c-MET和COX-2在肝细胞癌中表达的意义及其相关性

目的探讨c-MET和COX-2在肝细胞癌组织中表达的意义及其相关性。方法将2006年1月至2006年12月手术后经病理证实为肝细胞癌患者28例分为肝硬化组和非肝硬化组,再根据癌肿的大小分为大于5 cm组和小于5 cm组。采用免疫组织化学法对28例肝细胞癌患者肝组织进行染色,利用美国S imp lePC I6专业图像分析系统截取显微镜下的10-15个视野,测算c-MET和COX-2的平均光密度值。结果肝硬化组的c-MET和COX-2平均光密度值均比非肝硬化组高;大于5 cm组的c-MET和COX-2平均光密度值均比小于5 cm组高;c-MET和COX-2呈正相关。结论HGF-c-MET-COX-2-VEGF通路可能是促进肝细胞癌血管生成的一个潜在通路,为肝细胞癌抗血管生成治疗策略提供新的靶点。     

Hepatocellular carcinoma and chronic persistent hepatitis.

The morphologic type of cirrhosis that is followed most frequently by hepatocellular carcinoma is posthepatitic cirrhosis. Furthermore, HB AG is detected in a high rate among cases with hepatocellular carcinoma suggesting the intimate causal relationship between hepatitis b virus and hepatocellular carcinoma. It has been considered that hepatocellular carcinoma might develop during destruction and regeneration of fully developed liver cirrhosis. However, hepatocellular carcinoma is combined with not only liver cirrhosis but also with mild liver fibrosis. An attempt was made to determine HBs Ag in the liver tissue of liver fibrosis with hepatocellular carcinoma. HBs Ag was found in non-cancerous liver tissue of 40 percent of those cases. Therefore, it may be concluded that, at least some of those fibrosis is caused by chronic viral hepatitis and hepatocellular carcinoma may develop not only on posthepatitic cirrhosis but also on chronic persistent hepatitis. This evidence also suggests the carcinogenicity of hepatitis B virus.     

HEPATOCELLULAR CARCINOMA AND CHRONIC PERSISTENT HEPATITIS

The morphologic type of cirrhosis that is followed most frequently by hepatocellular carcinoma is posthepatitic cirrhosis. Furthermore, HB Ag is detected in a high rate among cases with hepatocellular carcinoma suggesting the intimate causal relationship between hepatitis B virus and hepatocellular carcinoma. It has been considered that hepatocellular carcinoma might develop during destruction and regeneration of fully developed liver cirrhosis. However, hepatocellular carcinoma is combined with not only liver cirrhosis but also with mild liver fibrosis. An attempt was made to determine HBs Ag in the liver tissue of liver fibrosis with hepatocellular carcinoma. HBs Ag was found in non-cancerous liver tissue of 40% of those cases. Therefore, it may be concluded that, at least some of those fibrosis is caused by chronic viral hepatitis and hepatocellular carcinoma may develop not only on posthepatitic cirrhosis but also on chronic persistent hepatitis. This evidence also suggests the carcinogenicity of hepatitis B virus.     

Sarcoidosis-associated hepatocellular carcinoma

Sarcoidosis is a systemic granulomatous inflammation of unknown etiology, and seems to involve the liver parenchyma in most cases. However, sarcoidosis-associated hepatocellular carcinoma is rare. We report here a case in which a hepatocellular carcinoma occurred within the liver, which was probably involved as a result of systemic sarcoidosis. A 57-year-old Japanese man had been followed up for 2 years because of diabetic nephropathy and sarcoidosis. On admission for pneumonia, imaging studies revealed an unexpected hepatic tumor. Histology revealed a hepatocellular carcinoma accompanied by T-lymphocytic infiltration and marked granulomatous inflammation, which was surrounding some tumor nodules. The background liver parenchyma exhibited a moderate degree of fibrosis with granulomatous inflammation. The patient had no other apparent liver disease such as viral hepatitis, steatohepatitis, or primary biliary cirrhosis. Therefore, in the present case, sarcoidosis may be considered the probable background etiology for hepatocarcinogenesis.     

