Hepatocellular carcinoma in a non-cirrhotic liver. Two case reports and literature review

Hepatocellular carcinoma (HCC) is closely associated with cirrhosis, but it also develops, although much less frequently, in a non-cirrhotic liver. It is suspected that hepatocellular carcinoma has a different etiology when associated and not associated with chronic liver disease. We report two cases of patients with hepatocellular carcinoma that developed in a non-cirrhotic liver. In the first case we describe an incidental liver nodular lesion containing multiple foci of HCC including pseudogland or trabecular formation and areas of sclerosis. The non-cancerous parenchyma of the liver was histologically unremarkable except for mild fatty changes of hepatocytes and minimal dysplasia. The second case describes a combined hepatocellular carcinoma and cholangiocellular carcinoma (CCC) (mixed carcinoma) in a patient who was serologically negative for both hepatitis B and C viruses. The adjacent liver parenchyma showed mild piecemeal necrosis and mild lobular activity compatible with chronic viral hepatitis, but cirrhosis was not established. This case appears to indicate that mixed type carcinoma can develop in a non-cirrhotic liver, with CCC being far more dominant than HCC; such a finding is extremely unusual, based on previously published reports.     

Dietary Patterns and Hepatocellular Carcinoma Risk among US Adults

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001–2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. A vegetable-based dietary pattern was inversely associated with HCC risk (highest compared with lowest tertile: OR 0.66, 95% CI 0.46–0.94). A Western diet pattern was directly associated with HCC risk (highest compared with lowest tertile: OR 1.79, 95% CI 1.19–2.69). These findings emphasize the potential role of dietary intake in HCC prevention and clinical management.     

肝硬化、肝细胞肝癌中PTEN的表达及其临床意义

目的:探讨PTEN在肝硬化、肝癌组织中的表达及其临床意义.方法:用S-P免疫组织化学方法分别检测71例肝细胞性肝癌(HCC)15例肝硬化及10例正常肝脏PTN蛋白表达.结果:10例正常肝组织中PTEN蛋白均为阳性表达.HCC中PPTEN蛋白的阳性率为69.0%(49/71),明显低于肝硬化组(93.3%)及正常肝组织(100%)(P<0.01).PTEN蛋白在高分化、中分化、低分化肝细胞性肝癌中的阳性率分别为73.5%、69.6%和57.1%,肝细胞性肝癌中PTEN蛋白阳性表达率与肿瘤的组织分化及其它临床病理因素无关(P>0.05).肝癌PTEN蛋白阳性表达率与有无合并肝硬化无关(P>0.05).结论:PTEN表达缺失在肝细胞性肝癌的发生和发展过程中发挥重要作用,检测PTEN蛋白表达有助于肝细胞性肝癌的诊断.     

肝癌组织、癌旁组织中HBsAg、HCV抗原表达与肝组织纤维化分期的相关性研究

目的研究肝癌组织、癌旁组织中乙型肝炎表面抗原（HBsAg）、丙型肝炎病毒（HCV）抗原表达与肝组织纤维化分期的相关性.方法采用免疫组织化学方法对肝癌组织及癌旁组织中的HBsAg、HCV抗原表达进行了标记和分析,同时对肝癌组织及癌旁组织进行肝组织纤维化分期.结果肝组织纤维化程度与HBV、HCV感染有明显相关性（rs=0.32,P=0.001）;HBsAg和HCV抗原在癌组织及癌旁组织中表达有差异,HBsAg主要在癌旁组织表达（79%）,高于癌组织（23%）;而HCV抗原在癌组织（15%）与癌旁组织表达（23%）水平相当.结论有病毒感染背景的肝癌组织,其纤维化程度高于无病毒感染的肝癌组织;病毒的感染是肝癌发生的原因,长期的病毒血症会加速肝纤维化的进展.     

Notchl、P21^WAF1／Cip1及活化caspase3在肝细胞癌中表达的相关性

目的研究Notct／1、P21^WAF1／Cip1及活化caspase3在肝细胞癌中表达的相关性。方法利用免疫组织化学检测60例肝细胞癌（HCC）和15例正常肝组织中Notchl、P21^WAF1／Cip1及活化caspase3的表达。结果HCA2中Notch1、P21^WAF1／Cip1及活化caspase3的阳性率和阳性表达强度显著低于正常肝组织（P〈0．01）;Notch1、P21^WAF1／Cip1及活化caspase3的表达强度与HCC分级和肿瘤大小密切相关,肿瘤分化愈差和肿瘤直径愈大,3种蛋白表达愈弱（P〈0．01）;在HCC中,P21^WAF1／Cip1和活化caspase3的表达强度与Notch1表达强度呈显著正相关（r分别为0．76和0．71）。结论提示Notch1信号通路可能是通过影响细胞周期和细胞凋亡在HCA2发生发展过程中发挥负性调控作用。     

