Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Cancer. 2018 Jun 15;124(12):2607-2620. doi: 10.1002/cncr.31348. Epub 2018 Apr 6.
Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH.
Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease.
Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E cells with monocyte phenotype (CD14 CD33 CD163 P2RY12 ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement.
In LCH-ND patients, BRAFV600E cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207 cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.
中枢神经系统朗格汉斯细胞组织细胞增生症（CNS-LCH）的脑受累可能包括肿块病变和/或病因不明的神经退行性疾病（LCH-ND）。本研究的目的是确定导致 CNS-LCH 的发病机制。
与患有脑瘤和其他神经退行性疾病的患者相比，分析了患有 CNS-LCH 病变患者的脑脊液（CSF）生物标志物，包括 CSF 蛋白和细胞外 BRAFV600E DNA。此外，还检测了 LCH-ND 患者外周血单核细胞（PBMC）和脑活检中 BRAFV600E 的存在，并在 4 例进行性疾病患者中评估了 BRAF-V600E 抑制剂的反应。
与其他脑部病变患者相比，CNS-LCH 患者中仅骨桥蛋白是唯一持续升高的 CSF 蛋白。仅在 20 例（10%）病例的 CSF 中检测到 BRAFV600E DNA，这些病例既有 LCH-ND 也有中枢神经系统外的活跃病变。然而，在所有治疗阶段，患有 LCH-ND 的 LCH 患者的 BRAFV600E PBMC 检测频率均明显较高。LCH-ND 患者的脑活检显示弥漫性血管周围浸润，有 BRAFV600E 细胞表现出单核细胞表型（CD14 CD33 CD163 P2RY12），并伴有骨桥蛋白表达。用 BRAF-V600E 抑制剂治疗的 4 例 LCH-ND 患者中有 3 例经历了显著的临床和影像学改善。
在 LCH-ND 患者中，PBMC 中的 BRAFV600E 细胞和脑内浸润性髓系/单核细胞与 LCH-ND 一致，作为一种源自突变造血前体的活跃脱髓鞘过程，而 LCH 病变 CD207 细胞也源自该前体。针对具有激活 MAPK 信号的髓样前体的治疗可能对 LCH-ND 有效。癌症 2018;124:2607-20。©2018 美国癌症协会。