Diagnose und Differenzialdiagnose des hepatozellulären Karzinoms

The incidence of hepatocellular carcinoma (HCC) will continue to increase for the next decade due to a latency of about 30 years due to cirrhosis caused by chronic hepatitis C. The diagnosis of an underlying cirrhosis is of diagnostic importance. According to WHO guidelines, HCC encompasses the following: trabecular, pseudoglandular, acinar, compact, scirrhous and fibrolamellar subtypes. Cytological appearance includes hepatocellular pleomorphic, clear cell and sarcomatous subtypes. Tumor cells in hepatocellular carcinoma may display intracytoplasmic inclusions that are helpful for establishing the diagnosis. Differential diagnosis has to be considered for such hepatic tumors as adenoma and precancerous lesions such as dysplastic nodules or mesenchymal tumors. Metastases in the liver may be difficult to differentiate, especially for primary tumors from the gastrointestinal tract which may be similar to glandular or scirrhous type of HCC. The existence of underlying cirrhosis is helpful for the diagnosis and an ample spectrum of antibodies against liver antigens and adenocarcinomas are commercially available to confirm the correct diagnosis.     

Clinicopathologic features and survival in fibrolamellar carcinoma: comparison with conventional hepatocellular carcinoma with and without cirrhosis.

Fibrolamellar carcinoma arises in noncirrhotic livers of young individuals and has been considered to be less aggressive than conventional hepatocellular carcinoma. This study compares survival and clinicopathologic features of fibrolamellar carcinoma with hepatocellular carcinoma arising in noncirrhotic and cirrhotic livers. Clinical and pathologic features including age, gender, tumor size, stage and survival were recorded in 20 resected cases of fibrolamellar carcinoma. Survival was compared with resected hepatocellular carcinoma without (n=32) and with cirrhosis (n=30). Proliferative activity was determined by immunohistochemistry for Ki-67. In all, 12 (60%) patients with fibrolamellar carcinoma died during follow-up; the 5-year survival was 45%. Mortality in fibrolamellar carcinoma was higher with metastatic disease at presentation (6/7, 86% vs 5/13, 39%, P=0.06). Age, gender and tumor size did not correlate with survival. The 5-year (45 vs 56%, P=0.4) as well as overall survival (40 vs 56.3%, P=0.3) was similar in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis. The 5-year and overall survival in hepatocellular carcinoma with cirrhosis was 27 and 23.3%, respectively, which was not significantly different compared to fibrolamellar carcinoma (P=0.2). Among the cases without metastases at presentation, 5-year survival in fibrolamellar carcinoma (62%) and hepatocellular carcinoma without cirrhosis (57%) was significantly better (P=0.03) than hepatocellular carcinoma with cirrhosis (27%). The mean Ki-67 index was similar in all three groups (P=0.1). In conclusion, fibrolamellar carcinoma is an aggressive neoplasm with 45% 5-year survival and overall mortality of 60%. Nearly half the patients develop lymph node or distant metastasis. The prognosis of fibrolamellar carcinoma is similar to conventional hepatocellular carcinoma. Among nonmetastatic cases, the prognosis is better in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis compared to hepatocellular carcinoma with cirrhosis. The better outcome in fibrolamellar carcinoma appears to be due to the absence of cirrhosis rather than its distinct clinicopathologic features.     

肝细胞癌和肝硬变中bcl-2蛋白表达与细胞凋亡的关系

目的：研究肝细胞癌和肝硬变中ｂｃｌ－２蛋白表达与细胞凋亡的关系。方法：应用原位脱氧核糖核酸末端转移酶标记法和Ｓ－Ｐ免疫组化技术检测２８例肝硬变和３５例肝细胞癌组织中凋亡细胞的分布、密度及ｂｃｌ－２蛋白的表达。结果：肝细胞癌组织中凋亡细胞密度显著低于肝硬变，且随其恶性程度的增高呈逐渐降低趋势；凋亡细胞在肝硬变中多分布于假小叶周边区域。ｂｃｌ－２蛋白在肝细胞癌组织中的表达强度明显高于肝硬变，但表达的阳性率差异不明显。结论：ｂｃｌ－２通过其表达产物调控肝硬变和肝细胞癌中的细胞凋亡，在肝细胞癌发生中起重要作用，但ｂｃｌ－２蛋白并非细胞凋亡的唯一调控因素     

Nucleolar organiser regions in normal, cirrhotic, and carcinomatous livers.

