Sunday May 21: Liver Cell Cancer Research Forum

 

 

166. MELD allocation policy: Does a high AFP score in the absence of liver mass equate to Hepatocellular Carcinoma?

N. Kemmer; G. Neff; S. Satiwah; v. Zacharias; F. Weber; J. Buell; R. Giesting; D. Russell; M. Thomas; A. Tevar; R. Shukla; S. Rudich

 

Introduction:

The current UNOS criteria for Liver Transplant (LTx) gives priority to patients with elevated serum AFP > 500 ng/ml in the absence of radiologic evidence of Liver mass. Reports have shown that an elevated serum AFP is a poor diagnostic indicator for Hepatocellular Carcinoma (HCC) in patients with cirrhosis. Aim: To determine if AFP level above 500 ng/ml in the absence of a liver mass by imaging study correlates with the presence of HCC.

 

Methods:

Using the UNOS database we queried all patients transplanted in the United States between 2/02 and 10/05 based on these criteria. The data collected included; patient demographics, clinical information and pathological outcomes. The data was analyzed using chi-square t – test and confirmed by logistic regression modeling.

 

Results:

To date twenty-three patients have received a liver transplant. Median age (range 40 – 69), 70% Caucasian, 61% male and a median AFP 658 ng/ml (range 504 - 7836). Etiology of liver disease: 83% Hepatitis C infection, 9% Primary biliary cirrhosis, 4% HCV-HBV Coinfection and 4% cryptogenic cirrhosis. Twenty-two patients received a cadaveric liver transplant, and one received a living donor transplant. HCC was confirmed post-transplant in only six patients (26%). There was no difference in race, gender, etiology of liver disease or AFP level between patients with and without HCC but a significant difference in age (59.8 for HCC pts vs. 51.3 for Non-HCC group; p = 0.01).

 

Conclusion:

Majority of the patients who received extra MELD points based on an elevated AFP did not have HCC. Older age was a significant predictor for the presence of HCC in patients with a serum AFP greater than 500. These results demonstrate the poor correlation of an elevated AFP with the presence of HCC in patients without a documented liver mass.


167. Risk Factors for Primary Hepatocellular Carcinoma in Hispanic and Asian Americans in 2000

M. Dunnigan; C. Howell

 

The incidence of primary hepatocellular carcinoma (HCC) has been increasing in the USA during the past 20 years. Both the HCC incidence and mortality rates are greater in Black, Asian, and other race groups compared to Whites. Analyzing the Nationwide Inpatient Sample (NIS) 2000, we found higher rates of HBV, HCV, HBV plus HCV, and diabetes plus viral hepatitis among Black HCC cases. However, there are few recent data regarding HCC risk factors in US Hispanics and Asians.

 

Goal

To determine HCC risk factors in Asian and Hispanic HCC cases in 2000 compared to White cases. Methods. HCC cases were identified in the NIS 2000 using ICD-CM-9 code 155.00. HCC risk factors including HBV, HCV, alcohol (ALD), cryptogenic, cirrhosis not otherwise specified (NOS), autoimmune hepatitis, hemochromatosis, alpha-1-AT deficiency, Wilson’s disease, tobacco use, and diabetes (DM) were identified by ICD-9 codes. The proportion of each HCC risk among the racial groups was compared using chi-square tests. Odds ratios (OR) and 95% confidence intervals (CI) for each risk factor in Asian and Hispanic relative to White HCC cases was determined by logistic regression analysis.

 

Results

We identified 701 White, 216 Asian and 226 Hispanic HCC cases. Asian (61.9 ± 13.7 yr.) and Hispanic (62.3±14.0 yr.) cases were younger than White HCC cases (65.1±13.7, p<0.002 ANOVA for both). HBV, HBV plus HCV (OR 2.5 CI 1.04-6.0), and HBV plus DM (OR 2.5 CI 1.04-6.0, p=0.03) were more common among Asian than White HCC cases (OR 8.5, 95% CI 5.2-13.9, p<0.0001), whereas ALD was less common in Asian cases (OR 0.54, CI 0.3-0.9, p=0.02). Hispanic HCC cases were more likely to have HCV (OR 1.6, CI 1.2-2.2, p=0.005), DM (OR 1.5, CI 1.1-2.1, p=0.01), cirrhosis NOS (OR 1.6, CI 1.04-2.6, p=0.01) and DM plus HCV (OR 2.1, CI 1.2-3.8, p=0.01) than White cases. White cases were more likely to have no identified HCC risk factor than either Asian or Hispanic cases.

