Intrahepatic cholangiocarcinoma: report of 272 patients compared with 5,829 patients with hepatocellular carcinoma

Purpose  To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC. Methods  Comparison of clinicopathologic data was made between patients who underwent hepatectomy for ICC (n = 272) and HCC (n = 5,829) during the same period. Twenty-five clinicopathologic variables were selected for univariate and multivariate analyses to evaluate their influence on prognosis of ICC. Results  Compared with patients with HCC, ICC patients were more common in females and more elderly, had a lower proportion of asymptomatic tumors, lower serum alpha-fetoprotein, higher serum carcinoembryonic antigen, carbohydrate antigen 19–9 and alkaline phosphatase levels; lower incidence of hepatitis history, associated cirrhosis and serum hepatitis B surface antigen; lower proportion of small tumors, well-encapsulated tumors and tumor emboli in the portal vein; higher proportion of single tumor, perihila lymph node involvement and poor differentiation; and less frequency of limited resection (all, P < 0.0001). Distant metastasis was less frequent in patients with ICC (P = 0.027). A total of 5-years overall and disease-free survival (in brackets) after resection was 26.4% (13.1%) and 44.5% (33.1%) (P < 0.0001, P < 0.0001) for patients with ICC and HCC, respectively. Factors influencing survival after resection of ICC can be divided mainly into two categories: early detection of asymptomatic ICC (P < 0.0001) and curative resection (P = 0.002). Conclusion  ICC Patients have distinct clinicopathologic features as compared with HCC patients. Surgery remains the only effective treatment for ICC. Early detection of asymptomatic ICC and curative resection were the key to achieve optimal survival.     

Increased mast cells in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

BACKGROUND/AIMS: Human mast cells are categorized into those positive only for tryptase (MC(T)) and those positive for both tryptase and chymase (MC(TC)). METHODS: We investigated mast cells in "normal" livers (n=13), hepatocellular carcinoma (HCC) (n= 49) and intrahepatic cholangiocarcinoma (ICC) (n= 44) by double immunostaining and quantitative morphometry. RESULTS: In "normal" livers, mast cells were located in portal tracts, and to a lesser extent in the sinusoids. In HCC, mast cells were noted in tumoral sinusoids and fibrous septa. In ICC, many mast cells were present in tumoral stroma. Morphometry showed that densities of mast cells in HCC and ICC were significantly higher than those in "normal" livers. The density of mast cells in ICC (57.6+/-62.4/mm2) was significantly higher than that in HCC (9.32+/-12.9/mm2). The density of sinusoidal mast cells was significantly higher in HCC (1.79+/-2.35/mm2) than in "normal" livers (0.13+/-0.07/mm2). The density of stromal mast cells was significantly higher in ICC (57.6+/-62.4/mm2) than that of portal tracts in "normal" livers (28.4+/-7.0/mm2). MC(T) and MC(TC) were approximately 20% and 80%, respectively, being consistent in any anatomical compartments. CONCLUSIONS: Mast cells increase during carcinogenesis in HCC and ICC, and they may play a role in fibrosis or tumor immunology in HCC and ICC.     

肝内胆管细胞癌患者超声造影表现特征分析

目的 分析肝内胆管细胞癌（ICC）的超声造影 (CEUS)表现特征,旨在为临床诊断提供依据。方法 2014年8月~2016年8月我院诊治的ICC患者64例,接受常规CT、MRI和彩色多普勒超声检查,并与CEUS检查结果进行对比分析。结果 64例患者存在64个肝内病灶,其中46例（71.9%）病灶边界较为模糊,18例（28.1%）边界较为清晰;56例（87.5%）病灶呈低回声,术后组织病理学检查表现为中或低分化,8例（12.5%）病灶也呈低回声,但术后病理学检查提示癌细胞为高分化;彩色多普勒超声检查显示,64例肿瘤病灶少血供26例（40.6%）,无血供38例（59.4%）;CEUS显示,33例（51.6%）ICC患者病灶表现为环状增强向内充填, 10例（15.6%）表现为整体条片状高增强,21例（32.8%）表现为无强化。在门脉期,11个（17.2%）病灶可见造影剂灌注未消退,53个（82.8%）病灶未见造影剂灌注。延迟期均未见造影剂存留;超声造影显示病灶范围较大、不规则,无包膜样结构,而常规CT检查则形态较为规则,MRI平扫T1WI呈混杂低信号,T2WI呈混杂略高或高信号,DWI呈高信号。结论 ICC的超声造影主要表现为病灶边界较为模糊、环形灌注、病灶呈现低回声、于动脉期出现一过性增强、无包膜样结构,了解这些特征有助于作出临床诊断。     