葡萄糖转运蛋白1、缺氧诱导因子-1α和Ki-67在肝细胞癌中的表达及其相关性研究

目的探讨葡萄糖转运蛋白1（Glutl）、缺氧诱导因子-1α（HIF-1α）和Ki-67在肝细胞癌中的表达及其相关性。方法运用组织芯片技术,通过免疫组织化学Envision法检测171例肝细胞癌组织、55例癌旁组织、22例正常肝组织中Glutl、HIF-1α和Ki-67的表达情况,并结合临床病理因素进行分析。结果Glutl、HIF-1α和Ki-67在171例肝细胞癌组织中的阳性表达率分别为15．2％、19．9％和66．1％,明显高于其在癌旁肝组织（1．8％、1．8％和5．5％）和正常肝组织（均阴性）中的表达率（P〈0．05）。Glutl和HIF-1α表达与肝细胞癌分化程度和TNM分期有关（P〈0．01,P〈0．05）;Ki-67表达与肝细胞癌分化程度有关（P〈0．01）。肝细胞癌组织中Glutl与HIF-1α的表达呈正相关（r1=0．553,P〈0．05）;Glutl、HIF-1α与Ki-67均呈正相关（r2=0．560,r3=0．613,P〈0．05）。结论Glutl、HIF-1α和Ki-67在肝细胞癌的发生发展中起着不同程度的作用,联合检测Glutl、HIF-1α和Ki-67可能有助于判断肝细胞癌的恶性程度、转移潜能及预后分析。     

Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan

BACKGROUND: There is a tendency for familial aggregation of hepatocellular carcinoma (HCC). The aims of this study were to assess the degree to which familial aggregation of hepatitis B surface antigen (HBsAg) carriers accounts for familiality of HCC in families of hepatitis B-related HCC patients, and whether HCC shares a familial predisposition with liver cirrhosis among HBsAg carriers. METHODS: A total of 671 first-degree relatives of HBsAg-positive HCC cases were recruited using abdominal ultrasonography and tests for HBsAg and serum aminotransferases. They were from 165 simplex families defined as having only one HCC case and 72 multiplex families with more than one case. In analyses of family history of HCC and cirrhosis, the data set consisted of 4,471 unrelated asymptomatic HBsAg carriers recruited in a prospective study. RESULTS: There was no significant difference in the HBsAg-positive rate among relatives between multiplex (55.7%) and simplex (48.1%) families. Sonographic evidence of liver cirrhosis was present in 14.4% of HBsAg-positive relatives from multiplex families but in only 7.8% of HBsAg-positive relatives from simplex families (multiplex versus simplex families: adjusted odds ratio [OR] = 2.29; 95% CI: 1.10-4.77). Among unrelated asymptomatic HBsAg carriers, the adjusted OR of liver cirrhosis associated with a first-degree family history of HCC was 2.80 (95% CI: 1.68-4.66). This association was stronger in HBsAg carriers <50 years. No association was seen between family history of HCC and hepatitis activity based on elevated levels of aminotransferases. CONCLUSIONS: Familial aggregation of HCC in HBsAg carriers is associated with familial clustering of liver cirrhosis.     

Excess mortality from hepatocellular carcinoma in an HCV-endemic township of an HBV-endemic country (Taiwan)

Taiwan is an endemic area of hepatitis B virus (HBV). All previous studies have concluded that HBV is the major cause of hepatocellular carcinoma (HCC) in Taiwan. An HBV- and hepatitis C virus (HCV)-endemic township, Tzukuan, in southern Taiwan has been identified with the prevalence of 24% for HB surface antigen (HBsAg) and 37% for anti-HCV antibodies. To elucidate the aetiology of HCC and impact of HCV in this township, we conducted a case-control study and compared HBV-related liver cancer mortality in Tzukuan and Taiwan as a whole. Based on cancer registration datasets of 2 medical centres from 1991 to 1995, we recruited 18 male and 9 female HCC cases from the study township. Their mean age (+/- standard deviation) was 60.3 (+/- 7.3) years. Randomly sampled from a community-based survey, 4 age- (+/- 2 years) and sex-matched residents were selected as community controls for each HCC case. The HBsAg carrier rate was 40.7% in cases and 25.0% in controls (P = 0.1). Anti-HCV positive rate was 88.9% in cases and 53.7% in controls (P = 0.008). Age-adjusted liver cancer mortality in Tzukuan (36.5 per 10(5)) was significantly higher than that of Taiwan as a whole (20 per 10(5)). Based on the HBsAg-positive rate among HCC patients (40.7% in Tzukuan and 77.4-86.6% in Taiwan), the estimated HBV-related liver cancer mortality was similar in Tzukuan (14.9 per 10(5)) and Taiwan (15.8-17.3 per 10(5)). We concluded that HCV was the major risk factor for excess liver cancer mortality in this HCV-endemic township of the HBV-endemic country.     

