Non-cirrhotic Hepatocellular Carcinoma Research Articles

PWE-141 Hepatocellular carcinoma and microvascular invasion in cirrhotic and non-cirrhotic livers: are they different diseases?

IntroductionHepatocellular carcinoma (HCC) behaves differently in cirrhotic and non-cirrhotic livers. Microvascular invasion (MVI) is a key determinant of outcome following curative treatment for HCC. Despite attempts to reach a consensus,...

Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection

Background and aimsTelomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker. MethodsWe conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 hepatitis B virus (HBV)-related HCC cases and 280 frequency-matched cancer-free HBV controls. ResultsCases had a significantly longer RTL (median, 0.31; range, 0.02–2.31) than controls (median, 0.20; range, 0.01–1.60) (P=0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR]=1.55, 95% confidence interval [CI]=1.02–2.33, P=0.038). This association attenuated after multivariate adjustment (OR=1.40, 95% CI=0.90–2.19, P=0.132). In a quartile analysis, a significant dose-response relationship was noted in univariate analysis (Ptrend=0.017) which was again attenuated in multivariate analysis (Ptrend=0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR=3.54, 95% CI 1.58–7.93 P=0.002), but not cirrhotic (OR=0.95, 95% CI 0.55–1.64, P=0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (Pinteraction=0.013). ConclusionsRTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention.

The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients

It is well established that hepatocellular carcinoma (HCC) develops in a multistep process, from chronic hepatitis, cirrhosis to HCC. Adipose tissue is not simply an energy storage organ but also a secretory organ, producing a variety of bioactive molecules known as adipokines, including adiponectin and leptin. Hyaluronic acid (HA) is an extracellular matrix protein, often associated with a variety of human cancers. Our retrospective study determines serum levels of adiponectin, leptin, and HA in HCC of cirrhotic and noncirrhotic patients and compares these levels to patients with cirrhosis and normal subjects. Noncirrhotic HCC (n = 19), cirrhotic HCC (n = 50), cirrhosis (n = 36) patients and twenty one age-, sex-, and body mass index (BMI)-matched normal healthy controls were subjected in the present study. Serum adiponectin, leptin, and HA levels were determined using enzyme-linked immunosorbent assay technique. Levels of serum adiponectin were significantly higher in the cirrhosis and cirrhotic HCC groups than in the normal subjects, whereas serum HA levels were found to significantly increase in all three patients groups. The elevation of serum leptin in our HCC patients, regardless of being cirrhotic or noncirrhotic, but not in the patients with cirrhosis, may shed some light on the significance of serum leptin level in HCC. Further studies are recommended to evaluate the prognostic value of serum leptin level in HCC.

Liver resection for non-cirrhotic hepatocellular carcinoma in South African patients.

We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur Hospital, Cape Town, to identify all patients who underwent surgery for HCC with non-cirrhotic liver parenchyma between 1990 and 2008. Twenty-two patients (10 men, 12 women, 3 black, 19 white, median age 47 years, range 21-79 years) underwent surgery for non-cirrhotic HCC. Sixteen patients had non-fibrolamellar HCC (Group 1); 6 patients had fibrolamellar HCC (Group 2). Group 1 had a median age of 55 years, and 6 (38%) were men; group 2 had a median age of 21 years, and 5 (83%) were men. Most patients had a solitary tumour at diagnosis; median largest tumour diameters in Groups 1 and 2 were 10 cm (range 4-21) and 12 cm (range 4-17), respectively. Patients in Group 1 underwent extended right hepatectomy (N=3), right hepatectomy (N=3), left hepatectomy (N=3), partial hepatectomy (N=7), cholecystectomy (N=6), and appendicectomy (N=1). Patients in Group 2 underwent extended right hepatectomy (N=1), right hepatectomy (N=1), left hepatectomy (N=2), segmentectomy (N=2), and portal lymphadenectomy (N=3). Recurrence rates in Groups 1, 2, and overall were 81%, 100% and 86%, respectively. Median overall survival was 46 months, with 1-, 3-, and 5-year survival rates of 95%, 59% and 45%, respectively. In Group 1, median survival was 39 months, with 1-, 3-, and 5-year survival rates of 100%, 56% and 38% respectively. In Group 2, median survival was 61 months, with 1-, 3-, and 5-year survival rates of 83%, 67% and 67%, respectively. Despite aggressive surgical resection, HCC arising in normal liver parenchyma has a high recurrence rate and an ultimately poor outcome. This finding is similar to both the recent international experience of non-cirrhotic HCC and local experience of fibrolamellar HCC.

