Recurrent fibrolamellar hepatocellular carcinoma with biliary invasion: Successful resection

A jaundiced 17-year-old man was diagnosed as having a local recurrence of fibrolamellar hepatocellular carcinoma 2 years and 4 months after left hepatic trisegmentectomy with total caudate lobectomy had been performed. The patient had a tumor occupying the upper part of the extrahepatic and intrahepatic bile ducts. Complete resection of the recurrent tumor was carried out. The patient remains well 3 years after the second surgery. Fibrolamellar hepatocellular carcinoma, a rare type of liver cancer, is a well defined disease entity with distinct clinical and histopathological features and a favorable prognosis. The good prognosis seems to warrant aggressive surgical intervention in patients with recurrences. Therefore, additional surgery for tumor recurrence should be considered. To our knowledge, this is the first report of a case in which a recurrent tumor of fibrolamellar hepatocellular carcinoma invaded the entire bile duct wall was successfully resected.     

肝细胞癌组织中PTEN蛋白表达

探讨抑癌基因PTEN在肝细胞癌 (HCC)组织及癌旁组织的表达、临床意义。采用免疫组织化学SP法检测PTEN。 4例正常肝组织均呈PTEN蛋白阳性 ;HCC及其癌旁肝组织中的阳性率分别为 5 8 8%(2 0 / 34)和 10 0 %(34/ 34) ,两者比较差异有显著性 (P <0 0 5 )。中分化癌阳性率为 77 8%(14 / 18) ,低分化阳性率为 2 5 %(3/ 12 ) ,两者比较差异有显著性 (P <0 0 0 1)。PTEN蛋白表达与年龄、性别、肿瘤大小、有无包膜及门脉癌栓均无明显关系 (P >0 0 5 ) ,但与HCC分化程度明显相关 ,HCC分化愈差 ,PTEN蛋白表达愈弱。PTEN蛋白表达与HCC分化程度明显相关。     

Lamellar fibrosis in the fibrolamellar variant of hepatocellular carcinoma: a role for transforming growth factor beta

Abstract: Transforming growth factor-beta (TGF-β) is a pluripotent regulatory molecule, found in at least five different isoforms. It is produced in many different organs. In the liver, TGF-β is expressed in non-parenchymal cells, but not in hepatocytes. This growth factor is known to induce fibrosis in the course of a variety of pathologic processes. Recently, TGF-β has also been identified in hepatocellular carcinoma (HCC) cells, and the suggestion has been made that this growth factor may play a role in hepatocarcinogenesis. In this study, we report the findings of immunohistochemical stains for TGF-β, performed on paraffin sections of 14 human HCCs of the usual type and 11 examples of the fibrolamellar variant (FLC). TGF-β was detected in tumor cells of 3 HCCs (21%) and 9 FLCs (82%). Compared with the HCCs, the FLCs displayed a more diffuse and intense staining pattern for TGF-β. Our findings suggest that lamellar fibrosis, which is a histologic hallmark of FLC, may be due to the action of TGF-β produced by tumor cells.     

Novel approaches for molecular targeted therapy against hepatocellular carcinoma

Systemic chemotherapy using a multitargeted tyrosine kinase inhibitor is an established treatment for advanced‐stage tumors in various organs. Comprehensive genomic analyses using next‐generation sequencing technology revealed the intra‐ and intertumor heterogeneity of human hepatocellular carcinomas (HCCs), and provided evidence for the use of therapeutic agents effective against multiple targets in tumor cells. Recently, the efficacy and safety of a multitargeted tyrosine kinase inhibitor, lenvatinib, was confirmed by a randomized global phase III trial; thus, lenvatinib was approved as first‐line therapy for HCC, providing a new therapeutic option for patients at an advanced stage. In this article, we introduce the application of molecular targeted therapy using lenvatinib and discuss future aspects of therapeutic options for advanced HCC.     

Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma

Aim: Non‐alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC. Methods: In this retrospective multicenter study conducted in Japan, we examined 19 patients (53% female), who had been previously diagnosed with histologically proven NASH and developed HCC during the follow‐up period. The median age of the patients at the time of initial diagnosis of NASH was 65 years. Results: NASH progressed to HCC after a median follow‐up period of 3.8 years (range: 0.5–11.6 years). All patients had been identified as having HCC during screening, which included 12 patients assessed by ultrasound, four patients assessed with computerized tomography, two patients that underwent serum des‐γ‐carboxy prothrombin testing and one patient that underwent serum α‐fetoprotein testing. The median diameter of HCC tumors was 1.8 cm (range: 0.8–3.0 cm). The majority of patients (n = 13; 68%) presented with only one HCC tumor. The stage of liver fibrosis was significantly more advanced at the time of diagnosis of HCC than at the time of initial diagnosis of NASH, whereas there were no significant differences in the degree of steatosis. Conclusion: Screening for HCC with imaging is necessary not only in NASH patients with advanced fibrosis, but also in those with less advanced forms of fibrosis, particularly if they are old men. Liver fibrosis progresses to a more advanced stage during the development of HCC in NASH patients.     

Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants

The natural history of hepatocellular carcinoma (HCC) varies greatly with the global region, because the carcinogenic factors are not the same among countries. Besides the clinicopathological factors such as tumor characteristics, sex, and age, background liver disease is a major determinant of prognosis. Hepatocellular carcinoma, mainly associated with chemical carcinogens such as aflatoxin, does not have severe background cirrhosis, and grows quickly, whereas HCC developing in association with a virus in a cirrhotic liver generally grows more slowly, and the severity of cirrhosis is the major prognostic factor. The median survival of untreated sub-Saharan African patients is less than 1 month from diagnosis, contrasted by an average survival of 4 months in virus-induced HCC associated with cirrhosis. Tumor characteristics, such as size, number, and growth speed, which vary considerably from case to case, affect the prognosis. Vascular (portal) invasion portends a poor prognosis, and alpha-fetoprotein levels also correlate with prognosis. Several distinct clinical types of HCC occur, namely diffuse-type HCC caused by rapid portal spread of cancer cells, febrile-type caused by poorly differentiated sarcomatoid cancer cells, and cholestatic HCC caused by intraductal invasion; all have a short survival. There are several histological variant forms: combined hepato-cholangiocarcinoma behaves like HCC, with a poorer prognosis because of more frequent lymph node metastases; fibromellar carcinoma, which is relatively common in young Caucasian adults, has a good prognosis if diagnosed early, permitting resection; and cholangiolocellular carcinoma, which derives from the canalicular epithelium, is indistinguishable from HCC, with a similar prognosis.     

牛蒡子苷元对肝癌SMMC-7721细胞增殖、凋亡的影响及机制探讨

目的观察牛蒡子苷元（ARG）对肝癌SMMC-7721细胞增殖、凋亡的影响,并探讨其机制。方法将不同浓度的ARG作用于SMMC-7721细胞,并设不加ARG对照组。MTT法测算细胞增殖抑制率、流式细胞术检测细胞周期及凋亡率,RT-PCR法检测细胞中的Bcl-2 mRNA。结果与对照组比较,随ARG浓度增加,SMMC-7721细胞增殖率逐渐降低（P均〈0.05）,G0/G1期细胞比例显著增加（P均〈0.05）,G2、M、S期细胞比例减少（P均〈0.05）;随ARG浓度增加、作用时间延长,SMMC-7721细胞凋亡率显著增加（P均〈0.05）,Bcl-2 mRNA表达量减少（P均〈0.05）。结论 ARG可明显抑制SMMC-7721细胞增殖并诱导其凋亡;可能与ARG下调细胞中Bcl-2基因的表达有关。     

Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma

BACKGROUND/AIMS: Gastrin is a trophic factor within the normal gastrointestinal tract and is also a mitogen for a number of gastrointestinal and non-gastrointestinal tumours. Precursor forms of gastrin including progastrin (proG) and glycine-extended gastrin (G-gly) as well as the fully processed amidated gastrin (G-NH2) are expressed by tumours. There has been little study of the role of gastrin in either normal liver or liver tumours. The aim of this study was to identify the expression of CCK-B/gastrin receptor (CCK-BR), proG, G-gly and G-NH2 in normal liver and liver tumours. METHODS: Tissue sections from patients with hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinoma as well as normal liver biopsies were assessed for expression of CCK-BR and gastrin isoforms. RESULTS: Most liver tumours express CCK-BR and are able to process gastrin as far as proG and G-gly, although not as far as the amidated form. There appears to be little expression of the receptor and no expression of precursor forms of gastrin in normal liver. CONCLUSIONS: Liver tumours express the CCK-BR and precursor forms of gastrin. This expression may be associated with tumour proliferation.     

HMGB1在肝癌及癌旁肝组织中的表达及意义

目的了解高迁移率族蛋白B1（HMGB1）在肝炎、肝癌癌旁组织、肝癌组织中的表达,及其与肝组织损伤程度、肝癌发生发展的关系。方法慢性乙型肝炎（CHB）患者46例,肝癌癌旁组织标本20例,肝癌组织标本20例（配对组织）,采用常规HE染色法观察肝组织炎症与纤维化程度,用免疫组化方法判断HMGB1在肝组织中的表达。结果（1）正常肝、CHB、癌旁组织、肝癌组织中的HMGB1的表达差异有统计学意义（H=7．29,P=0．027）;（2）肝组织炎症不同分级与HMGB1的表达有等级相关关系（0=0．318,P=0．031）,肝组织纤维化不同程度与HMGB1的表达有等级相关关系（rs=0．296,P=0．042）;（3）肝癌组织中HMGBI的表达与肝癌Edmondson分级间无等级相关关系（rs=0．206,P〉0．05）。结论HMGB1有可能作为反映肝脏炎症和纤维化的间接指标,与肝癌的发生发展密切相关。     

Controversies in staging of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. As the natural history of HCC is better delineated, treatment strategies are in constant evolution. Classic staging systems based on histopathology following resection are often inadequate because the majority of patients present with advanced disease. The dissatisfaction with anatomic staging systems has resulted in the emergence of several new clinical staging systems, which attempt to integrate tumor biology and the underlying function of the nondiseased liver. Tragically, the byproduct of multiple staging strategies is confusion for physicians, patients, and clinical researchers; this undermines the principles on which staging systems are created. To address this issue, a consensus conference was organized in 2002 to identify the best staging strategy for HCC. The purpose of this article is to review the current clinical and pathologic staging strategies and to highlight the recommendations from the consensus conference.     

Diagnostic and therapeutic approach to hepatocellular carcinoma in the USA

It is now apparent that hepatocellular carcinoma is occurring with increasing frequency in the USA. This mirrors a trend that occurred in Japan approximately 10 years earlier. Although the approach to diagnosis and treatment are similar in Japan and the USA, there are some differences. Thus, imaging is the primary modality of diagnosis and computed tomography and magnetic resonance imaging are favored over ultrasound. Liver transplantation is an important modality oftherapy, which is associated with excellent survival and, with the introduction of the Model for End-Stage Liver Disease (MELD) system, there has been a sharp rise in liver transplants performed for hepatocellular carcinoma since 2002.     