Aflatoxin B1 DNA-Adducts in Hepatocellular Carcinoma from a Low Exposure Area

Aflatoxin B1 (AFB1) is a class 1 carcinogen with an ascertained role in the development of hepatocellular carcinoma (HCC) in high exposure areas. Instead, this study aimed to assay whether chronic/intermittent, low-dose AFB1 consumption might occur in low-exposure geographical areas, ultimately accumulating in the liver and possibly contributing to liver cancer. AFB1-DNA adducts were assayed by immunostaining in liver tissues from three Italian series of twenty cirrhosis without HCC, 131 HCC, and 45 cholangiocarcinoma, and in an AFB1-induced HCC rat model. CD68, TP53 immunostaining, and TP53 RFLP analysis of R249S transversion were used to characterize cell populations displaying AFB1-DNA adducts. Twenty-five HCCs displayed AFB1-adducts both in neoplastic hepatocytes and in cells infiltrating the tumor and non-tumor tissues. Nuclear immunostaining was observed in a few cases, while most cases showed cytoplasmic immunostaining, especially in CD68-positive tumor-infiltrating cells, suggestive for phagocytosis of dead hepatocytes. Similar patterns were observed in AFB1-induced rat HCC, though with higher intensity. Cholangiocarcinoma and cirrhosis without HCC did not displayAFB1-adducts, except for one case. Despite not providing a causal relationship with HCC, these findings still suggest paying attention to detection and control measures for aflatoxins to ensure food safety in low exposure areas.     

A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients

We carried out a hospital-based, case-control study to assess the association of both the Hepatitis B Virus (HBV) infection and the lifetime daily alcohol intake with the risk of developing hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC). Cases were 62 consecutive inpatients of a Gastroenterology Division in whom a first diagnosis of HCC superimposed on LC was made. Two control groups were used: 310 patients without liver disease, matched 1:5 with cases and randomly selected from inpatients of the same hospital, and 97 consecutive asymptomatic inpatients in whom the first diagnosis of LC was made. Alcohol intake was quantified in all subjects by a standardized questionnaire. HBV infection was associated with HCC development in cirrhotics (odds ratio =6.8; 95% confidence interval =1.4–32.3), whereas we observed a trend towards a decreased HCC risk at increased alcohol intake values (odds ratio from 1 for lifetime abstainers to 0.2 for drinkers of 175 g/day or more). Our results suggest that alcohol intake is not a direct determinant of HCC, but its role is mediated by LC. Cirrhotics with high alcohol intake do not usually survive long enough to develop HCC.     

环氧化酶-2基因在肝细胞癌中的表达及其意义

目的探讨环氧化酶-2（COX-2）在肝细胞癌发生发展中的作用及其意义.方法用免疫组织化学的方法检测41例肝细胞癌组织、16例乙型肝炎后肝硬化组织及5例正常肝脏组织中COX-2蛋白的表达情况,并分析COX-2蛋白表达与肝细胞癌临床生物学特征的关系.结果COX-2蛋白在肝细胞癌和肝硬化组织中的表达率分别为61.0%（25/41）和56.3%（9/16）,正常肝脏组织中无表达,与以上各病变组织COX-2蛋白表达差异有显著性（P＜0.05）;而在肝硬化组织与肝细胞癌组织COX-2蛋白表达差异无显著性（x^2=0.11,P＞0.05）.COX-2蛋白表达与肝细胞癌组织分化程度、癌肿转移状况有关（x^2=10.3,4.81,P＜0.05）.结论COX-2蛋白在肝硬化、肝细胞癌组织中表达上调,在肝细胞癌发生发展过程中可能起重要作用.     

