Clinical Features and Prognosis of Langerhans Cell Histiocytosis in Children: An Analysis of 31 Cases
-
摘要:
目的 分析儿童朗格汉斯细胞组织细胞增生症（LCH）临床特征，探讨BRAF-V600E突变在LCH中的表达特征及预后分析。 方法 回顾性分析昆明市儿童医院血液科2017年2月至2021年12月收治的31例儿童LCH临床病例资料。参考上海儿童医学中心LCH-2011修订版化疗方案（SCMC-LCH-2011方案），同时BRAF-V600E突变阳性者加用靶向药达拉非尼（Dabrafenib）治疗。总结单系统受累组LCH（single system LCH，SS-LCH）和多系统受累组LCH（multisystem LCH，MS-LCH）2组间的临床表现特征、BRAF-V600E突变情况及治疗反应，采用Kaplan-Meier方法绘制生存曲线，采用Log-Rank检验进行组间生存率的比较。 结果 31例患儿中男性18例，女性13例，中位发病年龄为10个月（1个月～84个月），9例为SS-LCH，22例为MS-LCH，其中5例患儿发生垂体受累/尿崩症。27例进行BRAF-V600E突变检测，其中20例为阳性（SS-LCH组3例，阳性率37.5%；MS-LCH组17例，阳性率89.5%），2组间BRAF-V600E突变阳性率比较，差异具有统计学意义（P = 0.011）。中位随访时间为24个月（3个月～62个月），6周诱导化疗后SS-LCH组有效率为88.9%（8/9），MS-LCH组有效率81.8%（18/22），观察期截止进展复发率达29.0%（9/31），3例死亡均为MS-LCH合并危险器官受累，SS-LCH与MS-LCH组间及BRAF-V600E突变阳性组与阴性组间的总生存率比较，差异无统计学意义（χ2 = 1.156、0.437，P = 0.282、0.508）。 结论 儿童LCH多见于婴幼儿阶段，患儿BRAF-V600E基因突变率高，且常见于MS-LCH。达拉非尼可能有助于改善BRAF-V600E突变阳性的患儿的预后。 -
关键词:
- 朗格汉斯细胞组织细胞增生症 /
- 儿童 /
- BRAF-V600E基因
Abstract:Objective To analyze the clinical characteristics of pediatric Langerhans cell histiocytosis（LCH）, and to analyse the expression characteristics and prognosis of BRAF-V600E mutation in LCH. Methods The clinical data of 31 children with LCH admitted to the Department of Hematology, Kunming Children's Hospital from February 2017 to December 2021 were retrospectively analyzed. Reference to LCH Shanghai children’ s medical center - 2011 revision chemotherapy（SCMC - LCH - 2011）, at the same time BRAF mutation - V600E targeted biopsies was treated by Dabrafenib. The clinical features, BRAF-V600E mutation and treatment response between single system LCH（SS-LCH） and multisystem LCH（MS-LCH） were summarized. The Kaplan-Meier method was used to draw the survival curve, and the Log-Rank test was used to compare the survival rate between groups. The Shanghai Children's Medical Center LCH-2011 revised chemotherapy regimen（SCMC-LCH-2011 regimen） was referenced, and the targeted drug Dabrafenib was added to treat those with the BRAF-V600E mutation. The clinical characteristics, BRAF-V600E mutation status, and treatment response between the single-system LCH（SS-LCH） group and the multisystem LCH（MS-LCH） group were summarized. Survival curves were plotted using the Kaplan-Meier method, and the Log-Rank test was used to compare the survival rates between the two groups. Results This study included a total of 31 cases, with 18 males and 13 females. The median age of onset was 10 months（ranging from 1 to 84 months）. 9 cases were SS-LCH, and 22 cases were MS-LCH, with 5 cases experiencing pituitary involvement/diabetes insipidus. Among the 27 cases that underwent BRAF-V600E mutation testing, 20 were positive（3 cases in the SS-LCH group, with a positivity rate of 37.5%; 17 cases in the MS-LCH group, with a positivity rate of 89.5%）. The difference in the BRAF-V600E mutation positivity rate between the two groups was statistically significant（P = 0.011）. The median follow-up time was 24 months（ranging from 3 to 62 months）. The effective rate after 6 weeks of induction chemotherapy was 88.9% in the SS-LCH group（8/9） and 81.8% in the MS-LCH group（18/22）. The observed progression-free rate at the end of the observation period reached 29.0%（9/31）. All three deaths occurred in the MS-LCH group with involvement of high-risk organs. There was no statistically significant difference in the overall survival rate between the SS-LCH and MS-LCH groups, as well as between the BRAF-V600E mutation positive and negative groups（χ2 = 1.156, 0.437; P = 0.282, 0.508）. Conclusion LCH in children is more common in infants and young children, with a high incidence of BRAF-V600E gene mutation in affected children, and is often seen in MS-LCH. Dabrafenib may help improve the prognosis of children with BRAF-V600E mutation. -
Key words:
- Langerhans cell histiocytosis /
- Child /
- BRAF-V600E gene
-
表 1 SS-LCH与MS-LCH患儿的临床特征[n（%）]