A series of 54 liver biopsy specimens was studied by means of the argyrophil (AgNOR) technique for nucleolar organiser region (NOR)-associated proteins. These included normal livers and livers affected by chronic active hepatitis, cirrhosis, hepatocellular carcinoma and adenoma. Four of the cases of cirrhosis showed liver cell dysplasia. The mean numbers of NOR sites in normal, cirrhotic, and carcinomatous livers were significantly different: adenoma had similar mean counts to those in chronic active hepatitis (CAH). There was no overlap between the ranges of NOR counts in normal, cirrhotic, and malignant liver specimens. Where cirrhosis and hepatocellular carcinoma were present in the same specimen, the AgNOR counts were higher in the carcinomatous than cirrhotic areas. To investigate the prospective value of the method a further seven biopsy specimens were studied; in these it had not been possible to decide on a diagnosis between normality and cirrhosis or cirrhosis and hepatocellular carcinoma. In all seven specimens a repeat biopsy or necropsy gave results as predicted by AgNOR staining. It is therefore proposed that quantitation of staining for NOR-associated proteins is a diagnostically useful method in liver disease.     

Clinicopathological studies of liver cirrhosis and hepatocellular carcinoma in a general hospital

Clinicopathological studies of 181 patients with liver cirrhosis undergoing autopsy in the pathology department of a municipal hospital between 1973 and 1976 are reported. The main etiological types were alcoholic (25.4 per cent), HBsAg positive (14.9 per cent), and cryptogenic cirrhosis (54.7 per cent). Four patients had multifactorial and secondary biliary cirrhosis and one patient had congestive cirrhosis. The morphological characteristics of the condition and the age and sex distribution of the patients were analyzed in each etiological group. Hepatocellular carcinoma occurred in 28.7 per cent of the cases, most frequently in association with HBsAg positive cirrhosis. Hepatocellular atypia was significantly more frequent in HBsAg positive than in other etiological types of cirrhosis and significantly more frequent in cases associated with hepatocellular carcinoma than in those not associated with it.     

Chronic liver disease in Peru: Role of viral hepatitis

The prevalence of antibodies to hepatitis C virus (anti-HCV) was determined in 105 patients with biopsy-proven chronic liver disease and 128 comparison patients without any evidence of liver pathology living in Lima, Peru. Using a second-generation EIA screening and supplemental immunoblot assay, anti-HCV was detected in four of 13 patients with chronic hepatitis, in 11% of 85 patients with cirrhosis, and in none of seven patients with hepatocellular carcinoma. Only two (1.6%) comparison patients without liver disease had anti-HCV. Hepatitis B surface antigen (HBsAg) was found in 23% of patients with chronic hepatitis, 12% of patients with cirrhosis, and three of seven patients with hepatocellular carcinoma. There was no evidence of chronic viral hepatitis or alcohol abuse (reported by one-third of subjects) in 48% of chronic liver disease patients. These preliminary data suggest that among this South American population neither hepatitis B nor hepatitis C infection is the predominate cause of chronic liver disease and that other infectious or environmental factors may be important. © 1994 Wiley-Liss, Inc.     

Histological assessment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome, which is becoming an increasingly common cause of chronic liver disease. Histological changes typically mainly affect perivenular regions of the liver parenchyma and include an overlapping spectrum of steatosis, steatohepatitis and persinusoidal or pericellular fibrosis, in some cases leading to cirrhosis. Once cirrhosis has developed, typical hepatocellular changes are often no longer conspicuous, leading to such cases being mistakenly diagnosed as 'cryptogenic'. Portal inflammation, ductular reaction and periportal fibrosis can also be seen as part of the morphological spectrum of NAFLD, particularly in the paediatric population. Hepatocellular carcinoma has also been described as a complication of NAFLD-associated cirrhosis. NAFLD is also an important cofactor in other chronic liver diseases, especially hepatitis C. Histological assessments have an important role to play in the diagnosis and management of NAFLD. These include making the potentially important distinction between simple steatosis and steatohepatitis and providing pointers to the aetiology, including cases where a dual pathology exists. A number of systems have been devised for grading and staging the severity of fatty liver disease. These require further evaluation, but have a potentially important role to play in determining prognosis and monitoring therapeutic responses.     

Assessment of nucleolar organizer regions (NORs) in proliferative conditions of the liver.