CD 34 expression in chronic and neoplastic liver diseases

BACKGROUND: Capillarisation of hepatic sinusoids is a well recognized phenomen occurring in long standing liver disease, in hepatic cirrhosis as well as in hepatocellular carcinoma. To study immunohistochemically the expression and distribution of CD34 in chronic liver disease and hepatocellular carcinoma in order to evaluate the possible diagnostic implication of this marker. METHODS: Sixty-five samples of liver tissue showing normal liver, different degrees of chronic inflammation, cirrhosis and histological features of hepatocellular adenoma and carcinoma (HCC) were included in the study. The specimens were fixed in formalin and embedded in paraffin and an immunohistochemical investigation was performed by the standard avidin-biotin-peroxidase complex method with CD34. RESULTS: The sinusoids of normal liver showed no immunoreactivity. The sinusoids of liver affected by different degrees of chronic active hepatitis showed no or focal immunostaining for CD34; an increased immunoreactivity was observed in the periportal sinusoids of the cirrhotic nodules whereas diffuse and strong staining was observed in the overall HCC as well as in the hepatocellular adenoma tested. CONCLUSIONS: In HCC, immunoreactivity for CD34 represents an effective method to evaluate angiogenesis and to distinguish well-differentiated HCC from non-neoplastic liver. Its role in clinical stage and prognostic evaluation needs further investigation.     

原发性肝癌组织中螺杆菌感染的研究

目的研究螺杆菌感染与原发性肝癌（HCC）的关系。方法选取34例HCC患者的肝癌组织为研究对象（实验组），20例非肝癌手术患者肝组织作对照组。将两组标本制成病理切片，用于螺杆菌属的cDNA-mRNA原位杂交实验。通过定位测定来评价肝组织螺杆菌感染与HCC的相关性。结果利用原位杂交技术检测实验组和对照组标本螺杆菌属16SrRNA-mRNA，实验组有22例阳性，对照组皆为阴性（P〈0．01）。进一步用幽门螺杆菌（Hp）和肝螺杆菌（Hh）的cDNA探针进行原位杂交，Hp探针杂交结果与螺杆菌属探针杂交结果相符，阳性率为64．71％，而Hh探针杂交结果为阴性。结论HCC组织中存在Hp感染。     

CD133、CD90在肝癌组织中的表达及其临床意义

目的 检测肝癌干细胞标志物CD133和CD90在原发性肝癌组织中的表达情况,分析其临床病理学意义.方法 取93例原发性肝癌和10例正常肝组织,采用免疫组织化学(SP法)染色检测CD133和CD90表达.结果 93例肝癌组织中,71例(76.3%)CD133表达阳性,阳性细胞百分数为(6.4±3.3)%,64例(68.8%)CD90表达阳性,阳性细胞百分数为(4.3±3.9)%,10例正常肝组织中未见CD133和CD90阳性表达,差异有统计学意义(P<0.01);肝癌TNM分期Ⅲ～Ⅳ期患者CD133和CD90阳性细胞百分数[(8.1±3.7)%,(5.7±4.2)%]显著高于Ⅰ～Ⅱ期[(4.1±2.3)%,(2.3±1.9)%](P<0.01);Spearman相关分析显示,随病理组织学分级级别增高,CD133和CD90的表达增多(P<0.05);CD133与CD90在肝癌组织中的表达呈正相关(r=0.402,P<0.01).结论 肝癌组织中存在CD133和CD90阳性肝癌干细胞,其表达量与肝癌TNM分期和病理组织学分级呈正相关.     

抑癌基因PTEN与pAkt在肝细胞肝癌中表达及其意义

目的研究肝细胞癌（HCC）中抑癌基因第10号染色体上缺失与张力蛋白同源的磷酸酯酶基因（PTEN）与磷酸化丝氨酸／苏氨酸蛋白激酶B（pAkt）表达及其意义。方法采用免疫组化S—P法检测65例HCC及癌旁组织中FFEN与pAkt表达并分析两者与肝癌患者年龄、临床分期、病理类型及侵袭转移性之间关系。结果HCC中PTEN蛋白阳性率明显低于癌旁肝组织，且随HCC恶性程度、侵袭转移性升高而显著下降（P〈0．05）；pAkt在HCC中表达率明显高于癌旁肝组织，且其表达率随HCC恶性程度、侵袭转移性升高而增加（P〈0．05）；肝癌及癌旁组织中，FFEN与pAkt表达均呈负相关（P〈0．01）。结论PTEN与pAkt表达与肝癌组织恶性程度相关，联合检测PTEN与pAkt在癌组织中表达情况，可作为肿瘤预后评估指标之一。     

