肝细胞癌患者细胞免疫功能研究与肝脏少见占位的诊断和鉴别诊断
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摘要
研究背景
研究一
肝细胞肝癌(HCC)的患者常存在机体免疫平衡失调,且这种失调主要以细胞免疫功能受抑制为主,常表现为外周血T淋巴细胞数目的减少或功能的抑制。因此研究肝细胞肝癌患者机体细胞免疫功能的变化对认识肝细胞肝癌的免疫状态、诊断与治疗有着重要的临床意义。免疫系统是人体最复杂的系统之一,免疫细胞特别是淋巴细胞种类繁多,不同细胞的发生发展凋亡和免疫状态每时每刻都处于动态变化之中。单独研究一种淋巴细胞亚群完全不足以展现机体的免疫状态。
研究二
原发于肝脏的占位性病变种类繁多,可分为肝脏瘤样病变、肝脏良性肿瘤、肝脏恶性肿瘤三大类。临床上最常见肝脏原发性占位在瘤样病变中有肝囊肿、肝脓肿等；在肝脏良性肿瘤中有肝海绵状血管瘤等；在肝脏恶性肿瘤中有肝细胞癌(HCC)、肝内胆管癌(胆管细胞型肝癌,IHCC)等。肝脏瘤样病变中有一种常合并发热的肝脏占位性病变-肝脏炎性肌纤维母细胞瘤(IMTL)。这是一种较为罕见的预后良好的肝脏疾病。关于这种肝占位的相对大宗的研究特别是与原发性肝癌(PLC)、肝转移癌(MLC)比较的研究很少。同样为肝脏囊实性占位,肝内胆管囊腺瘤与囊腺癌的良恶性与预后完全不同,且术前无创鉴别诊断十分困难。临床上还有一些少见肝脏占位,比如肝癌合并肝脓肿,有些时候与单纯的肝脓肿难以区分,前者属于肝脏恶性肿瘤,后者属于肝脏瘤样病变,治疗原则以及预后完全不同。目前已有的文献关于这样的明确的鉴别与区分不尽如人意。
研究目的
研究一
初步探究肝细胞肝癌患者预后与淋巴细胞亚群等因素的相关性,以及不同疾病状态各淋巴细胞亚群特别是T细胞亚群的差别,从而达到初步研究HCC患者细胞免疫功能的目的。
研究二
探讨肝脏少见占位的诊断、鉴别诊断以及治疗：1.通过IMTL的临床表现、影像学征象以及病理学特点探讨其诊断和治疗方案；2.探讨肝内胆管囊腺瘤与囊腺癌的术前鉴别诊断；3.探讨脓肿型肝癌(表现为肝脓肿的原发性肝癌)诊治规律,以期早期诊断早期治疗。
研究方法
研究一：选取2009年1月至2010年4月在北京协和医院肝脏外科住院的未合并免疫疾病或应用免疫抑制剂成年患者。其中接受手术治疗的肝细胞肝癌的患者为43例,未手术接受介入治疗临床诊断为肝癌的患者为24例,接受手术治疗的确诊为胆管细胞肝癌的患者为4例,临床诊断肝硬化的患者为3例,接受手术治疗的肝血管瘤患者为4例。收集患者一般情况、血常规、肿瘤标记物、血常规、肿瘤标记物等资料,使用流式细胞仪检测了各组患者淋巴细胞亚群、T细胞亚群,并进行不同组别间比较。
研究二：
1.回顾性分析通过病理确诊的11例IMTL患者的流行病学资料、临床表现、影像学特点等病例资料。将IMTL患者与同期肝细胞肝癌(HCC)、胆管细胞肝癌(IHCC)、肝转移癌(MLC)患者按性别1：4分别配对,对病例资料进行比较分析；2.收集并分析通过病理确诊的15例囊腺癌和24例肝内胆管囊腺瘤的临床资料,结合文献进行讨论；3.回顾性分析14例临床表现类似肝脓肿且通过术后病理确诊的原发性肝癌(脓肿型肝癌),分析临床表现、既往史、辅助检查、治疗方式及预后。
结果
研究一
1.HCC手术组共入组43例患者,其中男性36例,女性7例,平均年龄56.5±12.1岁,至随访结束时(2012年4月)死亡14例,存活24例,3月内死亡2例,占4.7%,1年存活率62.8%,2年存活率34.9%,总体生存期为18.8±8.4月。
2.HCC手术组内死亡亚组AFP较非死亡亚组高(P=0.030),对两组合并瘤栓情况进行比较,发现瘤栓(P=0.001)具有显著统计学差异。单因素分析表明：瘤栓(P=0.000)、AFP(P=0.035)、WBC(P=0.010)、LY比例(P=0.010)、NEUT计数(P=0.018)、NEUT比例(P=0.019)、plt(P=0.013)、CD4+T细胞中纯真亚群CD4+CD45RA+的比例(P=0.026)是HCC手术患者死亡的危险因素。多因素分析表明：AFP(P=0.015)、瘤栓(P=0.001)是HCC患者死亡的独立危险因素。CD4+T细胞纯真亚群(CD4+CD45RA+T细胞)比例在死亡亚组与非死亡亚组之间具有显著统计学差异(P=0.029)。
3.HCC手术患者组T淋巴细胞(CD3+)平均计数高于HCC未手术患者组(P=0.001)。CD4+T细胞在T细胞中的比例方面,HCC手术组患者的平均值高于HCC未手术组,P值为0.008。HCC手术组CD8+T细胞平均计数高于与未手术组(P值为0.020)。CD4/CD8进行统计分析后发现并无明显统计学差异,P值为0.194。对于CD4+CD28+T细胞计数,HCC手术组与HCC未手术组比较后具有统计学差异：P=0.012。HCC手术组患者外周血调节性T细胞(CD4+CD25+CD127T细胞)的比例分别为2.94%±1.72%,经多组间方差分析发现各组间无统计学差异,P值为0.492。 CD8+T细胞功能亚群的计数方面却有一些差异,HCC手术组平均计数为(185±123)/ml, HCC未手术组平均计数为(120±87)/ml,前者高于后者(P=0.037)。