Role of hepatitis B virus base core and precore/core promoter mutations on hepatocellular carcinoma in untreated older genotype C Chinese patients

The aim of the study was to investigate the prevalence of mutations of basal core promoter (BCP) and precore (PreC) region of hepatitis B virus (HBV) and their association with hepatocellular carcinoma. A total of 341 untreated older HBV patients were divided into three groups: chronic hepatitis B (CHB, 185), cirrhotic hepatocellular carcinoma (LC-HCC, 113) and non-cirrhotic hepatocellular carcinoma (non-LC-HCC, 43). HBV BCP and PreC mutations and genotypes were determined by direct sequencing. Using univariate analysis, age (≥ 45 years), single mutations including A1896 and A1899 and multiple mutations T1762/A1764 + A1896, T1762/A1764 + A1899 and T1762/A1764 + A1896 + A1899 were more frequently detected in LC-HCC and non-LC-HCC patients than in CHB patients. BCP T1762/A1764 mutations were highly detected in LC-HCC patients than in CHB patients. Multivariate logistic regression analysis (adjusted for age and gender) revealed that among HBeAg-positive patients, BCP T1762/A1764 mutations (OR, 5.975; P = 0.05), PreC A1899 mutation (OR, 4.180; P = 0.013) and multiple mutations T1762/A1764 + A1899 (OR, 6.408; P = 0.006) were independently associated with the development of LC-HCC; PreC A1899 mutation (OR, 7.347; P = 0.034) was also independently associated with the development of non-LC-HCC. On the other hand, among HBeAg-negative patients, PreC A1896 mutation (OR, 5.176; P = 0.002) and multiple mutations T1762/A1764 + A1896 (OR, 4.149; P = 0.007) were independently associated with the development of non-LC-HCC. These results indicated that older age (≥ 45 years) was associated with LC-HCC and non-LC-HCC development. BCP T1762/A1764 mutations and PreC A1899 mutation were associated with the LC-HCC development in HBeAg-positive patients. PreC A1896 mutation was associated with the non-LC-HCC development in HBeAg-negative patients.

Non-Cirrhotic Hepatocellular Carcinoma in a Young Active Duty Male

A 22-year-old Airman was presented to the clinic with new onset abdominal pain, which revealed to be well-differentiated hepatocellular carcinoma. Hepatocellular carcinoma in a young patient with no cirrhosis or fibrosis is a relatively rare diagnosis with possible relationship to exercise supplement use. With the high incidence of supplement use in the military population, caution and further investigation into supplement use with correlation to the incidence of liver cancers may be warranted.

Hepatocellular Carcinoma in the Non-cirrhotic Liver is Associated with a High Body Mass Index Independent of Steatosis: 2010 Presidential Poster