常规超声和超声造影检查诊断肝内胆管细胞癌

目的 探讨肝内胆管细胞癌(ICC)常规超声和超声造影(CEUS)表现.方法 本组纳入52例ICC患者,常规行超声和CEUS检查,组织病理学诊断.结果 灰阶超声表现为均匀低回声者23例(44.2％,不均匀低回声者22例(42.3％),稍高和高回声者7例(13.5％);彩色多普勒血流(CDFI)表现为0级11例(21.2％...     

MSCT与MRI动态增强扫描对高血供肝内胆管癌与肝细胞癌的诊断价值分析

目的 探讨多层螺旋计算机断层扫描(MSCT)与磁共振成像(MRI)动态增强扫描对高血供肝内胆管癌(ICC)和肝细胞癌(HCC)的诊断价值。方法 2018年1月～2019年6月我科诊治的70例原发性肝癌患者,均接受MSCT和MRI动态增强扫描。以手术后组织病理学检查诊断作为金标准,评估两种检查方法的诊断效能。结果 经手术后组织病理学检查,在70例原发性肝癌患者中,诊断ICC 12例,HCC 58例;MSCT检查显示HCC病灶动脉期强化、静脉期强化减退,延迟期持续强化减退;MRI多期扫描检查显示39例HCC患者病灶呈快进快出型强化,17例患者病灶呈快进慢出型强化,2例患者病灶呈慢进慢出型强化。MRI多期扫描发现9例ICC患者病灶呈慢进慢出型,3例患者病灶在动脉期和门脉期未出现明显强化,延迟期逐渐呈均匀性强化;MRI诊断HCC患者56例(96.6%),与CT诊断的53例(91.4%)比,无显著性差异(P>0.05),而诊断ICC患者9例(75.0%),显著高于CT诊断的7例(58.3%,P<0.05)。结论 在富血供的PLC患者,ICC和HCC的影像学表现有所差异,应用MRI增强扫描有利于提高对ICC的诊断检出率,值得临床积累经验和应用。     

Potentiality of combined hepatocellular and intrahepatic cholangiocellular carcinoma originating from a hepatic precursor cell: Immunohistochemical evidence.

Hypothesizing that combined hepatocellular and intrahepatic cholangiocellular carcinoma originates from hepatic stem cells, we conducted a series of immunohistochemical studies using hepatic stem cell markers to better understand the origin of the tumor. Specially, we investigated 15 combined tumors confirmed to be immunoreactive to anti-hepatocyte paraffin 1, and anti-cytokeratin 7 and 19 antibodies. Macroscopic investigation revealed cancer cells morphologically intermediate between neoplastic hepatocytes and cholangiocytes (combined tumor with intermediate morphology) in 11 of 15 tumors. The remaining four tumors lacking these cells were considered ordinary combined tumors. We used 20 hepatocellular carcinomas and 10 cholangiocarcinomas as controls. Immunohistochemical analysis was performed using stem cell markers (c-kit and CD34). Of the 15 combined tumors, 8 stained for c-kit (2 of the 4 ordinary tumors and 6 of the 11 intermediate morphologic tumors). Both of the tumor cell types in both of the ordinary combined tumors stained for c-kit. The c-kit staining was present in cells of all three morphologic types, including the intermediate cells, in all six of the intermediate combined tumors. None of the cells in the combined tumors showed immunoreactivity for CD34. None of the 30 control tumors expressed CD 34 or c-kit. The present study suggests that combined hepatocellular and intrahepatic cholangiocellular carcinomas originate not from a hepatic stem cell, but from a hepatic precursor cell, such as the canal of Hering cell. Alternatively, these tumors might show up-regulation of c-kit in relation to angiogenesis.     

