Are oral contraceptive-associated liver cell adenomas premalignant?

From January 1977 to June 1990, 1,670 patients with a liver mass or masses underwent transabdominal fine needle aspiration biopsy of the liver. Of those cases, 99 were diagnosed cytologically as "hepatocellular carcinoma" and 9 as "consistent with liver cell adenoma." Among the 99 patients with hepatocellular carcinoma, 3 were users of oral contraceptives. The nine patients with liver cell adenoma were all users of oral contraceptives. Of them, two developed foci or areas of liver cell dysplasia within the adenomas. The mean periods of oral contraceptive use among these three groups of patients were different. It appeared that patients started to develop liver cell adenoma after five years of oral contraceptive use (mean, 6.3 years). Foci or areas of liver cell dysplasia began to arise within liver cell adenomas after 8 years of oral contraceptive use (mean, 9 years), and the patients started to develop hepatocellular carcinoma after 10 years of contraceptive use (mean, 11 years). The cytologic features of liver cell dysplasia strikingly mimicked those of hepatocellular carcinoma. From this study, the foci or areas of liver cell dysplasia appear to be the missing link responsible for the transformation of liver cell adenoma to carcinoma. It is believed that liver cell adenomas are not premalignant and may undergo reversible change after withdrawal of causative agents, whereas foci or areas of liver cell dysplasia within the adenomas are irreversible, premalignant changes and may transform into hepatocellular carcinoma.     

Detection of somatostatin receptors in human osteosarcoma

Background

Morbid obesity strongly predicts morbidity and mortality in surgical patients. However, obesity's impact on outcome after major liver resection is unknown.

Case presentation

We describe the management of a large hepatocellular carcinoma in a morbidly obese patient (body mass index >50 kg/m²). Additionally, we propose a strategy for reducing postoperative complications and improving outcome after major liver resection.

Conclusion

To our knowledge, this is the first report of major liver resection in a morbidly obese patient with hepatocellular carcinoma. The approach we used could make this operation nearly as safe in obese patients as it is in their normal-weight counterparts.     

Smo 蛋白在肝癌和肝硬化中的表达及临床意义

目的:研究Smoothened(SMO)在肝癌和肝硬化中的表达及临床意义。方法:选取组织标本后,运用石蜡包埋,切片后,HE染色,构建组织芯片,免疫组织化学和原位杂交方法检测Smo蛋白在肝癌和肝硬化中的表达。结果:Smo蛋白在肝癌细胞浆、良性肝肿瘤组织细胞浆、肝硬化组织中强染色,在正常组织中无染色。并且在典型肝硬化中强染色,在中度肝硬化中弱阳性。结论:Smo蛋白表达与肝癌的发生有关,Smo基因的高表达可能激活某种机制而参与诱导肝癌的发生。可能是通过异常激活Sonic hedgchog信号通路,从而诱导肝癌的发生与发展。     

慢性病毒性肝炎研究进展

近年,慢性病毒性肝炎研究领域有较大进展,慢性乙型肝炎病毒（HBV）感染,虽然有了应用广泛、历史较久、且效果较好的疫苗,但迄今仍是世界范围肝硬化和肝癌的主要诱因。传染途径可经产道、性接触和非肠道途径（包括静脉吸毒、血制品等）。成年病人有少有变慢性,但一岁以下患儿90％变成慢性肝炎。慢性肝损伤的临床表现可以是轻微的炎症重到晚期肝硬化,程度不等。α干扰素（IFNα）是治疗活动性肝炎的产宰药物,单核苷酸类药物（lamivudine和adefovir）也具有同样的疗效。晚期肝病和肝癌患者可进行移植,但异常伴发移植物的感染。乙型肝炎免疫球蛋白和新型抗病毒药物联合应用,可降低移植物感染的严重性。丙型肝炎病毒（HCV）在20世纪后期感染了大约1％的世界人口。这中RNA病毒非经口传播,绝大多数病人变成慢性肝炎,约20％逐渐演变成肝硬化或肝癌。用IFNα和病毒唑（Ribavirin）联合治疗,约40％病人的病理表现有所改善。肝移植对某些病例是适宜的,但移植物感染仍是悬而未决的问题,新发现的庚型肝炎病毒（HGV）和TT病毒目前认为并不引起严重的肝损害。     

SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.     

A biochemical comparison of normal human liver and hepatocellular carcinoma ferritins.

