难治性卡波希样血管内皮细胞瘤及卡梅综合征十例临床分析

Refractory kaposiform hemangioendothelioma with Kasabach-Merritt syndrome： clinical analysis of 10 cases

目的 探讨西罗莫司联合泼尼松治疗难治性卡波希样血管内皮细胞瘤（RKHE）及卡梅综合征（KMS）的临床效果.方法 临床资料回顾性分析,收集2014年1月至2017年1月首都儿科研究所附属儿童医院就诊的10例经普萘洛尔、泼尼松、平阳霉素和聚桂醇治疗无效或复发的RKHE和KMS（其中单发RKHE5例,RKHE合并KMS5例,年龄6d～9岁）;西罗莫司治疗剂量0.035 ml/（kg·d）,每天1次,治疗时间6 ～410 d;采用常规组织病理活检及免疫组化检查明确诊断;检测治疗过程中凝血指标和血小板计数的变化,采用B超和标尺计量瘤体及瘀斑的变化;随访记录治疗期间因服用西罗莫司引起的不良反应.结果 10例患儿中男6例,女4例.其中5例RKHE合并KMS临床特征主要表现为顽固复发的暗红色质硬的血管瘤样病变或皮下瘀斑,血小板计数（15 ±7）×10^9/L（均低于30.0×10^9/L）,凝血指标明显异常,纤维蛋白原（0.8 ±0.5）g/L,纤维蛋白裂解产物及D-二聚体（100±23） mg/L、（10 000±2 200） ng/L,凝血酶原时间及部分凝血酶原时间（25.0 ±2.1）s、（58.0 ±3.4）s.活检组织病理特征相似,肿瘤细胞呈梭性,团块状分布,细胞核深染;免疫组化：D2-40、CD31和CD34阳性,Ⅷ因子和GLUT-1阴性;5例RKHE伴发KMS经西罗莫司联合泼尼松治疗（6.5±0.7）d,血小板计数增加至（72.0±0.6）×10^9/L,纤维蛋白原（1.5 ±0.2）g/L,纤维蛋白裂解产物及D-二聚体（7±3） mg/L、（2 300±200） ng/L,凝血酶原时间及部分凝血酶原时间延长至（15.0±2.3）s、（42.0 ±3.4）s,瘤体和瘀斑缩小18％±3％、38％±5％;（30.0 ±5.7）d后血小板计数（146±36）×10^9/L,凝血指标均在正常值范围内,瘀斑消失,瘤体缩小73％±3％;（3.0±0.4）个月后,瘤体缩小93％±2％未触及.5例RKHE未伴发KMS临床表现为暗红色质硬的血管瘤样斑块,血小板及凝血指标均正常,采用西罗莫司治疗（2.0±0.6）个月未合并KMS的RKHE瘤体缩小8％±3％,随着治疗时间延长,（4.0±3.2）个月（2～18个月）后瘤体逐渐变小51％ ±7％.结论 RKHE及KMS具有特征性的临床表现、组织病理特征及实验检查结果,西罗莫司联合泼尼松治疗RKHE及KMS取得了较好的疗效,且不良反应较少.

Objective To analyze the clinical value of sirolimus plus prednisone for the treatment of the refractory kaposiform hemangioendothelioma（RKHE） and Kasabach-Merritt syndrome （KMS）.Method Clinical retrospective analysis was carried out for 10 patients recruited in Children＆#39;s Hospital Affiliated to Capital Institute of Paediatrics from January 2014 to January 2017 who were non responders to or relapsers after the treatment of propranolol,prednisone,pingyangmycin and lauromacrogol （5 cases RKHE,5 cases RKHE plus KMS,age ranged from 6 days to 9 years）;patients were treated with sirolimus at the dosage of 0.035 ml/（kg · d）,once a day,for 6-410 days;the diagnosis of 10 patients were confirmed by pathological biopsy and immunohistochemical examination （IHC）;the difference of the coagulation paraneters and the platelet counts,the size of tumor and ecchymosis at different stages of treatment were recorded and measured by scale and ultrasonography;the side effects of sirolimus were recorded as well.Result Clinical characteristics of 10 cases （6 male and 4 female） RKHE with KMS were refractory dark red hard hemangioma or ecchymosis,the platelet counts were lower than 30.0 ×10^9/L,（15 ±7） ×10^9/L,coagulation tests were obviously abnormal,fibrinogens were significantly decreased （0.8 ± 0.5） g/L,the fibrin lysates and D-dimer were significantly increased （100 ± 23） mg/L,（10 000 ± 2 200） ng/L,the prothrombin time and activated partial thromboplastin time were prolonged （25.0 ± 2.1） s,（58.0 ± 3.4） s.The pathologic characteristics of the tumors were simular：spindle tumor cells,mass distribution and deeply stained nuclei tumor cells.IHC revealed positive staining for D2-40,CD31 and CD34.Stainings for factor Ⅷ and GLUT-1 were negative.In five cases RKHE plus KMS were treated with sirolimus and prednisone.after （6.5 ±0.7） days treatment,the platelet counts were obviously increased （72.0 ± 0.6） ×10^9/L,coagulation parameters were obviously improved,fibrinogen significantly increased （1.5 ± 0.2）g/L.the fibrinlysates and D-dimer significantly decreased （7 ± 3） mg/L,（2 300 ± 200） ng/L,the prothrombin time and activated partial thromboplastin time were prolonged（15 ± 2.3）s,（42 ± 3.4） s,and the sizes of tumor and ecchymosis were slightly shrunken 18% ± 3%,38% ± 5%;after （30 ± 5.7） days treatment,the platelet counts and coagulation parameters returned to normal（146 ± 36） ×10^9/L,and the size of tumor and ecchymosis were obviously shrunken 73% ±3%,97% ±3%;after （3 ±0.4） months treatment,the tumor was obviously shrunken by 93% ± 2% and no longer palpable.In five cases with RKHE without KMS manifested stubborn dark red hard hemangiomatous plaques,coagulation tests and platelet were obviously normal,these patients were treated with sirolimus,after （2.0 ± 0.6） months treatment,the tumor became shrunken 8% ± 3%,with continuous treatment the tumor shrunk gradually,after （4.0 ± 3.2） months （2-18 mouths） the tumor was not eliminated 51% ±7%.Conclusion RKHE and KMS have typical clinical,laboratory and pathological characteristics,sirolimus plus prednisone have remarkable efficacy and minor side effects,it should be recommended for the treatment of KHE with KMS.