Liver transplantation in patients with incidental hepatocellular carcinoma/cholangiocarcinoma and intrahepatic cholangiocarcinoma:a single-center experience

BACKGROUND: Reports of liver transplantation (LT) in pa-tients with mixed hepatocellular carcinoma/cholangiocarci-noma (HCC/CC) and intrahepatic cholangiocarcinoma (ICC) are modest and have been mostly retrospective after patho-logical categorization in the setting of presumed HCC. Some studies suggest that patients undergoing LT with small and unifocal ICC or mixed HCC/CC can achieve about 40%-60%5-year post-transplant survival. The study aimed to report our experience in patients undergoing LT with explant pathology revealing HCC/CC and ICC.METHODS: From a prospectively maintained database, we performed cohort analysis. We identified 13 patients who un-derwent LT with explant pathology revealing HCC/CC or ICC. RESULTS: The observed recurrence rate post-LT was 31%(4/13) and overall survival was 85%, 51%, and 51% at 1, 3 and 5 years, respectively. Disease-free survival was 68%, 51%, and 41% at 1, 3 and 5 years, respectively. In our cohort, four pa-tients would have qualified for exception points based on up-dated HCC Organ Procurement and Transplantation Network imaging guidelines.CONCLUSIONS: Lesions which lack complete imaging char-acteristics of HCC may warrant pre-LT biopsy to fully eluci-date their pathology. Identified patients with early HCC/CC or ICC may benefit from LT if unresectable. Additionally, incor-porating adjunctive perioperative therapies such as in the case of patients undergoing LT with hilar cholangiocarcinoma may improve outcomes but this warrants further investigation.     

Risk factors for intrahepatic cholangiocarcinoma： A casecontrol study in China

AIM： To carry out a hospital-based case-control study to investigate risk factors for intrahepatic cholangiocarcinoma （ICC） in China. METHODS： A total of 312 ICC cases and 438 matched controls were included in the study. The presence of diabetes mellitus, hypertention, hepatolithiasis, primary sclerosing cholangitis, liver fluke infection （Clonorchis sinensis）, was investigated through clinical records. Blood from all participants was tested for hepatitis B surface antigen （HBsAg） and anti-HCV antibodies. Odds ratios （OR） and 95% confidence intervals （95% CI） were estimated using conditional logistic regression. RESULTS： Compared with controls, ICC patients had a higher prevalence of HBsAg seropositivity （48.4% vs 9.6%, P 〈 0.000）, and hepatolithiasis （5.4% vs 1.1%, P = 0.001）. By multivariate analysis, the significant risk factors for development of ICC were HBsAg seropositivity （adjusted OR, 8.876, 95% CI, 5.973-13.192）, and hepatolithiasis （adjusted OR, 5.765, 95% CI, 1.972-16.851）. The prevalence of anti-HCV seropositivity, diabetes mellitus, hypertention, cigarette smoking, and alcohol consumption were not significantly different between cases and controls. CONCLUSION： These findings suggest that HBV infection and hepatolithiasis are strong risk factors for development of ICC in China.     

超声造影联合血清CA19-9鉴别诊断胆管细胞癌与肝细胞癌应用研究

目的 探讨肝内胆管细胞癌(ICC)与肝细胞癌(HCC)患者超声造影(CEUS)和血清糖类抗原19-9(CA19-9)水平变化特征。方法 经组织病理学检查诊断的ICC患者48例和HCC患者78例,进行CEUS检查,常规检测血清CA19-9。建立鉴别诊断ICC与HCC的多指标二元Logistic回归方程,探索其诊断ICC的价值。结果 45.8%ICC患者以肿瘤周围环状增强为主,显著高于HCC患者的2.6%(P<0.05);58.3%ICC患者造影剂显著廓清,而94.9% HCC呈弱或无廓清(P <0.05);ICC组廓清时间为(54.6±10.2)s,显著早于HCC组【(76.1±25.1)s,P <0.05】;72.9%ICC患者血清CA19-9升高,显著高于HCC组的19.2%(P<0.05);建立多指标联合的二元Logistic诊断模型方程为:Logit(P)=-4.030+2.640×增强模式+2.486×廓清时间+2.579×廓清程度+2.731×血清CA19-9 (U/ml),该模型识别ICC的AUC为0.943,其敏感度和特异度分别为79.2%和93.6%。结论 熟悉ICC与HCC的超声造影表现特征,结合血清CA19-9水平,可以帮助鉴别这两种肿瘤。     

