ear involvement (HR=2.093, P=0.013) were independent prognostic factors of EFS. Conclusion BRAFV600E mutation was closely related to RO+ involvements in childhood LCH. The rate of progression/relapse of mutation-positive patients was significantly higher than that of mutation-negative patients, but BRAFV600E mutation was not an independent prognostic factor of childhood LCH.