DLC-1基因在肝细胞癌组织中表达的研究

目的 研究肝癌缺失基因-1（DLC-1）在人原发性肝癌组织中的表达及与肝细胞癌侵袭转移的关系。方法收集51例复旦大学附属中山医院外科手术切除的肝细胞癌及癌旁正常组织标本,用荧光定量RT-PCR方法分析组织中DLC-1基因的表达。结果在51对配对的肝细胞癌与癌旁无瘤肝组织中,前者DLC-1基因表达水平明显低于后者（P〈0．01）,且高侵袭性肝细胞癌组明显低于低侵袭性肝细胞癌组（P〈0．05）。结论DLC-1基因在HCC组织中呈低表达,其表达水平与其侵袭性高低相关。     

Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer

According to 2002 estimates, 1.35 million people were diagnosed with and 1.18 million died of lung cancer worldwide. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Responses were most pronounced in female non-smokers with adenocarcinoma histology. These patients were found more likely to harbour mutations of the receptor kinase domain, including in-frame deletions in exon 19 (such as deletions of codons 746-750) and point deletions in exon 21 (such as L858R). Other EGFR kinase domain mutations have been found to confer resistance (T790M) or differential susceptibility to erlotinib and gefitinib (E884K). Gene amplification of EGFR also may predict sensitivity, although the mechanism by which this occurs is unclear, because level of expression detected by immunohistochemistry has not been correlated with increased sensitivity. Phenotypic and genotypic epithelial to mesenchymal transition may be an indicator of resistance to EGFR kinase inhibitors. In this article, we review efforts that have been undertaken to identify genomic determinants of drug susceptibility to EGFR tyrosine kinase inhibitors, with particular focus on the role of gene mutations.     

Budd-Chiari syndrome as the primary manifestation of a fibrolamellar hepatocellular carcinoma.

An 18-year-old female patient was admitted with ascites, right upper abdominal tenderness and peripheral edema. Angiography showed complete occlusion of the vena cava inferior up to the level of the right atrium. By open heart surgery, masses of thrombotic material were pulled out of the v. cava inferior/vv. iliacae which histologically contained tumor cell populations consistent with a hepatocellular carcinoma. Celiacography showed a highly vascularized tumor in the right hepatic lobe. Histologically, it proved to be fibrolamellar subtype hepatocellular carcinoma.     

原发性肝细胞癌中cyclin D1基因表达与P16 及CDK4蛋白表达的关系

目的研究cyclin D1基因在原发性肝细胞癌中的表达,并探讨其与P16及CDK4蛋白表达的关系.方法用原位杂交检测cyclin D1基因mRNA表达,免疫组化检测Cyclin D1蛋白表达.结果 6例(14.3%)HCC可检测到cyclin D1基因过表达,5例属Ⅲ-Ⅳ级,1例属Ⅱ级.6例HCC均有CDK4蛋白表达,其中3例为P16蛋白阳性.结论①cyclin D1表达增加只在小部分恶性程度高的HCC中起作用,可能与肿瘤侵袭有关.②在HCC中,cyclin D1基因过表达和(或)P16蛋白丢失均起重要作用.     

超声造影检测肝癌高危患者早期微小肝癌的影像学比较研究

目的:分析超声造影检测肝癌高危患者早期微小肝癌的影像学比较情况。方法:选择我院2013年6月至2018年9月在我院长期随诊的185例肝癌高危患者,分析患者肝内微小结节的常规超声和超声造影检查资料,分析≤2.0cm肝内实质性小病灶的实时超声造影结果。结果:185例肝癌高危患者经超声造影诊断共发现24例(24灶)微小肝癌患者,其中18例表现为快进快出增强模式(占75.0%),经手术及病理证实其中15灶为中度分化癌,2灶为高度分化癌,1灶为透明细胞癌,6例表现为快进同出增强模式(占25.0%),经手术及病理证实其中5灶为高度分化癌,1灶为透明细胞癌;透明细胞癌开始增强时间明显迟于中度分化癌及高度分化癌,组间比较差异具有统计学意义(P<0.05),高度分化癌的开始消退时间明显迟于中度分化癌,组间比较差异具有统计学意义(P<0.05)。结论:超声造影可观察到微小肝癌患者肿瘤内的血流灌注过程,显示不同分化程度的肝肿瘤增强方式及灌注特点,有助于提高患者肝硬化背景下微小肝癌的诊断率。