Combined hepatocellular carcinoma and cholangiocarcinoma with components of mucinous carcinoma arising in a cirrhotic liver

A rare autopsy case of combined hepatocellular and cholangiocarcinoma, occurring in a 54-year-old man with liver cirrhosis, is presented. Initial laboratory data included CEA 52.1 ng/mL, DUPAN-2 1600 U/mL, AFP 2 ng/mL, and negativity for hepatitis B surface antigen, hepatitis B early antigen and hepatitis B core antibody. Ultrasonography and CT scan showed a large tumor node in the liver with ringed enhancement, swelling of several para-aortic lymph nodes, and ascites. Clinically, it was not possible to determine whether the hepatic tumor was an intrahepatic cholangiocarcinoma or a metastatic carcinoma. Histologically, the primary lesion was composed solely of hepatocellular carcinoma (HCC) with a trabecular pattern, and the intrahepatic metastases consisted of a variable admixture of HCC and cholangiocarcinoma (CC) with excessive mucin production. Interestingly, the tumor cell cluster showing a trabecular growth pattern produced mucin and had immunohistochemical expression of hepatocyte, cytokeratins 7 and 8. It is concluded that these hepatic tumor cells had both HCC and CC characters.     

Hepatoma presenting as extrahepatic biliary obstruction due to hemobilia

A case of hepatoma presenting as extrahepatic biliary obstruction due to hemobilia is reported. The patient, a 49-year-old woman, developed jaundice of the obstructive type after a history of B-viral hepatitis. On laparotomy, the liver revealed macronodular cirrhosis without any noticeable mass. A 4-cm sized friable tissue and blood clots were identified within the distended left hepatic duct. Pathologic examination of this tissue confirmed the diagnosis of hepatocellular carcinoma extended in the hepatic duct.     

Orcein-positive hepatitis B surface antigen and liver carcinoma: their association in an Eastern US population

We retrospectively examined the association of hepatitis B infection and hepatocellular carcinoma (HCC) in a US East Coast population using orcein staining of fixed liver tissue. Hepatitis B surface antigen (HBsAg) was present in non-neoplastic hepatocytes in eight of 53 cases of HCC, but in no cases of cholangiocarcinoma or metastatic tumor. In five of the eight positive cases, macronodular cirrhosis was present; in three positive cases, cirrhosis was absent. The rate of positivity in livers with both HCC and macronodular cirrhosis was 28%, compared with 4.7% in livers with macronodular cirrhosis but no carcinoma. The low, but significant association of HBsAg and HCC, both in the presence and absence of cirrhosis, suggests that HCC may develop in a subset of patients in the United States as a result of infection with hepatitis B virus.     

Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma: implication of HBx in upregulation of COX-2.

Hepatitis B virus is a major etiological factor of hepatocellular carcinoma, but the underlying mechanisms remain unclear. We have previously demonstrated that upregulation of cyclooxygenase (COX)-2 in chronic hepatitis B persisted despite successful antiviral therapy. In this study, we investigated the relationship between the transactivator HBx and COX-2 in hepatitis B virus-associated chronic liver diseases. Expressions of HBx and COX-2 in tissue specimens were determined by single and double immunohistochemistry. The effects of HBx on COX-2 and prostaglandin E2 production were studied by transfection. HBx was expressed in 11/11 (100%) of chronic hepatitis B, 23/23 (100%) of cirrhosis, and 18/23 (78%) of hepatocellular carcinoma, whereas no immunoreactivity was found in four nonalcoholic steato-hepatitis controls. COX-2 expression was also detected in all specimens of liver lesions except in only 29% of poorly differentiated hepatocellular carcinoma. Significant correlation between HBx and COX-2 immunoreactivity scores was found in different types of chronic liver diseases (chronic hepatitis B, rs = 0.68; cirrhosis, rs = 0.57; hepatocellular carcinoma, rs = 0.45). Double immunohistochemistry showed colocalization of HBx and COX-2 in hepatic parenchymal cells. Similar to COX-2, there was no significant change in HBx expression in patients with chronic hepatitis B after interferon and lamivudine therapy when hepatitis B virus DNA became undetectable and inflammation subsided. Transfection of Hep3B hepatocellular carcinoma cells with HBx increased COX-2 expression and prostaglandin E2 production. HBx was localized mainly in the cytoplasm and less in nucleus, as found in the liver lesions. In conclusion, our results strongly suggested that there was a close relationship between HBx and COX-2. COX-2 might represent an important cellular effector of HBx that contributes to hepatitis B virus-associated hepatocarcinogenesis.     