 

Conclusion

The prevalence of HCC risk factors varied between Hispanic, Asian, and White HCC cases in 2000. Higher rates of viral hepatitis and concurrent HCC risk factors might account for the higher incidence and younger age of HCC in Asian and Hispanic cases.

 

 

Asian
(n = 221)

Hispanic
(n = 226)

White
(n = 701)

p value
(Chi-square)

ALD

20 (9.3%)

43 (19.0%)

111 (15.8%)

0.01

HBV

55 (25.5%)

14 (6.2%)

27 (3.9%)

< 0.0001

HCV

40 (18.5%)

74 (32.7%)

163 (23.3%)

0.001

Cirrhosis NOS

18 (8.3%)

32 (14.1%)

64 (9.1%)

0.06

Cryptogenic

17 (7.9%)

30 (13.0%)

66 (9.4%)

0.13

DM

53 (24.5%)

72 (32.0%)

165 (23.5%)

0.04

No HCC Risk Factor

74 (34.3%)

66 (29.2%)

303 (43.0%)

0.0003

 

 


168. Survival and recurrence after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC)

S. Shiina; T. Teratani; R. Tateishi; M. Akamatsu; H. Yoshida; Y. Kondo; M. Yanase; J. Imamura; T. Ohki; S. Kondo; H. Nakagawa; R. Masuzaki; N. Yamashiki; S. Obi; H. Yoshida; T. Kawabe; M. Omata

 

RFA has been widely performed for HCC. Our randomized controlled trial demonstrated that RFA had higher survival and lower recurrence than ethanol injection, although there was no difference in adverse events between the two therapies (Gastroenterology, 2005;129:122). There have not been many reports, however, on its long-term results. We evaluated survival and recurrence after RFA.

 

Subjects & Methods

Indications of RFA were; 1) unresectable lesions or refusal of surgery, 2) no extrahepatic metastasis or vascular invasion, 3) no refractory ascites, 4) PT > 50% and Plt > 50,000, 4) T. Bil < 3.0, 5) obtainment of informed consent. We put no restrictions on lesion location. The subjects were 556 consecutive patients with HCC who received RFA as the initial treatment. There were 366 males and 190 females. The age was 67.7 + 8.0 (mean + S.D.) yrs. Lesion number was 1.8 + 1.3 (1-12). Maximum lesion size was 2.68 + 1.13 (0.9-9.7) cm. Liver function was in Child-Pugh A in 388 cases, in B in 162, and in C in 6. We performed RFA percutaneously with a cooled-tip electrode. As a general rule, we ablated not only the tumor but also some amount of the surrounding tissue. One to three days after RFA, CT was performed to determine the efficacy. If there were any possible undestroyed portions, RFA was repeated. All patients had CT and US every 4 months to find any recurrence. We examined 20 factors (age, sex, tumor size, tumor number, AFP, AFP-L3 & DCP before & after RFA, histological tumor differentiation, Alb, T. Bil, ALT, PT, Plt, Child-Pugh class, presence of cirrhosis, HBs-Ag, HCV-Ab) to predict survival and recurrence.

 

Results

Survival after RFA was 96% at 1-yr, 88% at 2-yrs, 79% at 3-yrs, 69% at 4-yrs, and 55% at 5-yrs. Age, Ascites, Alb, T. Bil, tumor size, and AFP were significant predictive factors for survival. Overall recurrence was 20% at 1-yr, 46% at 2-yrs, 62% at 3-yrs, 69% at 4-yrs, and 74% at 5-yrs. Age, anti-HCV, tumor size, tumor number and AFP were significant predictive factors for overall recurrence. Local recurrence was 1.3% at 1-yr, 3.1% at 2-yrs, and 3.5% at 3-, 4-, and 5-yrs. Complications were encountered in 78 (4.0%) of 1930 cases. One patient died from cerebellar bleeding on the 15th post-RFA day.

