朗格汉斯细胞组织细胞增生症

单病灶骨骼疾病只见于单个骨骼。

单纯局部骨骼刮除术或活检即可治愈疾病。[65]Woo KI, Harris GJ. Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg. 2003 Nov;19(6):429-39.http://www.ncbi.nlm.nih.gov/pubmed/14625488?tool=bestpractice.com

应避免扩大切除，否则需要进行假体移植术，可能导致永久性功能缺陷。

不包含软组织成分的单纯眶周骨质破坏进行局部刮除术（腔隙刮除术）即可治愈。[65]Woo KI, Harris GJ. Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg. 2003 Nov;19(6):429-39.http://www.ncbi.nlm.nih.gov/pubmed/14625488?tool=bestpractice.com 如果病变广泛，应避免手术，考虑系统治疗。

业已证明，病灶内滴注甲泼尼松龙作为手术辅助治疗或代替手术均有效。[66]Egeler RM, Thompson RC Jr, Voute PA, et al. Intralesional infiltration of corticosteroids in localized Langerhans' cell histiocytosis. J Pediatr Orthop. 1992 Nov-Dec;12(6):811-4.http://www.ncbi.nlm.nih.gov/pubmed/1452756?tool=bestpractice.com

多病灶骨骼疾病见于 >1 块骨骼。

对中枢神经系统 (CNS) 有影响风险的骨骼是指，该骨骼出现病变时，患者发生中枢神经系统疾病的风险更高，最常见的表现是尿崩症。这些骨骼包括面骨或前/中颅窝骨骼（即，颞骨、蝶骨、筛骨、颧骨和眶骨）。[37]Gadner H, Grois N, Arico M, et al. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001 May;138(5):728-34.http://www.ncbi.nlm.nih.gov/pubmed/11343051?tool=bestpractice.com

对这些患者，推荐方案是长春花碱＋泼尼松龙，6 个月。[64]ClinicalTrials.gov. LCH-III: treatment protocol of the third international study for Langerhans cell histiocytosis. 2016 [internet publication].http://clinicaltrials.gov/ct2/show/NCT00488605

有 CNS-危险骨受累患者应监测是否出现尿崩症。

参考当地专科医生治疗方案作为剂量指导。

通常均只需要观察，因为这些患者接受活检的风险高于获益。[72]Weitzman S, Egeler RM. Langerhans cell histiocytosis: update for the pediatrician. Curr Opin Pediatr. 2008 Feb;20(1):23-9.http://www.ncbi.nlm.nih.gov/pubmed/18197035?tool=bestpractice.com

推荐方案：长春花碱＋泼尼松龙，6 个月。[67]Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14.http://www.ncbi.nlm.nih.gov/pubmed/11496348?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

出现神经系统症状或颈椎不稳定时进行。[73]Mammano S, Candiotto S, Balsano M. Cast and brace treatment of eosinophilic granuloma of the spine: long-term follow-up. J Pediatr Orthop. 1997 Nov-Dec;17(6):821-7.http://www.ncbi.nlm.nih.gov/pubmed/9591990?tool=bestpractice.com

低剂量放疗（6 - 8 Gy）只限于紧急情况，如视神经或脊髓压迫。[74]Gadner H, Ladish S. The treatment of Langerhans cell histiocytosis. In: Weitzman S, Egeler RM, eds. Histiocytic disorders of children and adults. Cambridge, UK: Cambridge University Press; 2005:229-53.

多数病例通常只需观察。 不过，最多 50% 的患者会出现再激活或进展为多系统疾病；所以，推荐进行长期监测。[38]Lau L, Krafchik B, Trebo MM, et al. Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer. 2006 Jan;46(1):66-71.http://www.ncbi.nlm.nih.gov/pubmed/16261594?tool=bestpractice.com

局部皮质类固醇作为一线治疗，特别是对丧失功能、溃疡性病变；不过，治疗后难以达到完全缓解，复发也相当常见。[38]Lau L, Krafchik B, Trebo MM, et al. Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer. 2006 Jan;46(1):66-71.http://www.ncbi.nlm.nih.gov/pubmed/16261594?tool=bestpractice.com