研究二
1.与HCC、IHCC和MLC比较,IMTL患者发病年龄更早(P<0.001)。与HCC相比,IMTL患者的AST更低(P=0.003),ALP更高(P=0.034),与MLC相比,IMTL的GGT更高(P=0.010)。11例患者中只有1例患者的AFP升高(AFP值为98.78ng/ml)。IMTL患者的AFP明显低于HCC(P=0.000),而与IHCC、MLC无明显差异(P值分别为0.558、0.514)。三组患者的CA199均高于IMTL组,P值分别为0.008、0.000、0.022。超声表现上,有9例患者病灶表现为低回声,相反,另三组患者的病灶表现为混杂回声。在增强CT或增强MRI上,IMTL和MLC的病灶表现为周边增强；
2.囊腺癌男10例,女5例,年龄57.93±14.39岁；囊腺瘤男4例,女20例,年龄43.75±12.51岁,P值均为0.002;症状有无、病程长短以及CA199、CEA对比分析无明显统计学差异。囊腺癌组有14例患者病症只位于肝左叶,囊腺瘤组有16例位于肝左叶(P=0.115)。肿瘤最大径分别为7.38±3.98cm、10.21±7.82cm(P=-0.293)。囊腺癌组合并胆管扩张的有5例(5/11),而囊腺瘤组只有1例(1/21)合并胆管扩张(P=0.011)。其他的影像学特点无明显统计学意义。
3.男性12例,女性2例,平均年龄为(56.4±12.6)岁。临床表现有发热、上腹痛或上腹不适、肝区叩痛等,合并乙肝6例,AFP、CA19-9升高者各有4例;病灶位于右肝者8例,位于左肝者1例,5例患者左右肝均有病灶。病灶平均直径为(8.9±3.3)cm,边界欠清晰。CT表现方面,边缘强化者2例,内部不规则强化者7例。11例患者接受了抗感染治疗,但效果不明显。10例接受病灶切除手术治疗,4例行活检术。未行手术治疗的4例患者随访时均已死亡；接受手术治疗的患者7例复发,6例已死亡。
结论
研究一结论表明
1.AFP、瘤栓是HCC手术患者死亡的独立危险因素;
2.CD4+T细胞、CD8+T细胞功能亚群可能与抗肿瘤免疫相关,CD8+CD28+T细胞数目增多提示抗肿瘤免疫增强；
3.淋巴细胞亚群影响因素复杂,肿瘤只是其中一方面,需对CD4+T细胞、CD8+T细胞进一步分型并动态观察后再比较,得出的结果可能更有意义。
研究二结论表明
1.实验室检查、影像学特点以及既往病史有助于IMTL与HCC、IHCC或MLC之间的鉴别诊断。手术切除可治愈IMTL。
2.临床上遇到的肝脏囊实性占位,考虑囊腺癌或囊腺瘤诊断时,年龄偏大的男性,病灶合并邻近胆管扩张有助于诊断肝内囊腺癌,CA199、CEA以及临床表现、其他影像学特点对鉴别诊断帮助不大。
3.脓肿型肝癌术前难以与细菌性肝脓肿鉴别。是否合并乙肝,是否有AFP、CA19-9检测指标升高对术前诊断脓肿型肝癌有帮助。脓肿型肝癌诊断时病情较晚、预后差,术前抗感染治疗不应延误手术时机,应争取早期接受手术治疗。
Background and Objective
PARTI
The immune system of the patients with malignant tumors, such as liver cancer, is often unbalanced. This imbalance mainly manifests the inhibition of the cellular immune function, which shows the reduction in the number of T lymphocytes in peripheral blood or or the inhibition of function of these cells. Therefore, it is of important clinical significance to research the cellular immune function of the patients with hepatocellular carcinoma. This is helpful to understand the change of immune status of the patients and the diagnosis and treatment of HCC. The human immune system is one of the most complex human systems. There are great varieties of immune cells, especially lymphocytes. The occurrence, development and apoptosis of different cell and immune status are in the dynamic changes all the time.