Etiological and clinicopathologic characteristics of intrahepatic cholangiocarcinoma in young patients

AIM:To investigate the prevalence,risk factors,and clinicopathologic characteristics of intrahepatic cholangiocarcinoma(ICC)in young patients.METHODS:A retrospective analysis was performed in ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in Shanghai,China.Among 317 consecutively enrolled patients,40 patients were aged ≤40 years(12.61%).We compared the risk factors and clinicopathologic characteristics of these patients(groupⅠ:n=40)with those aged&gt;40 years(group Ⅱ:n=277).RESULTS:Group I...     

Hepatitis B virus infection: a favorable prognostic factor for intrahepatic cholangiocarcinoma after resection

AIM: To study the prognostic factors for intrahepatic cholangiocarcinoma (ICC) and evaluate the impact of chronic hepatitis B virus (HBV) infection on survival rate of ICC patients. METHODS: A total of 155 ICC patients who underwent macroscopic curative resections (R0 and R1) were enrolled in this retrospective study and divided into group A with HBV infection and group B without HBV infection according to their chronic HBV infection, represented by positive hepatitis B surface antigen (HBsAg) in serum or i...     

肝内胆管癌患者术后预后研究

目的 探讨影响肝内胆管癌（ICC）患者术后生存的因素。方法 2011年12月~2015年2月我院诊治的ICC患者94例,对其中35例行姑息性治疗,即肝内扩张胆管置管引流术,对另59例行根治性肿瘤切除术。采用单因素分析和多因素回归分析影响ICC患者术后生存的因素。结果 经随访,本组94例ICC患者生存期为3~35个月,平均为（26.1±4.6）个月;1 a生存率为76.6%,2a生存率为7.4%;单因素分析显示,ICC肿瘤数目、直径、肿瘤分化、血清CEA、CA19-9和是否发生淋巴结转移和远处转移以及手术方法为影响术后患者生存的因素（P<0.05）;经多因素回归分析,发现肿瘤多发、低程度分化、血清CEA大于25 μg/L、血清CA19-9大于182 U/ml、手术切除组织边缘肿瘤细胞阳性、淋巴结转移和姑息性手术是影响ICC患者术后生存的危险因素（P<0.05）。结论 ICC患者预后差,很多患者在诊断时已失去根治性切除肿瘤的机会,即使获得肿瘤切除而根治的患者仍存在很多影响预后的危险因素,临床医生需认真研究这些因素,而给予相应的处理。     

Clinicopathologic characteristics of intrahepatic cholangiocarcinoma in patients with positive serum a-fetoprotein

AIM：To explore clinicopathologic characteristics of intrahepatic cholangiocarcinoma （ICC） in patients with positive serum a-fetoprotein （AFP）. METHODS：One hundred and thirty one patients who underwent surgical dissection for pathologically confirmed ICC were divided into a positive AFP （〉 20 ng/mL） group （n = 32） and a negative AFP group （n = 99）, whose clinicopathologic features were analyzed and compared. RESULTS：The positive rate of HBsAg and liver cirrhosis of the positive AFP group was higher than that of the negative AFP group, while the positive rate of CA19-9 （〉 37 U/mL） and the lymph node metastasis rate was lower. CONCLUSION：ICC patients with positive AFP share many clinicopathologic similarities with hepatocellular carcinoma.     