The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology

Extracellular vesicles (EVs) are membrane-enclosed particles released from almost all cell types. EVs mediate intercellular communication by delivering their surface and luminal cargoes, including nucleic acids, proteins, and lipids, which reflect the pathophysiological conditions of their cellular origins. Hepatocytes and hepatic non-parenchymal cells utilize EVs to regulate a wide spectrum of biological events inside the liver and transfer them to distant organs through systemic circulation. The liver also receives EVs from multiple organs and integrates these extrahepatic signals that participate in pathophysiological processes. EVs have recently attracted growing attention for their crucial roles in maintaining and regulating hepatic homeostasis. This review summarizes the roles of EVs in intrahepatic and interorgan communications under different pathophysiological conditions of the liver, with a focus on chronic liver diseases including nonalcoholic steatohepatitis, alcoholic hepatitis, viral hepatitis, liver fibrosis, and hepatocellular carcinoma. This review also discusses recent progress for potential therapeutic applications of EVs by targeting or enhancing EV-mediated cellular communication for the treatment of liver diseases.     

Intrahepatic cholangitis and arteritis after transcatheter arterial embolization in a patient with tumor-like lesion-associated autoimmune hepatitis

Autoimmune hepatitis is a chronic liver disease characterized by immune-mediated, progressive hepatocellular damage, although the target autoantigen remains speculative. Intrahepatic biliary lesions are not a feature of this disease. We describe herein a female patient, 57 years, with autoimmune hepatitis who developed hepatic regenerative mass after acute exacerbation of hepatitis. This hepatic regenerative mass was clinically diagnosed as hepatocellular carcinoma and was surgically resected after transcatheter arterial embolization therapy. Widespread nonsuppurative destructive granulomatous cholangitis as well as necrotizing, granulomatous arteritis of the intrahepatic small arteries were found in the surgically resected hepatic regenerative mass. The bile duct lesions were histologically and immunohistochemically very similar to the granulomatous cholangitis of primary biliary cirrhosis. We would like to propose that these unusual lesions in the intrahepatic bile ducts and intrahepatic arteries represent a reaction of this patient to an anti-cancer drug included in chemoembolization. No such cases have been reported so far.     

Expression of alpha-smooth muscle actin in liver diseases.

To evaluate the distribution of alpha-smooth muscle actin (alpha-SMA) positive cells in various liver diseases, we undertook an immunohistochemical study of liver diseases including chronic persistent hepatitis, chronic active hepatitis, liver cirrhosis, intrahepatic cholelithiasis and hepatocellular carcinoma. As a control, fetal livers (gestational age: 22-26 weeks) showed alpha-SMA positive cells along the blood vessels of the portal area, terminal hepatic venules and at perisinusoidal spaces. Perisinusoidal alpha-SMA positive cells were bipolar shaped and had round nuclei. In chronic persistent hepatitis, a few alpha-SMA positive cells were admixed with the inflammatory infiltrates mostly along the intact limiting plate. They were also detected multifocally in a linear pattern along the dilated sinusoid. In chronic active hepatitis, very strong alpha-SMA staining was detected at the site of piecemeal necrosis and adjacent lobules. A-SMA expression was decreased in some cases after interferon treatment. In cases of transplanted liver biopsies, expression of intralobular alpha-SMA was diffusely increased but showed no correlation with degree of acute rejection. Cirrhotic livers revealed strong alpha-SMA positivity in fibrous septae as well as in the perisinusoidal space of intact hepatocytes at the leading edge of fibrosis. Interlobular bile ducts were concentrically circumscribed by alpha-SMA positive cells in cases of intrahepatic cholelithiasis. In trabecular type hepatocellular carcinomas, most sinusoidal lining cells were positive for alpha-SMA. Most intralobular alpha-SMA positive cells represent, if not all, perisinusoidal cells (PSCs) which are involved in intralobular fibrogenesis in various liver diseases.(ABSTRACT TRUNCATED AT 250 WORDS)     