Studying only one lymphocyte subset is totally inadequate to show the body's immune status. This part aims to study the correlativity of the prognosis of the patients with HCC and lymphocyte subsets as well as the differences among lymphocyte subsets, especially T-cell subsets, of the patients in various disease states.
PART II
No.1:Inflammatory myofibroblastic tumor of the liver (IMTL) is a very rare benign disease with a good prognosis. The aim of the current study was to determine the clinical, radiological, and pathological characteristics of IMTL. The diagnosis and treatment strategies were discussed; No.2:Intrahepatic biliary cystadenocarcinomas and cystadenomas share similar radiological and clinicopathological features, and the differential diagnosis is difficult. Our study aims to give a tactics to differ intrahepatic bilibary cystadenomas from cystadenocarcinomas in diagnosis; No.3:To discussed the abscess type of primary liver cancer (presented as liver abscess) for the purpose of the early diagnosis and treatment.
Methods
PARTI
Adult patients were chosen who admitted in the liver surgery department of Peking Union Medical College Hospital from January2009to April2010. These patients were not consolidated with immune diseases and taking any immunosuppressive agents. These patients were divided into five groups:HCC undergoing surgery Group (43cases), HCC undergoing no surgery Group (24cases) IHCC Group (4cases), Cirrhosis Group (3cases) and hepatic hemangioma Group (4cases). Data on laboratory tests, history, symptoms and signs of the patients were collected. Lymphocyte subsets of patients with hepatocellular carcinoma, bile duct carcinoma patients, cirrhosis and hemangioma,were detected by flow cytometry and compared between different groups.
PART II
No.1:A total of eleven patients with pathologically confirmed IMTL receiving treatment at Peking Union Medical College Hospital over a15-year period were reviewed retrospectively. The analysis included demographics information and pertinent clinical data. Results were compared that obtained from patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (IHCC) and, metastatic liver cancer (MLC) receiving surgical resetion. No.2:Patients with a pathological diagnosis of cystadenocarcinomas and hepatobiliary cystadenomas were retrospectively reviewed from January1991to July2012; No.3:Patients presenting as with a pathological diagnosis of primary liver cancer (PLC) were retrospectively reviewed from January2009to August2012.
Results
PARTI
43patients,36males and7females were enrolled into the HCC operation group. The mean age was56.5±12.1years.14patients had died until the end of the follow-up, while24cases survived.2patients died in3months after surgery, accounting for4.7%. The one-year and two-year survival rate were62.8%,34.9%, respectively. The overall survival time was18.8±8.4months. The serum AFP of death sub-group was higher than that of non-death sub-group (P=0.030). The number of tumor thrombus of the patients in death sub-group was more (P=0.001). Univariate analysis showed:tumor thrombus (P=0.000), AFP (P=0.035), WBC (P=0.010), the LY proportion (P=0.010), the Neut count (P=0.018), the Neut proportion (P=0.019), plt (P=0.013), and CD4+CD45RA+proportion (P=0.026) were risk factors of death for the patients with HCC after surgery. Multivariate analysis showed that:AFP (P=0.015) and tumor thrombus (P=0.001) were the independent risk factors of death for those patients. CD4+T cells innocence subsets (CD4+CD45RA+T cells) proportion of the death sub-group of death was significantly higher than that of the non-death sub-group(P=0.029). The average count of T lymphocytes (CD3+) of the patients in HCC surgery group was higher than of patients in HCC non-surgery group, respectively (P=0.001), as well as the average count CD3+CD8+T cells (P=0.020), the proportion of CD4+T cells in T cells (P=0.008) and CD4+CD28+T-cell count (P=0.012). There was no statistically significant difference of CD4/CD8between the two groups (P=0.194). The proportion of regulatory T cells (CD4+CD25+CD127" T cells) in peripheral blood of HCC surgery patients were2.94%±1.72%, there was no significant difference among each groups (P=0.492).