Lymphoepithelioma-like cholangiocarcinoma:A mimic of hepatocellular carcinoma on imaging features

Primary lymphoepithelioma-like carcinoma in the liver is extremely rare. A few cases of lymphoepithelioma-like cholangiocarcinoma have been reported, but few radiologic features were described. We reviewed 23 cases of lymphoepithelioma-like cholangiocarcinoma reported between 1996 and 2014 and describe a rare case of a 35-year-old woman in our hospital who was diagnosed with lymphoepithelioma-like cholangiocarcinoma of the liver and was a hepatitis B carrier. The tumor(1.6 cm) in our patient appeared to be hypoechoic in sonographic images and hypodense in computed tomography(CT) images. In addition, it was homogeneous hypointense in T1-weighted magnetic resonance(MR) images(MRI) and hyperintense in T2-weighted MRI. Dynamic gadolinium-enhanced MRI showed typical image pattern of hepatocellular carcinoma(HCC). The patient underwent a laparoscopic left hepatic lobectomy, and the resected tumor consisted of well-differentiated glandular cells with extensive lymphocytic infiltration that were immunoreactive to CK(AE1/AE3), CD3, and CD20. In addition, the tumor was positive for Epstein-Barr virus-encoded RNA in situ hybridization. Finally, lymphoepithelioma-like cholangiocarcinoma was diagnosed. In previous studies, the incidence is highest among middle-aged people. Most tumors appeared to be hypodense with either hypovascular or hypervascular patterns in CT images. This case report is the first study to address sonography, CT, and MRI observations and delineate pathologic correlations. We suggest that the imaging pattern of lymphoepithelioma-like cholangiocarcinoma, either the typical cholangiocarcinoma pattern or a mimic of HCC, should be considered in the differential lists for HCC.     

机器人与开腹手术治疗肝内胆管细胞癌患者近期疗效研究*

目的 比较机器人与传统开腹手术行肝叶切除术治疗肝内胆管细胞癌(ICC)患者的安全性和短期疗效。方法 2019年1月～2020年12月我院诊治的ICC患者27例,其中9例接受机器人手术,18例接受传统开腹肿瘤根治术,比较两组手术情况。结果 两组均完成肿瘤根治术;机器人组和开腹组患者手术时间【(198±32)分对(215±74)分】、术中出血量【200(100,250) ml对(275(200,300)ml】和术中输血次数(0次对2次)均无统计学差异(P>0.05);机器人组和开腹组患者肿瘤直径【4.0(2.5,5.5) cm 对6.3(3.9,6.5) cm】、R0切除率(100.0%对88.0%)和淋巴结转移率(44.4%对38.9%)比较,差异无统计学意义(P>0.05);机器人组术后卧床时间和住院日分别为2(1,2.5)d和7(4,8)d,显著短于开腹组【分别为3(1.8,3.5)d和11(8,12)d,P<0.05】,机器人组住院费用为11.3(9.1,13.5)万,与开腹组的10.1(8.8,11.5)万比,无统计学差异(P>0.05);两组术后并发症发生率为11.1%和27.8%,无统计学差异(P>0.05)。结论 开展机器人肿瘤根治术治疗ICC患者安全,术后恢复快。     

Prognosis of hepatocellular carcinoma expressing cytokeratin 19: Comparison with other liver cancers

AIM: To investigate whether expressing biliary phenotype predicted poor outcome after the surgical treatment in primary liver cancers.METHODS: Out of 204 patients that underwent liver resection due to hepatocellular carcinoma (HCC), liver specimens of 70 patients with HCC were evaluated for biliary components by cytokeratin (CK) 19 immunostain (CK19^- HCC and CK19⁺ HCC). CK19 positivity was defined as membranous and/or cytoplasmic expression in ≥ 5% of tumor cells with moderate or strong intensity. Patients with other primary liver cancers, such as combined HCC and cholangiocarcinoma (cHCC-CC), intrahepatic cholangiocarcinoma (ICC) who received curative liver resection, were also included in the study. Clinical characteristics of CK19^- HCC and CK19⁺ HCC patients, including survival outcome after curative liver resection, were compared with that of cHCC-CC and ICC patients.RESULTS: The overall survival (OS) rate of CK19^- HCC (n = 49) after the curative surgical treatment was 90.7%, and 80.4% at 1 and 5 years after the resection. OS rate of CK19⁺ HCC (n = 21) was 74.3%, 28.9% and OS rate of cHCC-CC (n = 22) was 66.7%, 32.2% at 1 and 5 years after the surgery. For ICC (n = 19), 1 and 5-year-OS rate was 50.2% and 14.3% after the curative resection. The OS rates of CK19⁺ HCC and cHCC-CC were significantly lower than that of CK19^- HCC, but higher than the OS rate of ICC (P = 0.000). There was no statistically significant difference in OS rate between CK19⁺ HCC and cHCC-CC. The disease free survival (DFS) rate of CK19^- HCC was 72.0% and 54.5% at 1 and 3 years after the surgical treatment. DFS rate of CK19⁺ HCC was 53.3%, 34.3% and DFS rate of cHCC-CC was 51.5%, 39.2% at 1 and 3 years after the resection. For ICC, 1 and 3-year-DFS rate was 28.0% and 14.0% after the curative resection. DFS rate of CK19^- HCC was significantly higher than that of ICC (P = 0.017), but marginally higher than DFS rate of either CK19⁺ HCC or cHCC-CC (P = 0.097, P = 0.089, respectively). Predictors of outcome after the surgery of primary liver cancer were pathology of the resected mass, existence of microvascular invasion and accompanying satellite nodule.CONCLUSION: Primary liver cancers with biliary components tended to show poorer surgical outcome. This suggested that immuno-phenotype of liver cancers was as important as their morphological classification.     