The histopathology of the liver in older patients with hepatitis B virus surface antigenaemia

Summary The histopathology of the liver and the detectability of intrahepatic hepatitis B virus (HBV) markers were studied in 34 autopsy cases in elderly patients (mean age 73.9 years, range 60–91 years) who had had a history of positive HBV surface antigenaemia prior to death. Seven of 14 persistent HBV carrier cases (group A) in which long-lasting HBV surface antigen (HBsAg) carriage in the sera had been confirmed by sequential assays, and 5 out of 15 HBV-infected people (group C, single assay) showed significant primary liver damages including chronic hepatitis, toxic hepatitis, liver cirrhosis and hepatocellular carcinoma. In 5 cases (group B), one of which was type B liver cirrhosis, HBsAg became negative and HBsAb appeared during the follow-up period (up to 33 months). Among confirmed HBV carriers, HBsAg and HBV core antigen were most frequently found in the liver of cirrhotic cases with and without hepatocellular carcinoma (5 of 6), whereas these were rarely detected in those with nonspecific changes or slight hepatitic activity (1 of 7). All 5 cases in group B were negative for histological HBV-related antigens and the findings in group C were variously interpreted. Post-mortem cases of the aged HBV carriers who survived their mean life expectancy represent an important population in which to study the natural history of HBV carriers.     

趋化因子在肝脏疾病中作用的最新进展

自从趋化因子被发现并于1992年正式命名以来,关于其在各种疾病中作用的研究层出不穷.近年来发现,趋化因子在肝脏疾病如病毒性肝炎和肝细胞癌的发生发展占有重要地位,如可以调节肝细胞、Kupffer细胞、肝星形细胞、内皮细胞等的迁移和活动,从而调节肝的炎性反应,还可促进癌细胞的存活、增殖、转移、侵袭,增强肿瘤炎性微环境,促进肝癌的进一步发展.因而深入理解CXCL9、CXCL10、CXCL11在病毒性肝炎以及CXCL12和CX3CL在肝细胞癌中的作用机制,有助于更好地认识趋化因子和肝脏疾病的关系,为临床治疗提供新思路.     

Hepatitis B and C: natural course of disease

Significant progress in the understanding of the natural history of hepatitis B and C has been made in recent years due to molecular diagnosis techniques. The most important biologic feature of hepatitis B and C viruses (HBV, HCV) is their ability to cause chronic hepatitis. The natural course of HBV infection is variable, ranging from inactive HBsAg carrier state to progressive chronic hepatitis that can evolve into liver cirrhosis and hepatocellular carcinoma. HBeAg-negative chronic hepatitis is due to a naturally occurring HBV variant with mutations in the precore or basic core promoter regions. It accounts for the majority of cases in many European countries and is generally associated with a more severe liver disease. The morbidity and mortality in chronic hepatitis B are linked to the evolution to cirrhosis and hepatocellular carcinoma. The progression of fibrosis is strongly associated with persistent active viral replication When the diagnosis is made, the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%. The 5-year cumulative incidence of hepatic decompensation is 20%. Hepatocellular carcinoma is one of the most common cancers worldwide, 75% of which are related to chronic HBV infection. Coinfection with hepatitis D virus can lead to a more progressive liver disease in a shorter period of time. Hepatitis C virus infection becomes chronic in 80% of infected persons resulting in different stages of chronic hepatitis, with 20%-30% progressing to cirrhosis within 20 years period. The progression of fibrosis determines the ultimate prognosis. The major factors known to be associated with fibrosis progression are older age, male gender and alcohol consumption. Viral load and genotype do not play a role in the disease progression. Progression to fibrosis is more rapid in immunocompromised patients.     