PART II
No.1:In comparison to HCC, IHCC, and MLC, IMTL has an earlier onset (P＜0.001). IMTL patients had significantly lower AST (P=0.003) and higher ALP (P=0.034) than HCC patients, and higher GGT (P=0.010) than MLC patients. Increased serum alpha-fetoprotein (AFP) level was detected in only one out of the11IMTL patients (98.78ng/ml). Serum AFP was significantly lower in patients with IMTL (P=0.000) than in those with HCC but not IHCC (P=0.558) or MLC (P=0.514). In contrast to elevated serum CA19-9in patients with HCC/IHCC/MLC, the serum CA19-9in IMTL cases was generally within the normal range (vs. HCC P=0.008; vs. IHCC P=0.000; vs. MLC P=0.022). In9IMTL patients, the tumor appeared as a hypoechogenic solid mass on the ultrasonography. In contrast, most patients with HCC, IHCC, or MLC showed hybrid echo. In contrast CT and MRI, the lesion of IMTL and MLC appeared as peripheral enhancement.
No.2:Thirty-nine patients had pathologically diagnosed Intrahepatic biliary cystadenocarcinomas (15/39,10males and5females, mean age:57.93±14.39years) or cystadenomas (24/33,4males and20females, mean age:43.75±12.51years). Significant differences were both shown in age (P=0.002) and gender (P=0.002) between Intrahepatic biliary cystadenocarcinoma and cystadenoma. There were no significant differences in symptom, symptom duration, CA199and CEA. In the cystadenocarcinoma group, the lesions of14cases located only in the left lobe of the liver, while16cases in the cystadenoma group (P=0.115). The maximum diameter of the tumors were7.38±3.98cm and10.21±7.82cm (P=0.293), respectively.5(5/11) Cystadenocarcinoma patients were combined with with introhepatic biliary dilatation nearby the lesions, while only1cystadenoma patient (1/21)(P=0.011) had the feature. Other imaging characteristics had no statistically significances.
No.3:The clinical feature of the14patients (12males and2females, with an average age of (56.4±12.6) years) included fever, right-upper-quadrant abdominal pain or discomfort, tenderness in the right-upper-quadrant abdomen. There were6patients who were accompanied with hepatitis B. The number of patients with either AFP or CA19-9was4, respectively. Patients whose lesions located in the right hepatic lobe, left and the whole liver were eight, one and five respectively. The average diameter was (8.9±3.3) cm, with less clear boundaries.2patients had edge enhancement on CT, and7had internal irregular enhancement.11patients were given anti-infection treatment, which was not effective.10patients (6died when followed up) underwent lesion resection, while4cases (all died) underwent biopsies.
Conclusions
PARTⅠ
1. Serum AFP and tumor thrombus were independent risk factors of death for the patients with HCC after surgery;
2. CD4+T cells, CD8+T cell subsets may be associated with anti-tumor immune. The increase of CD8+CD28+T cells might enhance anti-tumor immune;
3. There were so many complicated factors affecting lymphocyte subsets. Tumor was only one of these factors. The results might be more meaningful if CD4+T cells and CD8+T cells could be divided into more sub-type and dynamically observed in detail.
PART Ⅱ
1. Lab tests, imaging features, and patient history are helpful in differential diagnosis of IMTL from HCC/IHCC/MLC. Surgical resection is curative for IMTL.
2. Older age and male gender are associated with higher possibility of biliary cystadenocarcinoma. Intra-hepatic bile duct dilation near the lesion by radiology might be instrumental. CA19-9, CEA, clinical manifestations, and other imaging features are not of value for the differential diagnosis of cystadenocarcinoma and cystadenoma.
3. It is difficult to differentiate the abscess type of PLC from bacterial liver abscess before surgery or biopsy. A history of hepatitis B, increased AFP or CA19-9is helpful to identify primary liver cancer presenting as liver abscess. Preoperative anti-infective therapy should not delay surgery. It is often late to diagnose the type of PLC, with the prognosis being poor. Therefore, those patients suspected of this special type of PLC should undergo surgery as early as possible.