肝细胞癌患者肝内病灶超声造影参数变化*

目的 探讨超声造影参数诊断肝细胞癌的应用价值。方法 2018年1月～2021年5月我院收治的HCC患者50例和乙型肝炎肝硬化患者50例,经肝穿组织病理学检查诊断,使用超声造影检查,获得病灶峰值强度(PI)、达峰时间(TTP)、渡越时间(MTT)和上升时间(RT)等参数,记录动脉期、静脉期和延迟期局部血容量和局部血流量。结果 HCC组动脉期局部血容量和局部血流量分别为(3399.7±783.7)rBV和(64.1±18.7)rBF,显著高于肝硬化组【分别为(1363.8±773.5)rBV和(41.9±10.6)rBF,P<0.05】;静脉期和延迟期局部血容量分别为(1325.8±546.3)rBV和(463.2±143.2)rBF,显著低于肝硬化组 【分别为(1775.4±541.3)rBV和(721.2±242.5)rBF,P<0.05】;HCC组病灶RT、TTP和mTT分别为(15.7±8.3)s、(22.6±5.4)s 和(133.5±92.3)s,显著低于肝硬化组【分别为(26.3±6.4)s、(32.3±7.6)s和(160.4±112.8)s,P<0.05】,而PI为(85.2±48.2)dB,显著大于肝硬化组【(31.5±3.5)dB,P<0.05】;以病理学检查诊断为金标准,超声造影定量分析检测诊断的灵敏度为92.0%,特异度为92.0%,准确度为80.0%。结论 应用超声造影定量参数诊断HCC病灶具有很高的临床价值。     

Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience

Intrahepatic cholangiocarcinoma is the second most common primary liver tumor. The aim of this study was to analyze retrospectively the outcome of surgical treatment and prognostic factors. Clinical, histopathological and treatment data of 221 patients treated from 1995 to 2010 at our institution were investigated. Univariate and multivariate analysis of the patient's data was performed. Patients after R0 and R1 resection presented an overall survival of 67% and 54.5% after 1 year and 40% and 36.4% after 3 years, respectively. The survival of patients without resection of the tumor was dismal with 26% and 3.4% after 1 and 3 years, respectively. Survival after resection was not statistically different in cases with R0 versus R1 resection (P = 0.639, log rank). Univariate Cox regression revealed that higher T stages are a significant hazard for survival (P = 0.048, hazard ratio (HR): 1.211, 95% confidence interval (CI): 1.002–2.465). Patients with tumor recurrence had a significantly inferior long‐term survival when compared to patients without recurrence (P < 0.001, log rank). Presence of lymph node metastasis (N1) was an independent prognostic factor for survival after resection in risk‐adjusted multivariate Cox regression (P < 0.001, HR: 2.577, 95% CI: 1.742–3.813). Adjuvant chemotherapy did not improve patient survival significantly (P = 0.550, log rank). Surgical resection is still the best treatment option for intrahepatic cholangiocarcinoma regarding the patient's long‐term survival. R0 and R1 resection enable both better survival rates when compared to surgical exploration without resection. T status, N status, and tumor recurrence seem to be the most important prognostic factors after resection.