治疗 2 - 3 个月后重新评估病情。 如果病情缓解，则应停止治疗。 如果未缓解，则应尝试其他治疗。

针对经选择患者组全部患者的治疗推荐

对局部皮质类固醇耐药的患者，推荐使用口服甲氨蝶呤（6 个月）或沙利度胺，特别是有溃疡性和肛门生殖器病变的成人。[75]Steen AE, Steen KH, Bauer R, et al. Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol. 2001 Jul;145(1):137-40.http://www.ncbi.nlm.nih.gov/pubmed/11453923?tool=bestpractice.com[76]McClain KL, Kozinetz CA. A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007 Jan;48(1):44-9.http://www.ncbi.nlm.nih.gov/pubmed/16333818?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

局部应用氮芥 3-8 个月或PUVA照射 2-4 个月（补骨脂素＋紫外线 A）对口服治疗耐药的重症病例有效，特别是多发病变时；因上述治疗有继发恶性肿瘤的风险，均应短期使用。[77]Kwon OS, Cho KH, Song KY. Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy. J Dermatol. 1997 Jan;24(1):54-6.http://www.ncbi.nlm.nih.gov/pubmed/9046743?tool=bestpractice.com[78]Hoeger PH, Nanduri VR, Harper JI, et al. Long term follow up of topical mustine treatment for cutaneous Langerhans cell histiocytosis. Arch Dis Child. 2000 Jun;82(6):483-7.http://www.ncbi.nlm.nih.gov/pubmed/10833183?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

针对经选择患者组全部患者的治疗推荐

耐药患者局部应用他克莫司可快速起效；但只能用于>2 岁的儿童和成人中。[79]Krafchik B, Pope E, Walsh SR. Histiocytosis of the skin in children and adults. In: Weitzman S, Egeler RM, eds. Histiocytic disorders of children and adults. Cambridge, UK: Cambridge University Press; 2005:130-153.

针对经选择患者组全部患者的治疗推荐

如果上述治疗无效，考虑为重症患者或耐药，推荐进行系统化疗（即，长春花碱＋泼尼松龙，6 个月）。[67]Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14.http://www.ncbi.nlm.nih.gov/pubmed/11496348?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

手术切除是孤立性皮肤结节的首选治疗，应避免截肢手术。[80]Abla O, Egeler RM, Weitzman S. Langerhans cell histiocytosis: current concepts and treatments. Cancer Treat Rev. 2010 Jun;36(4):354-9.http://www.ncbi.nlm.nih.gov/pubmed/20188480?tool=bestpractice.com

对孤立性淋巴结肿大局部切除即可。[67]Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14.http://www.ncbi.nlm.nih.gov/pubmed/11496348?tool=bestpractice.com

推荐使用长春花碱＋泼尼松龙，6 个月。[67]Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14.http://www.ncbi.nlm.nih.gov/pubmed/11496348?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

儿童的治疗方案与多系统疾病中所用联合化疗方案一致。[74]Gadner H, Ladish S. The treatment of Langerhans cell histiocytosis. In: Weitzman S, Egeler RM, eds. Histiocytic disorders of children and adults. Cambridge, UK: Cambridge University Press; 2005:229-53. 不过，较为简单的化疗方案（长春花碱＋泼尼松龙）可能对青少年和成人有效。[81]McClain KL, Gonzalez JM, Jonkers R, et al. Need for a cooperative study: pulmonary Langerhans cell histiocytosis and its management in adults. Med Pediatr Oncol. 2002 Jul;39(1):35-9.http://www.ncbi.nlm.nih.gov/pubmed/12116077?tool=bestpractice.com

由于肺脏属于危险器官，通常进行 总疗程12 个月的治疗。

参考当地专科医生治疗方案作为剂量指导。

建议青少年和成人戒烟，建议所有患者避免吸入二手烟。

适用于成人重症进行性肺脏疾病（即，出现呼吸衰竭和严重肺动脉高压）。

LCH-III 研究推荐采用长春花碱＋泼尼松龙 6 个月治疗预防晚期并发症，包括生长激素缺乏和放射性神经退行性变。[41]Grois N, Potschger U, Prosch H, et al. Risk factors for diabetes insipidus in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2006 Feb;46(2):228-33.http://www.ncbi.nlm.nih.gov/pubmed/16047354?tool=bestpractice.com[57]Donadieu J, Rolon MA, Pion I, et al. Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab. 2004 Feb;89(2):604-9.http://www.ncbi.nlm.nih.gov/pubmed/14764769?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