研究一
肝细胞肝癌(HCC)的患者常存在机体免疫平衡失调,且这种失调主要以细胞免疫功能受抑制为主,常表现为外周血T淋巴细胞数目的减少或功能的抑制。因此研究肝细胞肝癌患者机体细胞免疫功能的变化对认识肝细胞肝癌的免疫状态、诊断与治疗有着重要的临床意义。免疫系统是人体最复杂的系统之一,免疫细胞特别是淋巴细胞种类繁多,不同细胞的发生发展凋亡和免疫状态每时每刻都处于动态变化之中。单独研究一种淋巴细胞亚群完全不足以展现机体的免疫状态。
研究二
原发于肝脏的占位性病变种类繁多,可分为肝脏瘤样病变、肝脏良性肿瘤、肝脏恶性肿瘤三大类。临床上最常见肝脏原发性占位在瘤样病变中有肝囊肿、肝脓肿等；在肝脏良性肿瘤中有肝海绵状血管瘤等；在肝脏恶性肿瘤中有肝细胞癌(HCC)、肝内胆管癌(胆管细胞型肝癌,IHCC)等。肝脏瘤样病变中有一种常合并发热的肝脏占位性病变-肝脏炎性肌纤维母细胞瘤(IMTL)。这是一种较为罕见的预后良好的肝脏疾病。关于这种肝占位的相对大宗的研究特别是与原发性肝癌(PLC)、肝转移癌(MLC)比较的研究很少。同样为肝脏囊实性占位,肝内胆管囊腺瘤与囊腺癌的良恶性与预后完全不同,且术前无创鉴别诊断十分困难。临床上还有一些少见肝脏占位,比如肝癌合并肝脓肿,有些时候与单纯的肝脓肿难以区分,前者属于肝脏恶性肿瘤,后者属于肝脏瘤样病变,治疗原则以及预后完全不同。目前已有的文献关于这样的明确的鉴别与区分不尽如人意。
研究目的
研究一
初步探究肝细胞肝癌患者预后与淋巴细胞亚群等因素的相关性,以及不同疾病状态各淋巴细胞亚群特别是T细胞亚群的差别,从而达到初步研究HCC患者细胞免疫功能的目的。
研究二
探讨肝脏少见占位的诊断、鉴别诊断以及治疗：1.通过IMTL的临床表现、影像学征象以及病理学特点探讨其诊断和治疗方案；2.探讨肝内胆管囊腺瘤与囊腺癌的术前鉴别诊断；3.探讨脓肿型肝癌(表现为肝脓肿的原发性肝癌)诊治规律,以期早期诊断早期治疗。
研究方法
研究一：选取2009年1月至2010年4月在北京协和医院肝脏外科住院的未合并免疫疾病或应用免疫抑制剂成年患者。其中接受手术治疗的肝细胞肝癌的患者为43例,未手术接受介入治疗临床诊断为肝癌的患者为24例,接受手术治疗的确诊为胆管细胞肝癌的患者为4例,临床诊断肝硬化的患者为3例,接受手术治疗的肝血管瘤患者为4例。收集患者一般情况、血常规、肿瘤标记物、血常规、肿瘤标记物等资料,使用流式细胞仪检测了各组患者淋巴细胞亚群、T细胞亚群,并进行不同组别间比较。
研究二：
1.回顾性分析通过病理确诊的11例IMTL患者的流行病学资料、临床表现、影像学特点等病例资料。将IMTL患者与同期肝细胞肝癌(HCC)、胆管细胞肝癌(IHCC)、肝转移癌(MLC)患者按性别1：4分别配对,对病例资料进行比较分析；2.收集并分析通过病理确诊的15例囊腺癌和24例肝内胆管囊腺瘤的临床资料,结合文献进行讨论；3.回顾性分析14例临床表现类似肝脓肿且通过术后病理确诊的原发性肝癌(脓肿型肝癌),分析临床表现、既往史、辅助检查、治疗方式及预后。
结果
研究一
1.HCC手术组共入组43例患者,其中男性36例,女性7例,平均年龄56.5±12.1岁,至随访结束时(2012年4月)死亡14例,存活24例,3月内死亡2例,占4.7%,1年存活率62.8%,2年存活率34.9%,总体生存期为18.8±8.4月。
2.HCC手术组内死亡亚组AFP较非死亡亚组高(P=0.030),对两组合并瘤栓情况进行比较,发现瘤栓(P=0.001)具有显著统计学差异。单因素分析表明：瘤栓(P=0.000)、AFP(P=0.035)、WBC(P=0.010)、LY比例(P=0.010)、NEUT计数(P=0.018)、NEUT比例(P=0.019)、plt(P=0.013)、CD4+T细胞中纯真亚群CD4+CD45RA+的比例(P=0.026)是HCC手术患者死亡的危险因素。多因素分析表明：AFP(P=0.015)、瘤栓(P=0.001)是HCC患者死亡的独立危险因素。CD4+T细胞纯真亚群(CD4+CD45RA+T细胞)比例在死亡亚组与非死亡亚组之间具有显著统计学差异(P=0.029)。
3.HCC手术患者组T淋巴细胞(CD3+)平均计数高于HCC未手术患者组(P=0.001)。CD4+T细胞在T细胞中的比例方面,HCC手术组患者的平均值高于HCC未手术组,P值为0.008。HCC手术组CD8+T细胞平均计数高于与未手术组(P值为0.020)。CD4/CD8进行统计分析后发现并无明显统计学差异,P值为0.194。对于CD4+CD28+T细胞计数,HCC手术组与HCC未手术组比较后具有统计学差异：P=0.012。HCC手术组患者外周血调节性T细胞(CD4+CD25+CD127T细胞)的比例分别为2.94%±1.72%,经多组间方差分析发现各组间无统计学差异,P值为0.492。 CD8+T细胞功能亚群的计数方面却有一些差异,HCC手术组平均计数为(185±123)/ml, HCC未手术组平均计数为(120±87)/ml,前者高于后者(P=0.037)。