To overcome the diagnostic dilemma in proliferative conditions of the liver which sometimes pose a problem to the working pathologist especially when the material is inadequate, a special staining technique (AgNOR) has been applied. By using this technique, nucleolar organizer regions were counted which determine the proliferative status of the cells. This prospective study included 65 cases of randomly selected liver core and fine needle aspiration biopsies. AgNOR staining was performed on formalin-fixed, paraffin-embedded tissue sections NOR dots were counted in 100 randomly selected hepatocytes at x100 oil immersion objective, and the mean count per cell was calculated for each case. Statistical analysis was done by using the Mann Whitney U test. AgNOR count results were later compared with the histologic diagnosis. The study revealed a gradual increase in mean AgNOR counts from normal liver through cirrhosis to hepatocellular carcinoma. The difference in NOR counts was significant in these three groups. The hepatocellular carcinomas were graded according to the Edmondson-Steiner histological grading system. The Grade I hepatocellular carcinomas show AgNOR counts ranging between 5-6/cell, a score which is much higher than in the normal liver, where it ranges between 1.2-2.0/cell. This technique can be used to assess the lesions where the distinction between normal liver and Grade I hepatocellular carcinoma is difficult with the use of routine methods. AgNOR counts in normal liver and chronic hepatitis cases were insignificant, but there was an appreciable difference between cases of chronic hepatitis, cirrhosis and hepatocellular carcinoma. In view of the results of this study, the AgNOR staining method is found to be a useful diagnostic tool to differentiate between normal liver, cirrhosis and hepatocellular carcinoma and also to precisely discriminate between cases of normal liver and Grade I hepatocellular carcinoma.     

Etiological and nosological structure of liver diseases (on autopsy data of clinics of I.M. Sechenov Moscow Medical Academy in 1988-1997)

4908 autopsy protocols were analysed and liver pathology was found in 1.7% of cases. Alcoholic and viral diseases dominated among liver pathology cases, steatosis among alcoholic damages, cirrhosis among viral diseases, primary biliary cirrhosis among autoimmune diseases and hepatocellular carcinoma among malignant tumors. Comparison of the two decades (1988-1997 and 1978-1987) revealed certain growth of alcoholic and viral diseases and their possible combinations. The number of liver tumors of viral etiology also went up.     

How does Japan differentiate hyperplasia from neoplasia?

A Japanese pathologist's contribution to the discussion of the problem on differentiation of hyperplasia from neoplasia is to introduce his experience and knowledge in human and experimental pathology of gastric, hepatic, and uterine cervical cancers, all of which are prevalent in Japan. Canine and rodent gastric cancers induced experimentally by N-ethyl-N'-nitro-N-nitrosoguanidine or N-methyl-N'-nitro-N-nitrosoguanidine, respectively, show different histologic types which are similar to human gastric cancer when examined routinely by endoscopic method. Dogs show more similarities to human gastric cancer than rats in the morphologic features and responses to chemotherapy. Serial liver biopsies performed on patients with liver diseases revealed the final stages of liver cell carcinoma in some of them. They all progressed to liver cirrhosis before terminating in carcinoma. However, this does not mean that the hyperplastic nodule is an obligatory precursor of carcinoma in human. Among experimental models of liver cancer produced by a large number of agents, only carbon tetrachloride and luteoskyrin seem to induce liver cell carcinoma combined with cirrhotic lesions in rodents. The mode of manifestation of atypical changes in the proliferating cells as preneoplastic or neoplastic lesions seems to differ according to tissue. The cellular pathology of cervicovaginal smears is a reliable index for detection of carcinoma in the cervix, where the appearance of atypical cells represents a landmark between benign and malignant tumors.     

Morphology and other prognostic factors of hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma is a malignancy found worldwide that has typically poor prognosis despite treatment. Although several studies have dealt with prognostic factors, just a few detailed analyses of large series correlating the pathology of hepatocellular carcinoma with prognosis are available. The present study was undertaken to address this limitation. PATIENTS AND METHODS: Our prior clinical study described 432 patients, but sufficient tissue was available for evaluation in only 299 patients. Of these, 224 samples contained primary hepatocellular carcinoma, while the remainder contained only metastatic tumor. Characteristics evaluated included degree of tumor differentiation, associated cirrhosis or hepatitis, presence of cytoplasmic inclusion bodies, and blood vessel invasion by the neoplasm. RESULTS: Of the 224 patients, 71% were male, 65% white, and 73% over the age of 45 years. Ninety-one percent were from North America. A total of 42 patients were found to have cirrhosis. Thirty-five percent had cytoplasmic inclusion bodies, and 25% showed evidence of blood vessel invasion. Tumor response rates (tumor shrinkage) were low (8%) regardless of treatment. Presence of cytoplasmic eosinophilic inclusion bodies and blood vessel invasion were not associated with increased survival. Some histopathologies (pelioid, spindle cell, fibrolamellar) were associated with a better prognosis. Patients with a predominant trabecular pattern (43%) did particularly poorly. Although sex was significantly associated with survival using a univariate analysis, this effect disappeared in a multivariate Cox model that adjusted simultaneously for other factors. CONCLUSION: This investigation suggests that histologic subtype and clinical features may provide useful prognostic information in hepatocellular carcinoma. Poorer survival was observed in males, older patients with poorly differentiated tumors, or when associated with cirrhosis. Age younger than 45 years was a good prognostic factor, and presence of cirrhosis had an adverse effect on survival.     