针对经选择患者组全部患者的治疗推荐

去氨加压素替代治疗对控制症状十分重要。

曾报道少数病例使用 3-12 个月克拉屈滨（有或无阿糖胞苷）出现放射学反应；[84]Büchler T, Cervinek L, Belohlavek O, et al. Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer. 2005 Mar;44(3):286-8.http://www.ncbi.nlm.nih.gov/pubmed/15481071?tool=bestpractice.com[85]Watts J, Files B. Langerhans cell histiocytosis: central nervous system involvement treated successfully with 2-chlorodeoxyadenosine. Pediatr Hematol Oncol. 2001 Apr-May;18(3):199-204.http://www.ncbi.nlm.nih.gov/pubmed/11293288?tool=bestpractice.com[86]Dhall G, Finlay JL, Dunkel IJ, et al. Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer. 2008 Jan;50(1):72-9.http://www.ncbi.nlm.nih.gov/pubmed/17455311?tool=bestpractice.com 但是可能出现永久性后遗症，如尿崩症、全垂体功能减退和神经认知功能障碍，目前认为一旦发生，即不可逆。[86]Dhall G, Finlay JL, Dunkel IJ, et al. Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer. 2008 Jan;50(1):72-9.http://www.ncbi.nlm.nih.gov/pubmed/17455311?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

预后极差，尚无有效治疗方案。[87]Imashuku S, Ishida S, Koike K, et al. Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2004 Nov;26(11):735-9.http://www.ncbi.nlm.nih.gov/pubmed/15543008?tool=bestpractice.com 仍需对这一破坏性疾病进行大规模前瞻性研究。

一些治疗似乎可以稳定少数患者的临床和影像学异常；但临床疗效并不明显。

具体的方案包括：静脉给予免疫球蛋白＋泼尼松龙，联合或不联合巯嘌呤和甲氨蝶呤，持续用药 12 个月；[87]Imashuku S, Ishida S, Koike K, et al. Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2004 Nov;26(11):735-9.http://www.ncbi.nlm.nih.gov/pubmed/15543008?tool=bestpractice.com 维甲酸，用药 12 个月；[88]Idbaih A, Donadieu J, Barthez MA, et al. Retinoic acid therapy in "degenerative-like" neuro-Langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer. 2004 Jul;43(1):55-8.http://www.ncbi.nlm.nih.gov/pubmed/15170890?tool=bestpractice.com 以及阿糖胞苷，用药 12 个月，联合或不联合长春新碱。[89]Allen CE, Flores R, Rauch R, et al. Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer. 2010 Mar;54(3):416-23.http://www.ncbi.nlm.nih.gov/pubmed/19908293?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

应与专科医师协商制定化疗方案；以下是一些常用方案。

最近完成的 LCH-III 研究探讨了如下方案的疗效，即长春花碱＋泼尼松龙诱导方案中加入中等剂量甲氨蝶呤、之后给予标准剂量长春花碱＋泼尼松龙和巯基嘌呤方案、联合或不联合低剂量每周一次甲氨蝶呤进行 12 个月的持续治疗。[90]Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14.http://bloodjournal.hematologylibrary.org/content/121/25/5006.longhttp://www.ncbi.nlm.nih.gov/pubmed/23589673?tool=bestpractice.com 结果显示，虽然添加甲氨蝶呤并无收益，但危险器官受累患者，生存期和再激活率得到显著改善。这可能与多种因素有关，包括初始治疗的第二个疗程、长期持续治疗、疾病进展患者有效的补救治疗以及持续改善支持护理。

参考当地专科医生治疗方案作为剂量指导。

在 LCH-III 试验中，危险器官未累及患者接受长春花碱和泼尼松龙、未加用巯基嘌呤。 若诱导治疗第 6 周开始出现疗效，则随机分组接受 疗程为6 或 12 个月的总治疗。 接受 12 个月治疗的患者其 5 年再激活率是 37%，相比之下，接受 6 个月治疗的患者为 54%。[90]Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14.http://bloodjournal.hematologylibrary.org/content/121/25/5006.longhttp://www.ncbi.nlm.nih.gov/pubmed/23589673?tool=bestpractice.com