研究二
1.与HCC、IHCC和MLC比较,IMTL患者发病年龄更早(P<0.001)。与HCC相比,IMTL患者的AST更低(P=0.003),ALP更高(P=0.034),与MLC相比,IMTL的GGT更高(P=0.010)。11例患者中只有1例患者的AFP升高(AFP值为98.78ng/ml)。IMTL患者的AFP明显低于HCC(P=0.000),而与IHCC、MLC无明显差异(P值分别为0.558、0.514)。三组患者的CA199均高于IMTL组,P值分别为0.008、0.000、0.022。超声表现上,有9例患者病灶表现为低回声,相反,另三组患者的病灶表现为混杂回声。在增强CT或增强MRI上,IMTL和MLC的病灶表现为周边增强；
2.囊腺癌男10例,女5例,年龄57.93±14.39岁；囊腺瘤男4例,女20例,年龄43.75±12.51岁,P值均为0.002;症状有无、病程长短以及CA199、CEA对比分析无明显统计学差异。囊腺癌组有14例患者病症只位于肝左叶,囊腺瘤组有16例位于肝左叶(P=0.115)。肿瘤最大径分别为7.38±3.98cm、10.21±7.82cm(P=-0.293)。囊腺癌组合并胆管扩张的有5例(5/11),而囊腺瘤组只有1例(1/21)合并胆管扩张(P=0.011)。其他的影像学特点无明显统计学意义。
3.男性12例,女性2例,平均年龄为(56.4±12.6)岁。临床表现有发热、上腹痛或上腹不适、肝区叩痛等,合并乙肝6例,AFP、CA19-9升高者各有4例;病灶位于右肝者8例,位于左肝者1例,5例患者左右肝均有病灶。病灶平均直径为(8.9±3.3)cm,边界欠清晰。CT表现方面,边缘强化者2例,内部不规则强化者7例。11例患者接受了抗感染治疗,但效果不明显。10例接受病灶切除手术治疗,4例行活检术。未行手术治疗的4例患者随访时均已死亡；接受手术治疗的患者7例复发,6例已死亡。
结论
研究一结论表明
1.AFP、瘤栓是HCC手术患者死亡的独立危险因素;
2.CD4+T细胞、CD8+T细胞功能亚群可能与抗肿瘤免疫相关,CD8+CD28+T细胞数目增多提示抗肿瘤免疫增强；
3.淋巴细胞亚群影响因素复杂,肿瘤只是其中一方面,需对CD4+T细胞、CD8+T细胞进一步分型并动态观察后再比较,得出的结果可能更有意义。
研究二结论表明
1.实验室检查、影像学特点以及既往病史有助于IMTL与HCC、IHCC或MLC之间的鉴别诊断。手术切除可治愈IMTL。
2.临床上遇到的肝脏囊实性占位,考虑囊腺癌或囊腺瘤诊断时,年龄偏大的男性,病灶合并邻近胆管扩张有助于诊断肝内囊腺癌,CA199、CEA以及临床表现、其他影像学特点对鉴别诊断帮助不大。
3.脓肿型肝癌术前难以与细菌性肝脓肿鉴别。是否合并乙肝,是否有AFP、CA19-9检测指标升高对术前诊断脓肿型肝癌有帮助。脓肿型肝癌诊断时病情较晚、预后差,术前抗感染治疗不应延误手术时机,应争取早期接受手术治疗。
Background and Objective
PARTI
The immune system of the patients with malignant tumors, such as liver cancer, is often unbalanced. This imbalance mainly manifests the inhibition of the cellular immune function, which shows the reduction in the number of T lymphocytes in peripheral blood or or the inhibition of function of these cells. Therefore, it is of important clinical significance to research the cellular immune function of the patients with hepatocellular carcinoma. This is helpful to understand the change of immune status of the patients and the diagnosis and treatment of HCC. The human immune system is one of the most complex human systems. There are great varieties of immune cells, especially lymphocytes. The occurrence, development and apoptosis of different cell and immune status are in the dynamic changes all the time.