Table 1. clinical characteristic of SS-LCH and MS-LCH children[n（%）]
临床特征 LCH
（n = 31）SS-LCH
（n = 9）MS-LCH
（n = 22）皮疹/皮肤软组织受累 21（67.74） 4（44.44） 17（77.27） 骨质损害 12（38.71） 4（44.44） 8（36.36） 肝、脾肿大 17（54.84） 17（77.27） 发热 15（48.39） 15（68.18） 淋巴结肿大 7（22.58） 7（31.82） 血液系统≥2系受累 7（22.58） 7（31.82） 肺受累 6（19.35） 6（27.27） 中耳炎 5（16.13） 5（22.73） 垂体受累 3（9.68） 3（13.64） 口腔/肛周溃疡 2（6.45） 2（9.09） 体表肿物 1（3.23） 1（11.11） 
下载: 导出CSV
表 2 BRAF基因突变阳性与阴性患儿临床特征[n（%）]
Table 2. Clinical characteristics of children with positive and negative BRAF gene mutations[n（%）]
临床特征 BRAF基因阳性
（n = 20）BRAF基因阴性
（n = 7）P 性别 男 12（60） 4（57） 1.000 女 8（40） 3（43） 年龄（岁） ≤1 15（75） 3（43） 0.175 > 1 5（25） 4（57） 累及系统 SS-LCH 3（15） 5（71） 0.011* MS-LCH 17（85） 2（29） *P < 0.05。
下载: 导出CSV
-
[1] Rollins B J. Genomic alterations in langerhans cell histiocytosis[J]. Hematology/Oncology Clinics of North America,2015,29(5):839-851. doi: 10.1016/j.hoc.2015.06.004 [2] 方凯弘,徐倩玥,余红. 儿童朗格汉斯细胞组织细胞增生症病因和治疗进展[J]. 临床儿科杂志,2019,37(3):228-232. [3] Allen C E,Merad M,Mcclain K L. Langerhans-cell histiocytosis[J]. The New England Journal of Medicine,2018,379(9):856-868. doi: 10.1056/NEJMra1607548 [4] 吴升华. 郎格罕细胞组织细胞增生症评估与治疗指南介绍[J]. 中华儿科杂志,2012, 50(2):155-158. doi: 10.3760/cma.j.issn.0578-1310.2012.02.016 [5] Allen C E,Rodriguez-Galindo C. Langerhans cell histiocytosis[J]. Blood,2020,135(16):1319-1331. doi: 10.1182/blood.2019000934 [6] Krooks J,Minkov M,Weatherall A G. Langerhans cell histiocytosis in ch-ildren history,classification,pathobiology,clinical manifestations,and prognosis[J]. Journal of the American Academy of Dermatology,2018,78(6):1035-1044. doi: 10.1016/j.jaad.2017.05.059 [7] Leung A,Lam J M,Leong K F. Childhood Langerhans cell histiocytosis: A disease with many faces[J]. World J Pediatr,2019,15(6):536-545. doi: 10.1007/s12519-019-00304-9 [8] 王颖超,李壮壮,殷楚云,等. 伴口腔颌面部受累的朗格罕细胞组织细胞增生症12例临床分析[J]. 中国当代儿科杂志,2019,21(5):415-420. [9] 廉红云,张莉,李志刚,等. 儿童颅面骨受累的朗格罕细胞组织细胞增生症临床分析[J]. 中华实用儿科临床杂志,2019,34(15):1151-1155. doi: 10.3760/cma.j.issn.2095-428X.2019.15.007 [10] Zeng K,Ohshima K,Liu Y,et al. BRAFV600E and MAP2K1 mutations in Langerhans cell histiocytosis occur predominantly in children[J]. Hematologi-cal Oncology,2017,35(4):845-851. doi: 10.1002/hon.2344 [11] Minkov M. An update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy[J]. Expert Opin Pharmacother,2018,19(3):233-242. doi: 10.1080/14656566.2018.1429405 [12] Héritier S,Emile J,Barkaoui M,et al. BRAF mutation correlates with high-risk langerhans cell histiocytosis and increased resistance to first-line therapy[J]. Journal of Clinical Oncology,2016,34(25):3023-3030. doi: 10.1200/JCO.2015.65.9508 [13] 唐雪,郭霞,孙林雍,等. 儿童朗格汉斯细胞组织细胞增生症的BRAF-V600E基因突变及临床意义[J]. 中国当代儿科杂志,2018,20(4):290-294. [14] 李建红,李萍,唐鹏跃,等. 儿童朗格汉斯细胞组织细胞增生症20例临床分析[J]. 中国皮肤性病学杂志,2018,32(6):650-653. doi: 10.13735/j.cjdv.1001-7089.201708051 [15] 冯楚础,黎阳,彭晓敏,等. 儿童朗格汉斯细胞组织细胞增生症临床特征与BRAF V600E基因突变的相关性分析[J]. 中华实用儿科临床杂志,2021,36(11):848-852. [16] Héritier S,Barkaoui M,Miron J,et al. Incidence and risk factors for clinical neurodegenerative langerhans cell histiocytosis: A longitudinal cohort study[J]. British Journal of Haematology,2018,183(4):608-617. doi: 10.1111/bjh.15577 [17] Berres M,Lim K P H,Peters T,et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups[J]. Journal of Experimental Medicine,2014,211(4):669-683. doi: 10.1084/jem.20130977 [18] Donadieu J,Larabi I A,Tardieu M,et al. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: An international observational study[J]. J Clin Oncol,2019,37(31):2857-2865. doi: 10.1200/JCO.19.00456 [19] Hazim A Z,Ruan G J,Ravindran A,et al. Efficacy of BRAF-inhibitor therapy in BRAF(V600E)-mutated adult langerhans cell histiocytosis[J]. Oncologist,2020,25(12):1001-1004. doi: 10.1002/onco.13541 [20] Yang Y,Wang D,Cui L,et al. Effectiveness and safety of dabrafenib in the treatment of 20 Chinese children with BRAFV600E-mutated langerhans cell histiocytosis[J]. Cancer Res Treat,2021,53(1):261-269. doi: 10.4143/crt.2020.769 -