1. The iron contents, gel migration rates and isoelectric-focusing patterns of normal liver and hepatocellular carcinoma ferritins from the same patients were compared. 2. Sucrose-density-gradient centrifugation showed that the number of iron atoms per ferritin molecule was decreased to approximately half in carcinoma tissue when compared with normal liver. 3. On electrophoresis, hepatocellular carcinoma ferritin migrates faster and is therefore more negatively charged than normal liver ferritin, thus refuting the general view that the more negatively charged a ferritin molecule the greater its iron content. 4. Comparison of tumour and normal liver ferritin subunit compositions on acid/urea/polyacrylamide gels showed hepatocellular carcinoma ferritin to contain an additional, more negatively charged, subunit to normal liver ferritin. 5. Isoelectric focusing showed that hepatocellular carcinoma tissue contains isoferritins with isoelectric points intermediate between the ranges of normal liver and normal heart isoferritins.     

二甲双胍与肝细胞癌

二甲双胍作为一种口服降糖药,已被用于2型糖尿病的一线治疗,有报道指出其可以预防和控制多种癌症的发展。肝细胞癌(肝癌)是原发性肝癌的最常见形式,也是最常见的恶性肿瘤之一。目前,流行病学显示二甲双胍可以降低肝细胞癌的发生风险或改善肝癌患者的预后,实验室研究也证实二甲双胍可抑制肝癌细胞生长。因此文章将探讨二甲双胍抑制肝癌生长的相关机制。     

Multimodality treatment resulting in long-term survival in hepatocellular carcinoma.

The early detection and complex therapy of the hepatocellular carcinoma (HCC) is one of the most seasonable questions of the gastroenterology-oncology, because of the increasing prevalence of the primary liver cancer. The course of the hepatocellular carcinoma is rapid, untreated patients rarely live over 5-6 months. Combination of different treatment modalities in HCC can offer the best chances for survival. If possible, a surgical resection should be the primary procedure, followed by adjuvant cytostatic treatment and chemoembolisation. The authors report three cases with HCC with extremely long survival. The long-term survival achieved by multimodality therapy, as presented in these cases, seems to justify aggressive therapeutical approaches in HCC. It has been concluded, that early detection and complex, aggressive multimodality treatment--even repeated liver resections and surgical elimination of duplex distant metastases--can result in long-term survival with a good quality of life.     

Usefulness of diagnostic criteria for aspiration cytology of hepatocellular carcinoma.

OBJECTIVE: To establish new criteria for cytodiagnosis of hepatocellular carcinoma by comparing cytologic findings of hepatocellular carcinoma with those of liver cirrhosis. STUDY DESIGN: Review of cytologic findings of hepatocellular carcinoma on preoperative aspiration biopsy of 31 lesions from 27 patients who underwent surgical resection and comparison of these findings with those of liver cirrhosis in 17 patients. RESULTS: In the 11 lesions of moderately and poorly differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and abundant cytoplasm, thick cytoplasm, increased nuclear/cytoplasmic ratio, irregular nuclear contours, increased chromatin density, intranuclear vacuoles and naked nuclei. In the 20 lesions demonstrating well-differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei, increased nuclear/cytoplasmic ratio, thick nuclear membranes and increased chromatin density. We established the criteria for moderately and poorly differentiated hepatocellular carcinoma as including three cytologic parameters: increased nuclear/cytoplasmic ratio, irregular nuclear contours and increased chromatin density. We also established the criteria for well-differentiated hepatocellular carcinoma as including six cytologic parameters: monotonous cytoplasm, scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei and increased nuclear/cytoplasmic ratio. For all 31 hepatocellular carcinoma lesions, including 27 lesions that were < or = 2 cm in diameter, both sensitivity and specificity were 100% by concurrently employing both criteria. CONCLUSION: The new criteria for cytodiagnosis we established were useful for differentiating hepatocellular carcinoma from liver cirrhosis. In particular, our criteria ensured appropriate diagnostic accuracy for well-differentiated hepatocellular carcinoma.     