Studying only one lymphocyte subset is totally inadequate to show the body's immune status. This part aims to study the correlativity of the prognosis of the patients with HCC and lymphocyte subsets as well as the differences among lymphocyte subsets, especially T-cell subsets, of the patients in various disease states.
PART II
No.1:Inflammatory myofibroblastic tumor of the liver (IMTL) is a very rare benign disease with a good prognosis. The aim of the current study was to determine the clinical, radiological, and pathological characteristics of IMTL. The diagnosis and treatment strategies were discussed; No.2:Intrahepatic biliary cystadenocarcinomas and cystadenomas share similar radiological and clinicopathological features, and the differential diagnosis is difficult. Our study aims to give a tactics to differ intrahepatic bilibary cystadenomas from cystadenocarcinomas in diagnosis; No.3:To discussed the abscess type of primary liver cancer (presented as liver abscess) for the purpose of the early diagnosis and treatment.
Methods
PARTI
Adult patients were chosen who admitted in the liver surgery department of Peking Union Medical College Hospital from January2009to April2010. These patients were not consolidated with immune diseases and taking any immunosuppressive agents. These patients were divided into five groups:HCC undergoing surgery Group (43cases), HCC undergoing no surgery Group (24cases) IHCC Group (4cases), Cirrhosis Group (3cases) and hepatic hemangioma Group (4cases). Data on laboratory tests, history, symptoms and signs of the patients were collected. Lymphocyte subsets of patients with hepatocellular carcinoma, bile duct carcinoma patients, cirrhosis and hemangioma,were detected by flow cytometry and compared between different groups.
PART II
No.1:A total of eleven patients with pathologically confirmed IMTL receiving treatment at Peking Union Medical College Hospital over a15-year period were reviewed retrospectively. The analysis included demographics information and pertinent clinical data. Results were compared that obtained from patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (IHCC) and, metastatic liver cancer (MLC) receiving surgical resetion. No.2:Patients with a pathological diagnosis of cystadenocarcinomas and hepatobiliary cystadenomas were retrospectively reviewed from January1991to July2012; No.3:Patients presenting as with a pathological diagnosis of primary liver cancer (PLC) were retrospectively reviewed from January2009to August2012.
Results
PARTI
43patients,36males and7females were enrolled into the HCC operation group. The mean age was56.5±12.1years.14patients had died until the end of the follow-up, while24cases survived.2patients died in3months after surgery, accounting for4.7%. The one-year and two-year survival rate were62.8%,34.9%, respectively. The overall survival time was18.8±8.4months. The serum AFP of death sub-group was higher than that of non-death sub-group (P=0.030). The number of tumor thrombus of the patients in death sub-group was more (P=0.001). Univariate analysis showed:tumor thrombus (P=0.000), AFP (P=0.035), WBC (P=0.010), the LY proportion (P=0.010), the Neut count (P=0.018), the Neut proportion (P=0.019), plt (P=0.013), and CD4+CD45RA+proportion (P=0.026) were risk factors of death for the patients with HCC after surgery. Multivariate analysis showed that:AFP (P=0.015) and tumor thrombus (P=0.001) were the independent risk factors of death for those patients. CD4+T cells innocence subsets (CD4+CD45RA+T cells) proportion of the death sub-group of death was significantly higher than that of the non-death sub-group(P=0.029). The average count of T lymphocytes (CD3+) of the patients in HCC surgery group was higher than of patients in HCC non-surgery group, respectively (P=0.001), as well as the average count CD3+CD8+T cells (P=0.020), the proportion of CD4+T cells in T cells (P=0.008) and CD4+CD28+T-cell count (P=0.012). There was no statistically significant difference of CD4/CD8between the two groups (P=0.194). The proportion of regulatory T cells (CD4+CD25+CD127" T cells) in peripheral blood of HCC surgery patients were2.94%±1.72%, there was no significant difference among each groups (P=0.492).