Purpose: Hepatocellular carcinoma (HCC) in the absence of advanced fibrosis, cirrhosis or hepatitis B continues to be a relatively rare occurrence. However, it has been estimated that up to 10% of HCC occurs in non-cirrhotic livers. It has been suggested that obesity and insulin resistance may be risk factors for non-cirrhotic HCC. We aimed to review the clinical and histologic features of our patients with non-cirrhotic HCC to assess for an association with BMI and diabetes (DM). Methods: We analyzed data from a cohort of 12 patients with non-cirrhotic HCC who underwent partial hepatectomy between January 2008 and September 2009 at a single center. We evaluated preoperative data including age, gender, presence of liver disease, AFP, BMI, lesion size, number of lesions, prior locoregional therapy and other comorbidities. We also reviewed data related to the resection including background histology, tumor size, differentiation and vascular invasion (VI). Finally, we assessed post-operative complications and mortality. Results: The average age in our series was 60 with an equal mix of males and females. The average BMI was 27.6 (2 morbidly obese, 1 obese, 5 overweight, 4 normal), and 4/12 patients had DM. Overall, these patients had a higher prevalence of DM compared to the general population (33.3% vs. 5.8%), with a higher proportion being overweight or obese (67% vs. 60.3%), and an overall higher BMI (27.6 vs. 26.8). Preoperatively 7/12 had prior locoregional therapy, 12/12 had a single HCC (average size of 23.6 cm) and an average AFP of 1098.5 (available for 9/12). All patients had preoperative testing for underlying liver disease that was negative in all but 2 patients, both with hemochromatosis. Histology was obtained from resected specimens and was normal for all patients except one with hemochromatosis (stage 2 fibrosis), and 2/12 had mild steatosis. VI was present in 5/12 lesions, with 6 well and 6 moderately-differentiated HCCs, none were fibrolamellar. At the time of our review we had no known recurrences, and the average follow up was 17.5 (10-28) months. Conclusion: HCC in the absence of cirrhosis continues to be a rare occurrence. In our series, patients with non-cirrhotic HCC had a high prevalence of DM and elevated BMIs despite a lack of steatosis. This supports previous data that there may be an association with non-cirrhotic HCC and an elevated BMI as well as DM independent of steatosis. Patients were also noted to have advanced tumors that were large in size with VI. Despite advanced disease, patients tolerated resection very well with minimal complications, no operative mortality, and an average tumor-free follow-up of 17.5 months.

Hepatocellular Carcinomas in Cirrhotic and Noncirrhotic Human Livers Share Angiogenic Characteristics

BackgroundThe antiangiogenic drug sorafenib has been shown to be an effective treatment for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. It might also be effective in noncirrhotic HCC provided that the angiogenic properties of both tumor types are comparable. The aim of this study is to compare endothelial cell dynamics, microvessel density (MVD), and vessel maturation as indirect markers of angiogenesis in human HCC in cirrhotic and noncirrhotic livers.Materials and MethodsIn a tertiary care setting, 70 consecutive HCC tumors were analyzed for endothelial cell dynamics. CD34 was applied to identify tumor microvessels, double immunolabeling Ki67/CD34 and activated caspase-3/CD34 to assess endothelial cell proliferation and apoptosis, and α-smooth muscle actin/CD34 for pericyte coverage. These characteristics were compared in cirrhotic (n = 33) and noncirrhotic HCCs (n = 37). Microvessel density was correlated with radiological signs of hypervascularity as obtained with dynamic four-phase CT scans during the arterial and portal phase of contrast enhancement.ResultsMicrovessels in cirrhotic and noncirrhotic HCC were mainly mature. In both groups endothelial cell turnover was low and MVD was not different. There was no correlation between MVD and venous invasion, tumor size, and turnover of tumor cells or endothelial cells. MVD was negatively correlated with contrast washout in the portal venous phase of CT scanning. In transplanted patients, MVD was not correlated with survival, whereas in patients after liver resection a high MVD was associated with a better prognosis.ConclusionAngiogenic characteristics of HCC in cirrhotic and noncirrhotic livers have a remarkable similarity.

Asymptomatic Right Atrial Mass as Initial Manifestation of Non-Cirrhotic Hepatocellular Carcinoma

