肝上皮样血管内皮瘤临床特征、诊断、治疗及预后分析

肝上皮样血管内皮瘤临床特征、诊断、治疗及预后分析河北医科大学学位论文使用授权及知识产权归属承诺本学位论文在导师(或指导小组)的指导下，由本人独立完成。

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一} 蕊、、誓i．o蠢：一研究生签名：技新签章：肚／二级隧饕簟．1f ＼譬缪‘每I、≥月拥‘、二：◇一．．．‘‘I、河北医科大学研究生学位论文独创性声明本论文是在导师指导下进行的研究工作及取得的研究成果，除了文中特别加以标注和致谢等内容外，文中不包含其他人已经发表或撰写的研究成果，指导教师对此进行了审定。

本论文由本人独立撰写，文责自负。

研究生签名：越芝聊：年％日砂年l多月叮日万方数据lU L[II I ILI IIII IIII LIIl UllUIY2785077目录中文摘要1英文摘要4英文缩写8研究论文肝上皮样血管内皮瘤临床特征、诊断、治疗及预后分析刖吾9材料与方法9结果10附图 1 7附表27讨论43结论50参考文献 5 l 综述肝上皮样血管内皮瘤的临床特征及诊治策略54致谢：．．71个人简历72万方数据中文摘要肝上皮样血管内皮瘤临床特征、诊断、治疗及预后分析摘要目的：肝上皮样血管内皮瘤(Hepatic epithelioid haemangioendothe．1ioma，r皿HZ)是一种罕见的肝血管肿瘤，其临床过程介于血管瘤和血管肉瘤之间。

多发生于中年女性，临床病程多变，可自行缓解，也可发展为肝衰竭死亡。

本研究对该病的临床特征、诊断、治疗及影响预后的因素进行探索，并寻找中外肝上皮样血管内皮瘤患者的差异。

方法：本文总结了2004年至2014年之间在河北医科大学第四医院确诊的2例肝上皮样血管内皮瘤患者，以及文献检索出的1996年至2014年之间国内外报道的184例病例。

回顾指标包括人口统计学资料，临床特征，诊断，治疗措施及预后。

所有的资料应用SPSS21．0进行统计分析。

当尸值<O．05时认为具有统计学差异。

结果：1好发于中年女性：平均年龄42．6士14岁’(范围3．80岁)，男女比例为2：4．9。

2临床特征缺乏特异性：临床表现多样，最常见的症状体征为上腹痛(40％)，肝脾肿大(13．9％)，食欲不振(13．3％)，腹胀(12．2％)和体重下降(10．6％)，疲劳乏力、上腹不适、胸腹水等是其次常见的症状体征．然而，还有30％的患者是无症状的，为体检时偶然发现。

65．9％的患者为肝内多发病变累及肝脏双叶，只有15．4％的患者为单发病变。

无论是单发病变还是多发病变，均以肝右叶受累最常见。

大多数患者病变局限在肝脏内，31．7％的患者确诊时即出现肝外转移，最常见的为JJO(20．3％)、淋巴结(6．5％)、骨(4．1％)、腹膜(3．3％)和脾(3．3％)受累。

3诊断依赖组织病理学检查：该病的明确诊断需结合实验室、影像学及组织病理学检查。

40．2％的肝上皮样血管内皮瘤患者有肝功能异常表现，其中谷丙转氨酶(24．7％)、谷草转氨酶(23．7％)、总胆红素(10．3％)、碱性磷酸酶(24．7％)、Y一谷氨酰转肽酶(16．5％)增高最常见。

肿瘤标记物(甲胎蛋白、癌胚抗原、糖类抗原19—9)大多在正常水平。

肝上皮样血管内皮瘤的影像学表现为肝内单发或多发结节，多位于肝脏的周边区域，可万方数据中文摘要以融合形成较大结节。

CT平扫显示低密度结节(98．6％)，增强扫描后结节边缘强化(86．4％)。

“肝包膜回缩征’’(18．1％)，“靶征’’(26．2％)和“棒棒糖征"(11．7％)高度提示该病。

然而，最终确诊还需依赖组织病理学检查。

免疫组化染色示FⅧ因子相关抗原(98．9％) 、CD34(99．4％)、CD31(99．1％)阳性率较高。

D2．40仅在上皮样血管内皮瘤表达，而不在其他肝脏肿瘤表达，有望成为诊断该病的新的特异性标志物。

4治疗方法多样，首选手术治疗：本病的治疗包括肝切除(27．9％)、肝移植(17．6％)、单纯的随访观察(14．7％)、肝动脉化疗栓塞术(11．8％)、放化疗(10．3％)、干扰素治疗(4．4％)和其他治疗(包括抗血管生成药物、中药等)(13．2％)。