 

Conclusion

Although RFA achieved considerably good survival, HCC frequently recurred after RFA. Most recurrence was appearance of new lesions in other portions than the ablated site, which was partly because of micro metastasis and partly because of metachronous multicentric carcinogenesis. Strategy to prevent recurrence separate from the treated lesion is mandatory to improve long-term outcomes.

 


169. Title: Molecular Evidence for the Neoplastic Transformation of Hepatic von-Meyenburg Complexes

W. Ahrens; M. E. Robert; S. Finkelstein; D. Jain

 

Background:

The majority of the cholangiocarcinomas in the Western world arise in an otherwise normal liver and no precursor of these tumors has been identified. von-Meyenburg complexes (vMC) are a common, under reported finding both in surgical and autopsy liver specimens. The authors have previously reported cases of cholangiocarcinoma (CC) arising in a background of cirrhosis with multiple vMC. Two cases that revealed many vMC, a gradual transition from vMC to hyperplastic/adenomatous lesions and finally to cholangiocarcinoma were selected for this study. The goal was to determine if vMC harbor genetic alterations and whether histologic progression was accompanied by progressive accumulation of genetic alterations/mutations.

 

Design:

Two cases which showed many vMC and transition through hyperplastic/adenomatous lesions to cholangiocarcinoma were analyzed. Three separate histologically benign vMC and three foci of CC were identified on H/E stained slides and separately microdissected in each case under stereoscopic guidance. Aliquots of DNA were analyzed for allelic imbalance (LOH) using PCR/electrophoresis and a panel of 20 polymorphic microsatellite markers targeting 1p,3p,5q,9p,10q,11q,14q,17p,17q,21q,22q. The temporal sequence of mutation acquisition was based on a clonal expansion model and correlated with the topographic distribution and extent of imbalance.

 

Result:

The two cases of CC manifested 5 and 7 acquired mutations involving different genomic loci specific for each patient. Co-existing vMC also exhibited acquired LOH mutations ranging from 0-3 in total amount. In each case of CC, the earliest acquired mutations were present in the vMC supporting a causal relationship for neoplastic progression. Discordant LOH mutations were also present in the vMC providing support that mutations detected at these sites did not passively migrate or reflect contamination.

 

Conclusion:

The concept of hyperplasia, dysplasia, neoplasia pathway has been proposed in cholangiocarcinoma and the cases examined here show a histologic and genetic progression from vMC to cholangiocarcinoma. Malignant transformation of vMC has rarely been reported in the literature. However, this may be an underrecognized phenomenon and vMC may be the precursor of sporadic changiocarcinoma in some cases. Further studies are needed to determine the premalignant potential of vMC. Patients with multiple vMC's may be at a higher risk of developing CC and could be clinically followed with serial imaging similar to patients with cirrhosis.

 


170. Aberrant IL-6 Signaling in Cholangiocarcinoma Cells is Due to SOCS-3 Epigenetic Silencing

H. Isomoto; S. F. Bronk; N. W. Werneburg; G. Gores

 

 

Background and aims:

Interleukin 6 (IL-6) is a critical mitogen and survival factor for human cholangiocarcinoma cells. Indeed, we have recently demonstrated that IL-6 signaling in human cholangiocarcinoma cells is sustained and therefore aberrant, likely contributing to the malignant phenotype. Because suppressor of cytokine signaling 3 (SOCS-3) inhibits IL-6 signaling by a negative feedback loop, our aim was to determine if SOCS-3 expression is disabled in a human cholangiocarcinoma cell line.

 

Methods:

The studies were performed in the human cholangiocarcinoma cell line, Mz-ChA-1 and the nonmalignant human cholangiocyte cell line, H69. Phosphorylated signal transducers and activators of transcription 3 (STAT-3), a down stream target in the IL-6 signaling cascade, was assessed by phospho-immunoblot analysis. SOCS-3 protein and mRNA expression were examined by immunoblotting and real-time PCR, respectively. Methylation status in CpG islands of the socs-3 promoter was determined by methylation-specific PCR and sequencing using bisulfite-treated genomic DNA.

