儿童朗格汉斯细胞组织细胞增生症骨受累的临床特征与诊疗进展

Clinical Features and Advances in the Diagnosis and Treatment of Osseous Involvement in Pediatric Langerhans Cell Histiocytosis

摘要: 朗格汉斯细胞组织细胞增生症(Langerhans Cell Histiocytosis, LCH)是一种以CD1a和/或CD207 (Langerin)阳性髓系树突状细胞样细胞克隆性增殖为特征的炎性髓系肿瘤。儿童LCH临床异质性显著，可表现为自限性单骨病灶，也可出现多系统受累或累及肝、脾、造血系统等危险器官的多系统疾病。骨骼是儿童LCH最常见受累的部位，病灶数量和系统受累范围主要影响疾病再激活的风险和治疗强度，而病灶解剖部位则更多关系到中枢性尿崩症、听力损伤、牙颌发育异常和脊柱畸形等长期后遗症。儿童骨LCH的治疗需综合疾病范围、病灶部位及结构风险、早期治疗反应和MAPK通路分子特征制定。近年来，MAPK通路靶向治疗显著改善了部分难治患儿的疾病控制，但最佳疗程、停药后再激活、分子残留及不同驱动变异相关的药物敏感性差异仍是长期管理中的重要问题。异常MAPK信号与免疫及骨微环境之间的相互作用进一步丰富了对LCH发病机制的认识，但相关机制向临床治疗转化仍处于探索阶段。本文重点综述儿童LCH骨受累的临床风险分层与治疗策略，着重讨论孤立性中枢神经系统(Central Nervous System, CNS)危险部位骨病灶的系统治疗边界、MAPK抑制剂的长期管理及耐药相关问题，并提出未来值得关注的临床与转化研究方向。

Abstract: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by the clonal proliferation of CD1a- and/or CD207 (Langerin)-positive myeloid dendritic cell-like cells. Pediatric LCH is clinically heterogeneous, ranging from self-limited unifocal bone lesions to multisystem disease involving risk organs such as the liver, spleen, and hematopoietic system. Bone is the most commonly involved organ in children with LCH. The number of bone lesions and the extent of systemic involvement primarily influence the risk of disease reactivation and treatment intensity, whereas lesion location is more closely associated with long-term sequelae, including central diabetes insipidus, hearing impairment, dentofacial developmental abnormalities, and spinal deformities. Management of osseous LCH in children requires an integrated assessment of disease extent, lesion location and structural risk, early treatment response, and molecular alterations in the mitogen-activated protein kinase (MAPK) pathway. In recent years, MAPK pathway-targeted therapies have markedly improved disease control in some patients with refractory LCH; however, the optimal treatment duration, disease reactivation after treatment discontinuation, molecular residual disease, and differences in drug sensitivity across specific driver alterations remain major challenges in long-term management. Increasing evidence also indicates that aberrant MAPK signaling interacts with the immune and bone microenvironments, further advancing our understanding of LCH pathogenesis, although the clinical translation of these mechanisms remains at an exploratory stage. This review focuses on clinical risk stratification and therapeutic strategies for osseous involvement in pediatric LCH, with particular emphasis on the role and limitations of systemic therapy for isolated bone lesions at central nervous system (CNS)-risk sites, the long-term management of MAPK inhibitors, and issues related to therapeutic resistance. Future priorities for clinical and translational research are also discussed.