Purpose: A 51-year-old male with past medical history of Down syndrome and chronic hepatitis B virus (HBV) infection was referred from the clinic for evaluation of the right atrial mass which was found incidentally on his routine examination. Patient denied dyspnea, orthopnea, chest pain, confusion, tremors, malaise or weakness. Physical examination revealed classic craniofacial dysmorphology of Down syndrome. There was no evidence of icterus, hepatosplenomegaly, abdominal tenderness or distension. An electrocardiogram showed normal sinus rhythm with normal axis and a chest radiography showed enlargement of the cardiac silhouette. CT scan showed large infiltrating tumor within the liver with venous invasion into the middle hepatic vein, inferior vena cava and right atrium. The biopsy of hepatic mass was not performed because the positive HBsAg, elevated AFP and a new hepatic lesion seen on CT scan obviate the need for biopsy to diagnose hepatocellular carcinoma (HCC). The major risk factor for HCC is cirrhosis and only 10 to 20% of cases of HCC develop without cirrhosis. The incidence of metastatic HCC to the right heart cavity is reported to be less than 6% in an autopsy series. This group of patients often exhibits symptoms of heart failure owing to flow obstruction or thromboembolism. This case has the distinction of comprising three rare entities: 1) non-cirrhotic HCC, 2) intracardiac metastases, and 3) lack of clinical manifestations.Figure 1: An infiltrating 102 × 95 mm mass within the right lobe of the liver.Figure 2: Atrial phase of CT scan shows a filling defect within the right atrium.

An apoptosis biomarker for prediction of nonalcoholic steatohepatitis

We read with interest the article by Feldstein et al. that evaluated the use of cytokeratin-18 (CK-18) fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis (NASH).1 The authors reported that plasma levels of an apoptosis-associated CK-18 fragment were significantly elevated in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) as compared to healthy individuals. Moreover, they observed significantly higher CK-18 fragment levels in NASH compared to “borderline diagnosis” or simple steatosis. The authors conclude that such noninvasive determination of CK-18 fragments allows the prediction of NASH and severity of disease in patients with NAFLD. Liver biopsy is still considered the gold standard for assessment of liver disease activity, although it remains associated with several disadvantages including high costs and risks of clinical complications. Noninvasive techniques that can monitor disease activity and distinguish NASH from simple steatosis are therefore urgently needed.2 The multicenter study by Feldstein and coworkers is therefore of great clinical importance. Caspase-generated CK-18 fragments are released during hepatocyte apoptosis, a fundamental process in virtually all acute and chronic liver diseases that are characterized by inflammation, steatosis, or fibrosis.3-6 Previous studies in patients with chronic HCV infection have shown that activation of hepatic caspases closely correlates with inflammation.7 In addition, detection of caspase-generated CK-18 fragments in sera from patients with chronic hepatitis C virus (HCV) infection has recently been associated with fibrotic liver injury.8 Another study showed a correlation of CK-18 fragment levels with the proportion of HCV-associated liver steatosis.9 In this latter study, only patients with minimal inflammatory disease activity and low stages of fibrosis were included, suggesting that even under conditions of mild inflammation, CK-18 fragment levels correlate with the extent of steatosis. Hepatocyte apoptosis and elevated CK-18 fragment levels are also prominent features of cholestatic liver diseases.10 Furthermore, presumably due to increased cell turnover, elevated serum levels of CK-18 fragments have been reported even in noncirrhotic hepatocellular carcinoma.10 In conclusion, CK-18 fragments represent a strong predictor and useful noninvasive biomarker for the diagnosis of NASH in well-defined patients. However, it should be taken into account that a variety of hepatic pathologies may result in elevated CK-18 fragment levels. Thus, this marker is not specific for NASH but rather a general indicator of severe liver disease. Heike Bantel*, Matthias J. Bahr*, Klaus Schulze-Osthoff , * Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.

Reply:

Reply:

Clinicopathologic Features and Long-Term Outcomes of Chinese Patients with Hepatocellular Carcinoma in Non-Cirrhotic Liver

Background/Aims: Most hepatocellular carcinomas (HCC) are associated with cirrhosis. The clinicopathologic characteristics and outcomes of HCC present in non-cirrhotic livers are not well known in Chinese patients. This study was performed to explore the features of these patients and their outcomes after hepatectomy. Methods: 96 patients with histologically confirmed HCC in non-cirrhotic liver who underwent partial hepatectomy between 1995 and 2001 in our cancer center were reviewed. A retrospective analysis of the clinicopathologic features was performed, and survival of patients was analyzed by the Kaplan-Meier method and Cox regression model. Results: Operative mortality and morbidity were none and 8.3% (8/96), respectively. Postoperative overall survival (OS) rates at 1, 3, 5 and 10 years were 84.4, 62.5, 47.9 and 38.2%, respectively, with a median OS of 57 months. Disease-free survival (DFS) rates at 1, 3, and 5 years were 56.3, 39.6, and 33.3%, respectively, with a median DFS of 18 months. TNM stage was an independent prognostic factor for both OS and DFS of non-cirrhotic HCC. Operative blood loss was an independent prognostic factor for OS and DFS of patients who received curative resection. Conclusion: Curative partial hepatectomy was an effective and safe treatment for non-cirrhotic HCC. Aggressive local therapies were recommended for patients with intrahepatic recurrence.