 

Results:

Incubation of Mz-ChA-1 cells with IL-6 resulted in a sustained increase in phosphorylated STAT-3 over 6 hours. In contrast, the phospho-STAT-3 response to IL-6 in H69 cells was terminated within an hour following addition of the cytokine. Consistent with the phospho-STAT-3 response, SOCS-3 expression was not induced by IL-6 in Mz-ChA-1 cells, but was increased 20-fold in H69 cells. Treatment with a demethylating agent, 5-aza-2’-deoxycytidine restored SOCS-3 expression in Mz-ChA-1 cells. This “re-expression” of SOCS-3 terminated the sustained IL-6/STAT-3 response observed in the absence of 5-aza-2’-deoxycytidine. Methylation-specific PCR yielded a methylated 143-bp DNA product and bisulfite sequencing analysis demonstrated methylation of 57% of CpG sites in the socs-3 promoter.

 

Conclusions:

Our results indicate that SOCS-3 epigenetic silencing due to promoter hypermethylation is responsible for the aberrant sustained IL-6 signaling observed in human cholangiocarcinoma cells. Methylation inhibitors may be a therapeutic strategy to abrogate aberrant IL-6 signaling in this neoplasm.


171. Development of De Novo Hepatocellular Carcinoma in Patients Awaiting Orthotopic Liver Transplantation During the MELD Era

C. W. Brady; A. D. Smith; K. M. Stechuchak; C. J. Coffman; J. E. Tuttle-Newhall; D. Provenzale; A. J. Muir

 

Background:

Use of the Model for End Stage Liver Disease (MELD) score has increased the rate of orthotopic liver transplantation (OLT) among patients listed for hepatocellular carcinoma (HCC). As a result, patients listed for reasons other than HCC are at risk of developing de novo HCC, being removed from the waiting list, and dying without OLT. Existing data on the development of de novo HCC in this population have been described for only a small sample of subjects.

 

Aim:

To characterize the development of de novo HCC in a national sample of patients listed for OLT. Methods: Using the Organ Procurement and Transplantation Network database of the United Network for Organ Sharing, we abstracted clinical and demographic data on patients aged 18 years or older who were listed for OLT between February 2002 and December 2004 and underwent OLT. We excluded patients with HCC, cholangiocarcinoma, other primary and metastatic liver cancers, fulminant hepatic failure, and a history of previous organ transplant at the time of listing.

 

Results:

Of 8627 patients identified, 1200 (13.9%) developed de novo HCC while awaiting OLT. Among those who developed HCC, 967 (80.6%) were diagnosed with HCC before OLT, 118 (9.8%) had HCC that was found incidentally at explant, and 115 (9.6%) were diagnosed before OLT and had an incidental tumor reported at explant. The mean age of those who developed HCC was 54.9 ± 8.0 years and of those who did not develop HCC was 51.4 ± 9.6 years. Among those who developed HCC, 268 (22.3%) were female and 932 (77.7%) were male. Among those who did not develop HCC, 2544 (34.3%) were female and 4883 (65.8%) were male. The racial distribution of patients who developed HCC was 72.9% White, 7.4% Black, 5.2% Asian, and 14.5% other. The racial distribution of patients who did not develop HCC was 77.4% White, 7.9% Black, 2.3% Asian, and 12.4% other. The median number of days on the waiting list for those who developed HCC was 68.5 days (Q1-Q3: 23 –205.5) and was 61.0 days (Q1-Q3: 16-168) for those who did not develop HCC. Patients who developed HCC had initial and final mean calculated MELD scores of 13.6 ± 5.4 and 15.3 ± 7.0, respectively. Patients who did not develop HCC had initial and final mean calculated MELD scores of 19.0 ± 7.9 and 21.6 ± 9.1, respectively.

 

Conclusions:

A clinically significant proportion of patients develop de novo HCC while awaiting OLT. For patients listed for OLT, current HCC surveillance practices identify most cases of de novo HCC that develop prior to OLT. Future studies will examine specific diagnoses and comorbid conditions that may influence the development of de novo HCC in this population.