PART II
No.1:In comparison to HCC, IHCC, and MLC, IMTL has an earlier onset (P＜0.001). IMTL patients had significantly lower AST (P=0.003) and higher ALP (P=0.034) than HCC patients, and higher GGT (P=0.010) than MLC patients. Increased serum alpha-fetoprotein (AFP) level was detected in only one out of the11IMTL patients (98.78ng/ml). Serum AFP was significantly lower in patients with IMTL (P=0.000) than in those with HCC but not IHCC (P=0.558) or MLC (P=0.514). In contrast to elevated serum CA19-9in patients with HCC/IHCC/MLC, the serum CA19-9in IMTL cases was generally within the normal range (vs. HCC P=0.008; vs. IHCC P=0.000; vs. MLC P=0.022). In9IMTL patients, the tumor appeared as a hypoechogenic solid mass on the ultrasonography. In contrast, most patients with HCC, IHCC, or MLC showed hybrid echo. In contrast CT and MRI, the lesion of IMTL and MLC appeared as peripheral enhancement.
No.2:Thirty-nine patients had pathologically diagnosed Intrahepatic biliary cystadenocarcinomas (15/39,10males and5females, mean age:57.93±14.39years) or cystadenomas (24/33,4males and20females, mean age:43.75±12.51years). Significant differences were both shown in age (P=0.002) and gender (P=0.002) between Intrahepatic biliary cystadenocarcinoma and cystadenoma. There were no significant differences in symptom, symptom duration, CA199and CEA. In the cystadenocarcinoma group, the lesions of14cases located only in the left lobe of the liver, while16cases in the cystadenoma group (P=0.115). The maximum diameter of the tumors were7.38±3.98cm and10.21±7.82cm (P=0.293), respectively.5(5/11) Cystadenocarcinoma patients were combined with with introhepatic biliary dilatation nearby the lesions, while only1cystadenoma patient (1/21)(P=0.011) had the feature. Other imaging characteristics had no statistically significances.
No.3:The clinical feature of the14patients (12males and2females, with an average age of (56.4±12.6) years) included fever, right-upper-quadrant abdominal pain or discomfort, tenderness in the right-upper-quadrant abdomen. There were6patients who were accompanied with hepatitis B. The number of patients with either AFP or CA19-9was4, respectively. Patients whose lesions located in the right hepatic lobe, left and the whole liver were eight, one and five respectively. The average diameter was (8.9±3.3) cm, with less clear boundaries.2patients had edge enhancement on CT, and7had internal irregular enhancement.11patients were given anti-infection treatment, which was not effective.10patients (6died when followed up) underwent lesion resection, while4cases (all died) underwent biopsies.
Conclusions
PARTⅠ
1. Serum AFP and tumor thrombus were independent risk factors of death for the patients with HCC after surgery;
2. CD4+T cells, CD8+T cell subsets may be associated with anti-tumor immune. The increase of CD8+CD28+T cells might enhance anti-tumor immune;
3. There were so many complicated factors affecting lymphocyte subsets. Tumor was only one of these factors. The results might be more meaningful if CD4+T cells and CD8+T cells could be divided into more sub-type and dynamically observed in detail.
PART Ⅱ
1. Lab tests, imaging features, and patient history are helpful in differential diagnosis of IMTL from HCC/IHCC/MLC. Surgical resection is curative for IMTL.
2. Older age and male gender are associated with higher possibility of biliary cystadenocarcinoma. Intra-hepatic bile duct dilation near the lesion by radiology might be instrumental. CA19-9, CEA, clinical manifestations, and other imaging features are not of value for the differential diagnosis of cystadenocarcinoma and cystadenoma.
3. It is difficult to differentiate the abscess type of PLC from bacterial liver abscess before surgery or biopsy. A history of hepatitis B, increased AFP or CA19-9is helpful to identify primary liver cancer presenting as liver abscess. Preoperative anti-infective therapy should not delay surgery. It is often late to diagnose the type of PLC, with the prognosis being poor. Therefore, those patients suspected of this special type of PLC should undergo surgery as early as possible.
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