Identification of Cystatin B as a Potential Serum Marker in Hepatocellular Carcinoma

The poor survival rate of hepatocellular carcinoma (HCC) is in part due to the inability to diagnose patients at an early stage. Therefore, the aim of this study was to search for candidate serum marker for HCC and to test their ability to distinguish a HCC from benign liver disease. Genome-wide analysis by a microarray in 40 HCC patients was done between HCC and paired nontumor liver tissues. Expression of cystatin B (CSTB) was examined by mRNA expression analysis and immunohistochemistry. The serum CSTB levels were measured using a sandwich ELISA method in four groups, including normal healthy subjects (group 1, n = 52) and patients with noncirrhotic chronic hepatitis (group 2, n = 53), cirrhosis (group 3, n = 43), and HCC (group 4, n = 62). Microarray and statistical analyses identified 248 genes that were expressed differently between HCC and nontumor liver tissues. One of them, CSTB, was expressed preferentially in the HCCs compared with the nontumor tissues, 36 of 45 specimens (80%) by Northern blot and semiquantitative reverse transcription-PCR analyses. The serum CSTB level was much higher in HCC patients than in those with nonmalignant chronic liver disease (groups 2 and 3; P < 0.0001). The receiver operating characteristic curve indicated 5.34 ng/mL to be the optimal value for CSTB, and the sensitivity and specificity for this CSTB value were 85.5% (95% confidence interval, 74.2-93.1%) and 53.1% (95% confidence interval, 42.7-63.4%), respectively, in distinguishing between patients with HCC and those with nonmalignant chronic liver disease. CSTB is specifically overexpressed in most HCCs and is also elevated in the serum of a large proportion of HCC patients. CSTB or the combination of CSTB and alpha-fetoprotein may be a useful marker for diagnosing patients with HCC with a high sensitivity.

Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway

Obesity serves as an important risk factor for incidences of both cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC), which is the third leading cause of cancer death worldwide. Leptin, the obesity biomarker molecule secreted systemically by body fat mass and locally by activated hepatic stellate cells, is proposed to play a certain role in HCC growth. Here, we show both proliferative and anti-apoptotic effects of leptin in HCC cells. Leptin stimulated cyclin D1 promoter activity to increase cyclin D1 protein expression, which accelerated the cell cycle progression. The reduced ratio between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) Bcl-2 family proteins by transforming growth factor (TGF)-beta 1 caused HCC cells degradation of poly(ADP-ribose) polymerase and consequential apoptosis; whereas, leptin protected cells from apoptosis by reversing TGF-beta 1-reduced Bcl-2/Bax ratio as a result of down-regulating Bax. Any inhibitor specific for Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1/2 (ERK1/2) blocked these leptin functions. When intrahepatocytic JAK2 was activated by leptin, the active JAK2 afterward triggered a signaling cascade involving activations of PI3K/Akt and MEK/ERK1/2 in order of occurrence. As yet, in most cases, the crosstalks among signaling pathways primarily studied in diverse cancer cell types for mediating somatotropic effect of leptin are not well clarified and seem to be cell-type dependent. For the first time, our results demonstrate the direct effects of leptin on HCC growth and define its signal pathway with a crosstalking JAK2-PI3K/Akt-MEK/ERK1/2 connection. The identified hierarchy of intrahepatocytic leptin signaling pathway provides a clear basis potentially beneficial to make accurate and effectual strategies for facing both cirrhotic and non-cirrhotic liver carcinogenesis.