Primary hepatocellular carcinoma and IgG heavy chain allotypes.

We studied Gm typing of serum samples from 838 donors; 177 had chronic hepatitis, 166 liver cirrhosis, 113 primary hepatocellular carcinoma, 21 alcoholic hepatitis, 18 fatty liver and 343 were unrelated normal blood donors. The distribution of Gm phenotypes and haplotypes in sera from patients with primary hepatocellular carcinoma differed from that in the normal controls; the Gm phenotype (1,2,21,13,15,16) and the haplotype Gm1,2,21 were significantly more common in this patient group (X2 = 18.56, corrected P less than 0.01, relative risk = 3.12; X2 = 25.52, corrected P less than 0.005, respectively). Overall, in the other liver diseases, we observed no significant Gm phenotype or haplotype association. The commitment to progression to primary liver carcinoma seems to be ascribable to a gene or polygenes close to the IgG heavy chain loci.     

Management of HCV-related end-stage liver disease in HIV-coinfected patients

End-stage liver disease due to hepatitis C virus has become a major challenge in the management of HIV/HCV-coinfected patients. The diagnosis and management of cirrhosis and its complications in the scenario of HIV/HCV-coinfection are reviewed. Noninvasive approaches to the diagnosis of cirrhosis, such as biomarkers or transient hepatic elastography, may be considered. The clinical profile of cirrhosis decompensation in the coinfected population is different from that found in HCV-monoinfected individuals. Ascites and hepatic encephalopathy are much more frequent, whereas hepatocellular carcinoma is still uncommon, when simultaneous hepatitis B virus infection is absent. The newest and more conflicting topics on the management of these complications are also discussed. Liver transplantation seems to be a proper option of treatment in HIV/HCV-coinfected patients and should be considered early in their management, since mortality after the first hepatic decompensation is high.     

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.     

Hepatocellular carcinoma and hepatic cirrhosis in the west of Scotland: a 25-year necropsy review.

A two-fold increase in the incidence of hepatocellular carcinoma in the west of Scotland is reported on the basis of a 25-year retrospective necropsy review (313 cases). This increase is not accompanied by a corresponding increase in the incidence of hepatic cirrhosis. The relationship between hepatocellular carcinoma and hepatic cirrhosis is discussed in the light of these findings.     

Laboratory signs of acute or recent cytomegalovirus infection are common in cirrhosis of the liver

Human cytomegalovirus (CMV) is an ubiquitous pathogen that can cause severe and often fatal infections in immunocompromised patients. Patients with cirrhosis often show various degrees of impaired cellular immunity that could lead to acute CMV reactivation. The aim of the present study was to determine whether laboratory findings of active CMV infections are common in patients with cirrhosis. Fifty-five patients with cirrhosis were studied for acute CMV infection by virological (antigenemia and quantitative polymerase chain reaction in polymorphonuclear leukocytes) and serological (detection of anti-CMV IgM by immunoblot) methods. The same tests were carried out on 50 blood donors and on 20 chronic hepatitis patients, considered as control populations. Acute or recent CMV infection had occurred in 31 (56%) of 55 patients with cirrhosis, whereas only 1 out of 20 (5%) patients with chronic non-cirrhotic liver disease and none of the 50 blood donors had laboratory signs of active CMV infection. The difference between patients with cirrhosis and the control groups was significant (P < 0.001, chi(2) test). CMV in patients with cirrhosis was not related to age, gender, hepatitis C virus infection or hepatocellular carcinoma. There was no significant correlation between impairment of liver function and the presence of active CMV infection. Patients with cirrhosis should be considered at risk for CMV infection, that seems to be mild and asymptomatic.