Hepatobiliary effects of 90yttrium microsphere therapy for unresectable hepatocellular carcinoma

(90)Yttrium (Therasphere) microspheres administered via hepatic artery are a valuable option for treatment of hepatocellular carcinoma. This therapy targets tumor nodules while largely sparing hepatic parenchyma. This retrospective study examines liver explants from 13 adult patients with hepatocellular carcinoma who received intrahepatic Theraspheres and subsequently underwent liver transplantation. Histopathologic and laboratory reviews are performed. Theraspheres preferentially migrated to the lobe(s) supplied by the injected artery branches and frequently localized to tumors. Tumors showed a chronology of changes beginning with confluent necrosis typically accompanied by hemorrhage and later by fibrinoid change. This was followed by fibrosis with regenerative activity at tumor peripheries. Adjacent hepatic parenchyma went through a similar sequence of injury and repair that could lead to markedly fibrotic cirrhotic nodules in the vicinity of treated tumors. No consistent pattern of thrombomodulin loss was seen in endothelial cells of the tumors or adjacent parenchyma, suggesting that direct endothelial cell injury was likely not a major contributor to the necrotic process. However, the pattern of injury and repair is suggestive of a localized and subclinical form of radiation-induced liver disease. The pathologist should be aware of these changes to distinguish them from the diffuse "radiation hepatitis" associated with older forms of radiotherapy.     

Des-gamma carboxy prothrombin (PIVKA-II) and alpha-fetoprotein producing gastric cancer with multiple liver metastases

We describe the case of an 87-year-old woman who presented to Tokyo Kousei Nenkin Hospital because of appetite loss and general fatigue. Multiple liver masses and Borrmann type 2 gastric tumor were detected. A clinical diagnosis of hepatocellular carcinoma and gastric cancer was made based on the patient's high levels of serum alpha-fetoprotein (AFP; 490 200 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 2284 mAU/mL). The patient's general condition worsened gradually and she died 42 days after admission. Autopsy revealed that the predominant histological structure of the gastric tumor was trabecular or sheet-like, although a tubular structure was also found. Venous invasion was prominent. Immunohistochemically, the tumor tissue was positive for AFP and a few tumor cells were positive for PIVKA-II. The histological appearance and immunohistochemical features of the hepatic tumors resembled that of the gastric tumor. This case was pathologically diagnosed as AFP- and PIVKA-II-producing gastric carcinoma with multiple liver metastases. When tumors are found in the stomach and liver and serum PIVKA-II level is abnormally high, the possibility of PIVKA-II-producing gastric cancer with liver metastasis should be considered, especially when hepatitis virus markers are negative and liver cirrhosis is not present.     

Hepatitis B surface antigen, hepatocellular carcinoma and cirrhosis in south India--an autopsy study

This study is aimed at finding the association of hepatocellular carcinoma and cirrhosis with hepatitis B surface antigen in a particular geographical area, Andhra Pradesh State in South India. In total, 206 cases of autopsy livers were studied for the presence of hepatitis B surface antigen by orcein staining. Of the 114 cases of cirrhosis 67.54% were positive for the antigen. There were 13 cases of macronodular, 55 cases of mixed and 46 cases of micronodular cirrhosis. The antigen positivity was 100%, 98.7% and 21.74% respectively. The difference in positivity between micronodular and the other two types of cirrhosis was statistically significant (P less than 0.01). Of the 58 cases of hepatocellular carcinoma, 50 were associated with cirrhosis. In 80% of these cases, hepatitis B surface antigen was demonstrated, whereas 75% of cases of hepatocellular carcinoma not associated with cirrhosis, were positive for hepatitis B surface antigen. The geographical importance of these findings was discussed.     