无论何种治疗方式，总的1年，5年和10年生存率分别为79％，74％和66％。

5症状体征及肝功能是影响预后因素：对可能影响临床预后的因素进行单因素分析，性别、年龄、肿瘤标记物是否增高、有无肝炎、肝内病灶类型(多发／单发)、有无肝外转移、肿瘤是否切除均无统计学意义(尸>O．05)，但有无症状体征、肝功能是否正常能显著影响预后，有统计学意义∽<O．05)。

将单因素分析筛选出的对生存预后有显著影响的变量再进行多因素分析，最终显示有无症状体征及肝功能是否正常均是影响临床预后的独立危险因素。

6中外患者存在差异：中国患者的人口统计学资料、大多数临床特征、影像学表现、组织病理结果与国外人群类似，但国外患者胸、肩背部疼痛及肝功能异常的发生率明显高于中国患者(15％tK 1．4％，P=O．002；54．5％比32．8％，P=O．039)。

确诊时的中国患者的肝外转移率(21％比52．4％尸=o．ooo)显著低于国外患者，尤其是肺转移率(12．3％比35．7％，P= O．002)。

在治疗方面，中国患者选择TACE的比例要高于国外患者(21．6％比O％，P=0．017)。

结论：1肝上皮样血管内皮瘤临床表现及实验室检查缺乏特异性，影像学表现形式多种多样，最终确诊仍需依靠组织病理检查。

免疫组化特点是内皮细胞标记物(FⅧ因子相关抗原，CD34和CD31)呈强阳性表达。

D2—40有望成为诊断该病的新的特异性标志物。

2治疗方面：由于该病的罕见性和I临床病程多变性，目前尚无标准万方数据中文摘要治疗方案。

一般来说，对于可切除患者来说，首选肝切除。

对于弥漫型病变，无法行局部肝切除的患者，无论是否存在肝外受累，肝移植均是最佳选择。

而对于无法手术治疗的患者，最佳治疗方案目前尚有争议，干扰素治疗可能使患者受益。

该病临床病程多变，更应强调个体化治疗的问题。

3该病的预后好于其他肝脏恶性肿瘤，出现系统性症状及肝功能异常的患者提示预后不良。

4国内外患者对比：国外患者更容易出现胸及肩背部疼痛，确诊时肝功能异常及肝外转移率明显高于中国患者，疾病分期较晚。

治疗方面，中国患者选择TACE治疗的比例高于国外人群。

关键词：肝上皮样血管内皮瘤，临床特征，诊断，治疗，生存率，预后因素，国内外对比万方数据英文摘要A retrospective analysis of hepatic epithelioidhaemangioendothelioma cases respect to clinical features，diagnosis，treatment and prognosesABSTRACTobjective：Hepatic epithelioid hemangioendothelioma(HEHE)is a rare hepatic vascular tumor with a clinical course between benign hemangioma and angiosarcoma．It usually affects adult women and its clinical course is nonspecific，ranging from complete remission to hepatic failure and death．Theaim of the study was to recognize the characteristics of HEHE and identifyits prognostic factors．In addition，a comparative study were made to explore the difference between Chinese and foreign patients．Methods：Two cases diagnosed with HEHE in the Fourth Hospital ofHebei Medical University between 2004 and 20 1 4 combined with 1 84and 20 1 4 previously reported cases retrieved from the literature between 1 996were summarized．Parameters such as demographic statistics，clinical manifestations，diagnostic methods，therapeutic methods and clinical outcomewere reviewed．All data were analysed with the SPS S2 1．0 computer software．P<0．05 represented the difference possessing statistical significance．Results：1 General information：The male to female ratio of patients was 2：4．9with the mean age of 42．6+14 years(range，3—80 years)．2 Clinical features：Its clinical manifestations were variable．The typicalmanifestations of HEHE included epigastric pain(40％)，hepatosplenomegaly(13．9％)，inappetence(13．3％)，distension(12．2％)and weight loss(10．6％)，followed by fatigue，epigastric discomfort，hydrothorax and ascite．However,HEHE also had been discovered incidentally in asymptomatic patients(3 0％)．Most of the patientslobes ofpresented with multiple lesions involving boththe hepatic(65．9％)，only 1 5．4％of the patients were single lesion．Whetherthan the leftsingle lesion or multiple lesions，the right lobe was affected more4万方数据英文摘要lobe．3 1．7％of the patients had extra_hepatic metastases．The lungs(20．3％)，lymph nodes(6．5％)，bone(4．1％)，peritoneum(3．3％)and spleen(3．3％)were the mosttime of diagnosis．frequent sites of extrahepatic metastases at the3 Diagnosis：The combined use of laboratory tests，imaging andpathological examinations could help make a diagnosis．40．2％of the patients had abnormal liver function，most common changes were elevated alanine transaminase(舡正24．7％)，aspartate transaminase(AST,23．7％)，total bilirubin(TBIL，1 0．3％)，1，glutamyl transpeptidase(GGT,1 6．5％)and alkaline phosphatase(ALP,24．7％)．Alpha fetoprotein(AFP)，carcinoembryonic antigen(CEA)and carbohydrate antigen l 9—9(CA一1 99)were always in the normal level．