参考当地专科医生治疗方案作为剂量指导。

对于复发/再激活或难治性患者，无标准挽救治疗方案。 方案的选择取决于患者为单系统还是多系统疾病，以及累及何种器官。 最佳治疗方案有待确定。

长春花碱＋泼尼松龙加巯基嘌呤和甲氨蝶呤已用于复发性骨骼受累患者。[67]Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37(2):108-14.http://www.ncbi.nlm.nih.gov/pubmed/11496348?tool=bestpractice.com

沙利度胺对皮肤或口腔病变累及患者有效。[76]McClain KL, Kozinetz CA. A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007 Jan;48(1):44-9.http://www.ncbi.nlm.nih.gov/pubmed/16333818?tool=bestpractice.com[93]Lair G, Marie I, Cailleux N, et al. Langerhans histiocytosis in adults: cutaneous and mucous lesion regression after treatment with thalidomide [in French]. Rev Med Interne. 1998 Mar;19(3):196-8.http://www.ncbi.nlm.nih.gov/pubmed/9775141?tool=bestpractice.com

克拉屈滨已用于低危患者，如多灶性骨骼受累患者。

有多种方案已被用于复发性多系统疾病，包括：一种长春花生物碱＋一种蒽环类抗生素和一种烷化剂；[94]Arceci RJ, Brenner MK, Pritchard J. Controversies and new approaches to treatment of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998 Apr;12(2):339-57.http://www.ncbi.nlm.nih.gov/pubmed/9561904?tool=bestpractice.com 阿糖胞苷＋长春新碱＋泼尼松龙；[95]Egeler RM, de Kraker J, Voute PA. Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol. 1993;21(4):265-70.http://www.ncbi.nlm.nih.gov/pubmed/8469221?tool=bestpractice.com 克拉屈滨；[96]Rodriguez-Galindo C, Kelly P, Jeng M, et al. Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Am J Hematol. 2002 Mar;69(3):179-84.http://www.ncbi.nlm.nih.gov/pubmed/11891804?tool=bestpractice.com[97]Weitzman S, Wayne AS, Arceci R, et al. Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the Histiocyte Society and review of the literature. Med Pediatr Oncol. 1999 Nov;33(5):476-81.http://www.ncbi.nlm.nih.gov/pubmed/10531572?tool=bestpractice.com[98]Stine KC, Saylors RL, Saccente S, et al. Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004 Jul;43(1):81-4.http://www.ncbi.nlm.nih.gov/pubmed/15170896?tool=bestpractice.com 以及克拉屈滨＋阿糖胞苷。[99]Bernard F, Thomas C, Bertrand Y, et al. Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer. 2005 Nov;41(17):2682-9.http://www.ncbi.nlm.nih.gov/pubmed/16291085?tool=bestpractice.com[100]Apollonsky N, Lipton JM. Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol. 2009 Jan;31(1):53-6.http://www.ncbi.nlm.nih.gov/pubmed/19125089?tool=bestpractice.com 氯法拉滨是第二代核苷类似物，作为单药对克拉屈滨或阿糖胞苷难治性播散型 LCH 具有明显活性，并已报道具有可控毒性的可喜结果。[101]Rodriguez-Galindo C, Jeng M, Khuu P, et al. Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer. 2008 Nov;51(5):703-6.http://www.ncbi.nlm.nih.gov/pubmed/18623218?tool=bestpractice.com[102]Campbell PK, Abraham A, Jeng M, et al. Use of clofarabine in the treatment of refractory and recurrent multisystem Langerhans cell histiocytosis. Proceedings from the XXVI annual meeting of the Histiocyte Society. Boston, MA: Histiocyte Society; 2010.[103]Abraham A, Alsultan A, Jeng M, et al. Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer. 2013 Jun;60(6):E19-22.http://www.ncbi.nlm.nih.gov/pubmed/23255383?tool=bestpractice.com[104]Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer. 2014 Mar;61(3):479-87.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474604/http://www.ncbi.nlm.nih.gov/pubmed/24106153?tool=bestpractice.com

应与专科医师协商确定适当的化疗方案。

参考当地专科医生治疗方案作为剂量指导。

有报道高危患者（即，有危险器官累及的患者）接受ASCT后，病情得到良好控制，但治疗相关死亡率较高。[107]Caselli D, Arico M; EBMT Paediatric Working Party. The role of BMT in childhood histiocytoses. Bone Marrow Transplant. 2008 Jun;41(suppl 2):S8-13.http://www.ncbi.nlm.nih.gov/pubmed/18545250?tool=bestpractice.com