Role of Hepatitis B Virus Precore/Core Promoter Mutations and Serum Viral Load on Noncirrhotic Hepatocellular Carcinoma: A Case‐Control Study

Apart from the presence of liver cirrhosis, hepatitis B virus (HBV) factors have also been shown to play a role in the development of hepatocellular carcinoma (HCC). Studying HBV-related noncirrhotic HCC may help clarify the effect of viral factors. In a hospital-based, age- and genotype-matched study, we aimed to determine the role played by basal core promoter (BCP) T1762/A1764 mutation, precore A1896 mutation, and serum viral load in noncirrhotic hepatocarcinogenesis by comparing 44 patients with HBV-related noncirrhotic HCC, 45 patients with chronic hepatitis B, and 42 patients with HBV-related cirrhotic HCC. HBV genotype, precore and BCP mutations, and viral load were determined by molecular assays. In univariate analysis, statistically significant odds ratios were obtained for male sex (P=.005) and BCP T1762/A1764 mutation (P=.0003) in patients with noncirrhotic HCC, compared with patients with chronic hepatitis B. By multiple logistic regression analysis, male sex, BCP T1762/A1764 mutation, and viral load >or=10(5) copies/mL were independently associated with the risk of noncirrhotic HCC. The virologic characteristics were similar between patients with cirrhotic HCC and those with noncirrhotic HCC. Our results suggest that BCP T1762/A1764 mutation and higher viral load may be involved in the carcinogenesis of cirrhotic and noncirrhotic HCC.

Occult Viral Hepatitis and Noncirrhotic Hepatocellular Carcinoma

The achievement of a sustained virologic response to hepatitis C antiviral therapy represents a milestone occurrence that many tout as a cure. Recent studies, however, have found trace HCV viral material both among sustained responders and in patients with chronic liver disease who are HCV RNA negative, suggesting the entity of occult hepatitis C. As a body of literature emerges on the pathogenic role of occult hepatitis B, little is known of the potential importance of occult type C hepatitis. Specifically, occult hepatitis B has been strongly implicated as a culprit that facilitates the development of hepatocellular carcinoma, typically in the background of cirrhosis. Those cancers that develop in noncirrhotic livers, an especially rare entity in the West, usually occur in the setting of smoldering liver injury, often with some degree of fibrosis. The role of multiple hepatotoxins acting in concert to potentiate hepatic carcinogenicity has become increasingly recognized, including viral coinfection. The finding of occult hepatitis B in noncirrhotic hepatocellular carcinomas among patients with hepatitis C who achieved antiviral sustained virologic response raises provocative theories regarding the natural history of both of these viral hepatitis agents.

Prognostic factors after resection for hepatocellular carcinoma in noncirrhotic livers: univariate and multivariate analysis.

The aim of this study was to investigate the prognostic factors for hepatocellular carcinoma (HCC) in patients without cirrhosis who underwent hepatectomy. Between 1986 and 1998 a total of 197 men and 57 women with noncirrhotic HCC underwent hepatic resection in the Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan. We determined their surgical mortality and the disease-free and overall cumulative survival rates. The surgical mortality was 4.7% and the 5-year disease-free survival rate 24.01%. By Cox regression analysis, serum alkaline phosphatase [relative risk (RR) 1.761; 95% confidence interval (CI) 1.037-2.985)], albumin (RR 2.179; CI 1.215-3.908), multiple tumor status (RR 2.288; CI 1.272-4.115), and blood urea nitrogen (RR 4.651; CI 1.116-19.38) were shown to be independent prognostic factors for the 5-year disease-free survival rates. The 5-year overall cumulative survival rate was 25.91%. By Cox regression analysis, serum albumin (RR 1.656, CI 1.005-2.730), blood transfusion (RR 2.075, CI 1.153-3.731), resection margin (RR 2.562, CI 1.436-4.572), and multiple tumors (RR 2.801, CI 1.727-4.545) were shown to be significant independent factors that influenced cumulative survival rates. Hence in patients with a noncirrhotic HCC who underwent hepatectomy the prognosis depended on preoperative hepatic function, the presence of multiple tumors, the need for blood transfusion, and the surgical resection margin.