On imaging study,most tumors were found in subcapsularand formed large，locations，they presented as multiple hepatic nodulesconfluent masses over time．Abdominal computed tomography(CT) demonstrated round or oval areas of lOW density(98．6％)．Contrast—erdaanced CT showed the peripheral rim of the tumors were enhanced(86．4％)．“Capsular retraction”(18．1％)，“target sign”(26．2％)and“lollipop sign’’(1 1．7％)coulddefinitive diagnosis was highly suggest the diagnosis of HEHE．However,itscompletely dependent on pathological examination．In immunohistochemical staining，the neoplastic cells were positive for factor FN．RAg，CD3 1 and CD34．Among liver tumors，D2—40 was specifically expressed in epithelioid hemangioendothelioma but not in other hepatic tumors．D2．40 would be a useful tumor marker in the diagnoses of HEHE．4 Treatment and survival rate：Management for the HEHE patients included liver resection(LRx，27．9％)，liver transplantation(LTx，1 7．6％)，palliative treatment(1 4．7％)，transhepatic arterial chemotherapy and embolization(TACE， 1 1．8％)，chemotherapy or radiotherapy(1 0．3％)，——the 1-year．5-year and 1 0．year patient survival rates were 79％，74％and 66％．interferon(4．4％)and other treatments(such as antiangiogenic drugs，chinese traditional medicine and SO on)(1 3．2％)．No matter what kind of treatments，5 Prognostic analysis：On univariate analysis：gender,age，tumor万方数据英文摘要memstasis and tumor resection had no significantly(P>0．05)；but symptoms andliver function influenced the prognosis significantly(P<O ．05)．On multiplicityanalysis ：symptoms and liver function were independentprognostic factors ．6 Chinese and foreigner contrast ：The demographicstatistics and most of the clinical manifestations in chinese patients were similar to those found in abroad country ．The incidences of thoracalgia ，humeral back pain and liver dysfunction were significantly higher in foreign patients(15％VS 1．4％， P=0．002；54．5％VS 32．8％，P=0．039)．The percentage of extrahepatic metastasis(2 1％VS52．4％，P=O ．000)was lower in Chinese patients at diagnosis ，especially p ulmonarymetastasis r ate(12．3％VS 35．7％，P=0．002)· TACE was a more commontreatment in china ．Conclusion ：1 Hepatic epithelioid hemangioendothelioma was a rare vascular tumor· Forits nonspecific manifestations and variable imaging findings ，definite diagnosis was depended on pathologic study ．Pathological characteristics of tumor cellswere expressionsof endothelial markers(FVlII —RAg ，CD34 and CD3 1、)．D2—40 would be useful as a diagnostic markerfor HEHE ． 2 For patients with resectable HEHE ，LRx was preferred ．LTx had been proposed as the treatment of choice in patients with unresectableand diffuseHEHE ．Interferon treatment might benefit the patients ．Standardizedtreatment remained undefmed and individualized treatment might exhibit animproved clinical outcome ．3 Its prognosis was ftlrther betterthan that of other hepatic malignant tumors ．Patientswith obvious symptoms and liver dysfunction might encounter apoorerprognosis ．4 Notably,unlike foreigncases ，a number of HEHE patientsin China were asymptomaticwith normal liver function and exhibit less extrahepatic metastasis for a considerable part of the disease course ．Furthemaore ， TACE was a more common treatment option inChina ．万方数据英文摘要Key words：Hepatic epithelioid haemangioendothelioma，Clinical features，Diagnosis，Treatment，Survival rate，Prognostic factor,Chinese and foreigner contrast7万方数据英文缩写英文缩写英文缩写英文全称中文全称AFP Alpha fetoprotein 甲胎蛋白AU Alanine transaminase 谷丙转氨酶AST Aspartate transaminase 谷草转氨酶CEA Carcinoembryonic antigen 癌胚抗原CAl9．9 Carbohydrate antigen 1 9—9 糖类抗原19。