肝癌端粒酶逆转录酶表达与端粒酶活性相关性及临床意义

目的 探讨肝细胞肝癌（HCC）中端粒酶逆转录酶（hTERT）蛋白表达情况与端粒酶活性的相关性及其临床意义。方法 采用免疫组化S-P法检测52例HCC癌组织及相应癌旁组织中hTERT蛋白表达，并用TRAP-ELISA法检测上述组织中的端粒酶活性。结果 HCC癌组织中hTERT蛋白与端粒酶活性表达阳性率分别为86．5％（45／52）和80．8％（42／52），它们与相应癌旁组织比较差异均有显著性（P〈0．01）；且癌组织中hTERT蛋白阳性表达与端粒酶活性呈高度正相关（r=0．761，P〈0．001）。hTERT蛋白阳性表达与患者的性别、年龄、有无乙肝、肝硬化、肝功能、肿瘤包膜、病理分级及分期等临床指标无关，而与HCC肿瘤大小有关（P〈0.05）。结论 HCC癌组织中hTERT蛋白过度表达，可能参与肝癌端粒酶活性的调控，而在HCC发生、发展中起重要作用。hTERT蛋白表达与端粒酶活性均可作为HCC诊断的特异性指标。     

聚集素、P-糖蛋白在原发性肝细胞癌中的表达及其相关性研究

目的探讨聚集素（CLU）在原发性肝细胞癌（HCC）中的表达及其与P-糖蛋白（P—gP）表达的相关性。方法采用免疫组化法检测凋亡抑制基因CLU在HCC（41例）、肝硬化（10例）和正常肝脏（10例）组织中的表达及P—gp在HCC中的表达。结果CLU在41例HCC组织中阳性表达率为82．93％（34／41）,10例肝硬化和10例正常肝脏组织中表达阴性或弱阳性。在HCC组织中,CLU阳性表达与年龄、性别及有无合并肝硬化无相关性（P〉0．05）,而与Edmondson分级明显相关（P〈0．05）。P—gP在HCC组织中的阳性表达率为70．73％（29／41）。在HCC组织中,CLU的表达与P—gP表达呈正相关（P〈0．05）。结论CLU在HCC中呈高表达,与临床耐药密切相关,有望成为HCC靶向治疗的一个新靶点。     

Characteristics of hepatocellular carcinoma in a high arsenicism area in Taiwan: a case-control study

Arsenic contamination of drinking water is noticeably linked to the occurrence of skin, bladder, lung cancers, and hepatocellular carcinoma (HCC). Blackfoot disease (BFD) caused by arsenicosis is endemic in southwestern Taiwan, where artesian well water contains high concentrations of arsenic, and mortality from HCC shows a dose-response increase by concentration of arsenic in the well water. This case-control study was conducted to examine the clinical characteristics of HCC patients of BFD-endemic area. A total of 65 HCC cases (54 men and 11 women) were recruited from the BFD-endemic areas. The clinicopathological features were compared with 130 age- and sex-matched HCC control patients from non-BFD-endemic areas. Characteristics analyzed included hepatitis viral infection status, hepatitis activity, liver function, histological findings, computed tomography scan characteristics, and patient survival. No differences were observed between HCC patients or their tumors, from study and control areas.     

Mortality from liver disease among Italian vinyl chloride monomer/polyvinyl chloride manufacturers

The possible association in humans between nonangiosarcoma primary liver tumors (PLC-non-A), particularly hepatocellular carcinoma (HCC), and exposure to vinyl chloride monomer (VCM) is supported by both experimental and human data. This article presents a review of the information regarding 253 deaths that occurred in seven plants manufacturing VCM/PVC and one plant extruding PVC. The retrieval of clinical and pathological data, in addition to the information from death certificate, is referred to as "best evidence" (BE). BE has been carried out for 63 deaths. A total of 14 primary liver cancer (PLC) were detected: seven were angiosarcoma (PLC-A), and two of the remaining seven were hepatocellular carcinoma (HCC). In our series of 14 PLC cases, there was no significant difference between PLC-A and PLC-non-A as to length of exposure and latency. There was no noticeable difference in terms of job title between ASL and non-ASL cases. The list of longest held jobs shows the presence of various job titles, different from autoclave cleaner, for primary liver cancer, PLC-A and PLC-non-A. In conclusion, our observations show that VCM may have a broader carcinogenicity action on the liver and that exposure lower than that occurring in autoclave cleaning can cause primary liver cancer, both angiosarcoma and nonangiosarcoma.