Genomic imbalances in Korean hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent gastrointestinal malignant tumors in Southeast Asia. Thirty-one cirrhotic HCC, 14 noncirrhotic HCC, and 13 metastastic HCC in the Korean population were investigated on microdissected tissues for chromosomal aberrations by degenerate oligonucleotide–primed polymerase chain reaction (PCR) comparative genomic hybridization. A number of prominent sites of genomic imbalances were observed. The gains of 1q, 6p, 7, 8q, 12q, 13q31∼q32, 16p, 17q, and 20q and the losses of 1p, 4q, 6q, 8p, 9p, and 13q regions were observed with a similar high frequency in all types. Various chromosomal aberrations were observed preferentially to specific types. Gains of 4p15∼pter, 10q24∼qter, 18p11∼pter, and 19p10∼pter and a loss of 11q14∼q22 were observed in the cirrhotic HCC, whereas losses of 14q21∼q23 and 10q22∼q23 were observed in noncirrhotic HCC. In metastatic HCC, gains of 3q25∼qter and Xp21∼pter and losses of 21q11∼qter and Y were observed. The recurrent gains and losses of chromosomal regions identified in this study are consistent with several previous observations and provide possible candidate regions for the involvement of tumorigenesis and progressions of HCC.

Liver Transplantation for Hepatocellular Carcinoma in Cirrhosis

H epatocellular carcinoma (HCC), when left untreated, has an extremely poor prognosis with only 1 to 6 months’ survival from the time of diagnosis’; for this reason, many surgeons were initially enthusiastic for liver transplantation in the treatment of HCC in cirrhosis. However, since 1985, it has become apparent that the results of transplantation for hepatobiliary malignancy with cirrhosis have been less than ideal.2 Although liver transplantation for this primary hepatobiliary malignancy has traditionally been associated with decreased operative mortality,3 it actually has adversely affected short-term survival in cirrhosis”7 and, more distressing, at 5 years has the lowest long-term survival after transplantation compared with benign indications for liver transplantation. 2+‘* Further confusion arises from survival analysis, which includes noncirrhotic patients, fibrolamellar HCC, and unknown lesions,5,6,‘z~‘3 all elements associated with different outcomes and a major consideration in the ambiguity related to the exact role of transplantation for HCC in cirrhosis.t5 Presently, most institutions, with some variation, practice a restrictive transplantation policy’” for any type of primary hepatobiliary malignancys because of the dismal results. Conversely, the excellent potential for cure in patients with unknown HCC found on the hepatectomy specimen after transplantation”; the good results for small, less numerous lesionst7; and the poor long-term results after liver resection for HCC in cirrhosis have maintained support for persisting with liver transplantation. Some offer an approach with more advancedstage disease,4-6 whereas others have been conservative by only carefully selecting patients with a chance for cure.” Present multimodality therapy, primarily without transplantation, in the East’* and adjuvant and neoadjuvant protocols, with transplantation, in the West’g*20 emphasizes this complex

Apolipoproteinemia A and α-fetoprotein in the diagnosis of hepatocellular carcinoma and cirrhosis: Several interpretations

The serum apolipoprotein A (Apo A) and α-fetoprotein (AFP) were evaluated in histologically verified 30* cases of alcoholic cirrhosis and 18 cases of hepatocellular carcinoma (HCC). The latter were also divided into subgroups depending on the presence or absence of associated cirrhosis. Serum Apo A levels were found to be significantly decreased in cirrhotics (p < 0.001) compared to controls and non-cirrhotic HCC patients. In 22 cases of alcoholic cirrhosis (AFP < 10 ng/ml) and 12 cases of HCC (AFP > 600 ng/ml), the AFP levels itself* were diagnostic, but in the remaining cases, AFP levels (100-600 ng/ml) were not able to differentiate between cirrhosis and malignancy. In this later group of patients with low pathological range of AFP, serum Apo A levels found to be significantly decreased in alcoholic cirrhotic patients (p < 0.001) compared to HCC patients. Thus, estimation of Apo A levels may be helpful to interpret the AFP values at lower pathological range due to suspected liver pathology.