Hepatocellular carcinoma versus carcinoma metastatic to the liver. Value of stains for carcinoembryonic antigen and naphthylamidase in fine needle aspiration biopsy material

Staining for amino acid naphthylamidase and carcinoembryonic antigen (CEA) was examined as an ancillary technique to improve the accuracy of differentiating hepatocellular carcinoma from metastatic carcinoma to the liver in fine needle aspiration (FNA) biopsy specimens. Twenty-four cases of FNA specimens from the liver, in which air-dried smears and/or cell blocks were available, were examined. Naphthylamidase-positive bile canalicular structures were present in 2 cases of hepatocellular carcinoma and absent in 8 cases of metastatic carcinoma studied. Ninety percent of the hepatocellular carcinomas were immunoreactive with the antibody to CEA, showing a predominantly bile canalicular pattern. Ninety percent of the cases of metastatic carcinoma were positive with the antibody to CEA, showing a diffuse cytoplasmic pattern. These findings indicate that both staining techniques may be useful in differentiating hepatocellular carcinoma from metastatic carcinoma. Since the naphthylamidase stain requires air-dried smears, which may not be available, whereas immunocytochemistry can be done on fixed material, the latter technique is more practical.     

Controversies in patient selection for liver transplantation.

A variety of specific conditions often stimulate controversy regarding candidacy for liver transplantation. We review the published experience with liver transplantation for alcoholic liver disease, fulminant and chronic hepatitis B, and hepatocellular carcinoma and transplantation in older subjects. Liver transplantation for alcoholic liver disease and in subjects older than 60 years is becoming less controversial because recent data demonstrate that these patients have excellent survival and good quality of life after transplantation. Only 10% to 15% of persons with alcoholism return to drinking after transplantation, and most do so only transiently. Liver transplantation for patients with hepatitis B virus infection or primary liver cancer is more problematic because recurrent disease is common in both conditions. After transplantation for chronic hepatitis B, 80% to 90% of patients have reinfection of the allograft and long-term survival is 45% to 50%. Patients receiving transplants for hepatocellular carcinoma have only 20% to 30% long-term survival, but these survivors are cured of malignancy. Data are presented to support continued liver transplantation for chronic hepatitis B and hepatocellular carcinoma; however, patients must be selected based on factors that predict a favorable outcome, and experimental therapies should be employed to explore ways to improve the existing survival rates.     

Altered glycosaminoglycan composition in reactive and neoplastic human liver

We have investigated the glycosaminoglycan composition of normal human liver, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma. Uronic acid increased about 4 fold in the benign and reactive lesions, and greater than 7 fold in the carcinoma. Whereas in focal nodular hyperplasia and adenoma dermatan sulfate was the predominant glycosaminoglycan, in hepatocellular carcinoma chondroitin sulfate was the predominant species; it increased 24 fold over normal liver and 3-5 fold over all the other tissues. HPLC analysis of chondroitinase ABC or AC digests showed a 58 fold increase in Delta-Di-OS disaccharides in hepatocellular carcinoma, indicating significant undersulfation of chondroitin sulfate. Surprisingly, the normal-appearing liver surrounding the carcinoma showed glycosaminoglycan changes similar to adenoma and nodular hyperplasia. These results thus indicate that specific glycosaminoglycan changes occur in hepatocellular carcinoma, and suggest for the first time that proteoglycan metabolism is also altered in the non-cirrhotic, hepatic parenchyma adjacent to liver carcinoma.     

Hepatitis C virus network based classification of hepatocellular cirrhosis and carcinoma

Hepatitis C virus (HCV) is a main risk factor for liver cirrhosis and hepatocellular carcinoma, particularly to those patients with chronic liver disease or injury. The similar etiology leads to a high correlation of the patients suffering from the disease of liver cirrhosis with those suffering from the disease of hepatocellular carcinoma. However, the biological mechanism for the relationship between these two kinds of diseases is not clear. The present study was initiated in an attempt to investigate into the HCV infection protein network, in hopes to find good biomarkers for diagnosing the two diseases as well as gain insights into their progression mechanisms. To realize this, two potential biomarker pools were defined: (i) the target genes of HCV, and (ii) the between genes on the shortest paths among the target genes of HCV. Meanwhile, a predictor was developed for identifying the liver tissue samples among the following three categories: (i) normal, (ii) cirrhosis, and (iii) hepatocellular carcinoma. Interestingly, it was observed that the identification accuracy was higher with the tissue samples defined by extracting the features from the second biomarker pool than that with the samples defined based on the first biomarker pool. The identification accuracy by the jackknife validation for the between-genes approach was 0.960, indicating that the novel approach holds a quite promising potential in helping find effective biomarkers for diagnosing the liver cirrhosis disease and the hepatocellular carcinoma disease. It may also provide useful insights for in-depth study of the biological mechanisms of HCV-induced cirrhosis and hepatocellular carcinoma.     

Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients.     

Loss of the orphan nuclear receptor SHP is more pronounced in fibrolamellar carcinoma than in typical hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy.     

Differential diagnosis of hepatocellular carcinoma from metastatic tumors in the liver using microRNA expression

Distinguishing hepatocellular carcinoma from metastatic tumors in the liver is of great practical importance, with significant therapeutic and prognostic implications. This differential diagnosis can be difficult because metastatic cancers in the liver, especially adenocarcinomas, may mimic the morphology and immunoexpression of hepatocellular carcinoma. Biomarkers that are specifically expressed in either hepatocellular carcinoma or metastatic adenocarcinoma can therefore be useful diagnostic tools. To find such biomarkers, we studied microRNA expression in 144 tumor samples using custom microarrays. Hsa-miR-141 and hsa-miR-200c, microRNAs that promote epithelial phenotypes, had significantly higher levels in non-hepatic epithelial tumors. In contrast, endothelial-associated hsa-miR-126 showed higher expression levels in hepatocellular carcinomas. Combinations of these microRNAs accurately identified primary hepatocellular carcinoma from metastatic adenocarcinoma in the liver. These findings were validated using quantitative real-time PCR to measure microRNA expression in additional samples. Thus, the tissue-specific expression patterns of microRNAs make them useful biomarkers for the diagnosis of liver malignancies.     

Mechanism of cancer stemness maintenance in human liver cancer

Primary liver cancer mainly includes the following four types: hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA). Recent studies have indicated that there are differences in cancer stem cell (CSC) properties among different types of liver cancer. Liver cancer stem cells (LCSCs), also called liver tumor-initiating cells, have been viewed as drivers of tumor initiation and metastasis. Many mechanisms and factors, such as mitophagy, mitochondrial dynamics, epigenetic modifications, the tumor microenvironment, and tumor plasticity, are involved in the regulation of cancer stemness in liver cancer. In this review, we analyze cancer stemness in different liver cancer types. Moreover, we further evaluate the mechanism of cancer stemness maintenance of LCSCs and discuss promising treatments for eradicating LCSCs.Subject terms: Cancer stem cells, Tumour biomarkers, Prognostic markers, Cancer stem cells     

Giant cell hepatocellular carcinoma

A terminal case of giant cell hepatocellular carcinoma, subsequent to Hepatitis B-associated macronodular cirrhosis is presented, illustrated and discussed. The uncommon finding of malignant ascites, in itself atypical of hepatocellular carcinoma, with an almost exclusive content of giant cells as the cellular component, was a feature of this unusual variant of hepatocellular carcinoma.     

RNA干扰肝细胞肝癌中PECAM-1的表达对肿瘤细胞侵袭及增殖的影响

目的:探讨PECAM-1在肝细胞肝癌(Hepatocellular carcinoma,HCC)组织中的表达及意义。方法:选择2013年5月-2015年6月在我院接受治疗的HCC患者100例,收集肝癌患者HCC组织及癌旁组织,另选取100例正常肝脏组织作为对照组。应用免疫组织化学法检测PECAM-1在肝癌组织、癌旁组织以及正常肝脏组织中的阳性表达。利用小分子干扰RNA技术(si RNA)构建低表达的PECAM-1,并转染至肝癌细胞中抑制PECAM-1的表达。应用Transwell小室法检测肝癌细胞的侵袭能力,CCK-8法检测肝癌细胞的增殖能力。结果:PECAM-1在肝癌组织、癌旁组织及正常肝脏组织中呈不同程度阳性表达(P0.05);PECAM-1在肝癌组织及癌旁组织中的表达显著高于正常肝脏组织,差异具有统计学意义(P0.05);PECAM-1在肝癌组织中的表达显著高于癌旁组织,差异具有统计学意义(P0.05);转染si RNA PECAM-1后,肝癌细胞中PECAM-1 m RNA的表达水平明显下降,PECAM-1蛋白表达也明显降低,差异具有统计学意义(P0.05);转染si RNA PECAM-1后,肝癌细胞侵袭及增殖能力明显降低,差异具有统计学意义(P0.001)。结论:PECAM-1在肝癌患者血清中高表达,PECAM-1 si RNA能够抑制肝癌细胞的侵袭及增殖能力,提示PECAM-1可作为预测肝癌发生及发展的临床指标。