Synchronous hepatocellular carcinoma and cholangiocarcinoma arising in two different dysplastic nodules.

We present the first reported case of explant cirrhotic liver that had synchronous cholangiocarcinoma and hepatocellular carcinoma arising in two different high-grade dysplastic nodules. The patient was a 55-year-old woman who had hepatitis B virus-associated liver cirrhosis for 3 years. The moderately differentiated cholangiocarcinoma occurred in high-grade dysplastic nodule with a 1.7-fold cell density compared with that of cirrhotic nodule. The hepatocellular carcinoma arose in a nodule-in-nodule pattern within a peripherally low-grade and centrally high-grade dysplastic nodule and had a 2.7-fold cell density compared with that of cirrhotic nodule. By immunohistochemistry, the tumor cells of the cholangiocarcinoma as well as bile ductular cells in dysplastic nodule were diffusely positive for cytokeratin 7, whereas hepatocellular carcinoma cells and dysplastic hepatocytes were negative for cytokeratin 7. The c-kit-positive hepatic progenitor cells were singly scattered between hepatocytes, and their number was highest in cirrhotic nodule and decreased in dysplastic nodule, whereas they were absent in cholangiocarcinoma and hepatocellular carcinoma arising in dysplastic nodules. Proliferation indices were progressively increased in cirrhotic nodule, dysplastic nodule, and cholangiocarcinoma or hepatocellular carcinoma, sequentially. These observations indicate that cholangiocarcinoma as well as hepatocellular carcinoma can develop in dysplastic nodule and that hepatic progenitor cells might play a role in the early stage of cholangiocarcinogenesis and hepatocarcinogenesis.     

Characterization of hyperplastic foci observed in surgical specimens of hepatocellular carcinoma

By reviewing previous surgical specimens of hepatocellular carcinoma, 17 cases with hyperplastic foci (HPF) characterized by discernible increase in nuclear densities, could be histologically selected. Nuclear densities of HPF and control hepatic parenchyma were assessed quantitatively by counting the nuclear number of hepatic cells, and proliferating cell nuclear antigen labeling index was measured. HPF occurred multifocally, confined within a lobular unit, smoothly merging into surrounding hepatic parenchyma. Nuclear densities of HPF were 1.71 times greater than those of control hepatic parenchyma. The hepatocytes of HPF also showed significantly higher proliferative activities than those of control parenchyma. In addition, noticeable structural distortions, such as focal trabecular thickening or microacinar formation of hepatocytes, were sometimes observed in HPF. However, these HPF seemed to be distinguished from minute de novo hepatocellular carcinoma (HCC) or intrahepatic HCC metastasis, because of paucity of distinctive atypical changes, and intimate correlation with neighboring hepatocytes. Several adjacent HPF were aggregated to form a much larger unit of a hyperplastic area with loss of fibrous septa of liver cirrhosis. It was suggested that grossly detectable large regenerative nodules are produced via fusion of several adjacent HPF.     

Sarcomatoid hepatocellular-carcinoma showing rhabdomyoblastic differentiation in the adult cirrhotic liver

 An unusual case of a massive liver tumour composed of rhabdomyosarcoma with a small focus of hepatocellular carcinoma in a 52-year-old man is presented. He had hepatitis B virus (HBV) surface antigen in his serum. Macroscopically, a large tumour with satellite nodules occupied the right lobe of the cirrhotic liver. Microscopically, the tumours were composed of small and short spindle-shaped undifferentiated cells, mixed with desmin-positive round rhabdomyoblasts and elongated striated muscle cells, strongly suggestive of rhabdomyosarcoma of the liver. Elevated levels of alpha-fetoprotein in the serum led us to examine the liver tumour closely in multiple sections, which disclosed a hepatocellular carcinoma component measuring 2 cm in diameter within the massive tumour. Immunohistochemically, the hepatocellular carcinoma cells were alpha-fetoprotein positive. There was neither a tumour capsule, nor distinct demarcation, and cytokeratin-positive clusters of undifferentiated cells were intermingled with the hepatocellular carcinoma and rhabdomyosarcoma at the border. The invading tumour outside the liver and metastatic tumours were pure rhabdomyosarcomas. It is suggested that the present case should be diagnosed as rhabdomyosarcoma transformed from hepatocellular carcinoma. Received: 19 November 1998 / Accepted: 12 February 1999     

Expression and clinicopathologic significance of glypican 3 in hepatocellular carcinoma

Glypican 3 (GPC3) is a glycosylphosphatidylinositol-anchored membrane protein and plays an important role in regulation of cell growth, differentiation, and migration. The aims of this study were to investigate the expression of GPC3 in human liver, biliary tract, and pancreatic tumors and to evaluate its diagnostic role in differentiating hepatocellular carcinoma (HCC) from other hepatic mimickers. Immunohistochemistry was performed on a large collection of surgically resected samples from 941 primary liver tumors, 50 metastatic adenocarcinomas, and 30 normal livers as well as primary adenocarcinomas of the pancreas (n = 17), gallbladder (n = 30), and extrahepatic bile duct (n = 20). The relationship of GPC3 expression and clinicopathologic features in patients with HCC was determined. We found that 516 (52%) of the 991 liver neoplastic tissue samples demonstrated positive staining for GPC3. A high incidence of GPC3 expression (492/757; 65%) was observed in HCC, whereas intrahepatic cholangiocarcinomas, adenocarcinomas, and benign liver lesions displayed rare positive cases. There were significant correlations between GPC3 expression and clinicopathologic characteristics, including histologic grade (P < .001), intrahepatic metastasis (P = .007), and positive serum hepatitis B surface antigen (P = .042), in patients with HCC. In conclusion, our results confirm the high expression of GPC3 in HCC and suggest its potential diagnostic value as a clinical marker for this disease.     

Biliary lymphoepithelioma-like carcinoma not associated with Epstein-Barr virus

We report the case of a 64-year-old man who presented with a hepatic mass and macronodular cirrhosis. The pathologic findings revealed a lymphoepithelioma-like carcinoma arising in the hepatobiliary tract that was morphologically identical to nasopharyngeal undifferentiated carcinoma. However, this tumor was not associated with Epstein-Barr virus infection in molecular studies. Macronodular cirrhosis associated with hepatitis C virus was present in the background liver.     

CXCR1、CXCR2 及CXCL8 在乙肝相关肝癌中的表达及临床意义

目的:探讨乙肝相关肝癌患者外周血单个核细胞及肝活检组织CXCR1、CXCR2 及CXCL8 表达及其临床意义。方法:用实时荧光定量PCR 法检测36 例乙肝相关肝癌患者外周血PBMCs 中CXCR1、CXCR2 及CXCL8 mRNA 水平;SP 法检测肝活检组织CXCR1、CXCR2 及CXCL8 蛋白表达水平;化学发光免疫分析法检测血清CRP 水平,并对各指标进行相关性分析。结果:乙肝相关肝癌患者PBMCs 中CXCR1、CXCR2 及CXCL8 mRNA 水平分别为(0.952 7±0.197 2)、(0.896 9±0.173 0)、(1.771 9±0.248 9),较正常对照组明显升高,差异有统计学意义(P<0.01)。SP 结果提示,CXCR1、CXCR2 及CXCL8 的蛋白水平较对照组明显升高(P<0.05)。乙肝相关肝癌患者血清CRP 水平与PBMC 内CXCR1(r =0.54,P<0.01)、CXCR2(r =0.49,P<0.01)及CXCL8(r = 0.63,P<0.01)呈正相关。结论:乙肝相关肝癌患者外周血PBMCs 及肝活检组织CXCR1、CXCR2 及CXCL8 表达明显升高,且与血清CRP 呈正相关,推测CXCR1、CXCR2 及CXCL8 介导的信号转导过程可能在乙肝相关肝癌发病过程中发挥重要作用,为肝癌免疫干扰治疗提供新的靶点。