HBV DNA and HBsAg Levels as Risk Predictors of Early and Late Recurrence after Curative Resection of HBV-related Hepatocellular Carcinoma

Background

Recent studies have shown that high hepatitis B virus (HBV) load is associated with increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). The aim of our study was to investigate the predictive role of HBV DNA and hepatitis B surface antigen (HBsAg) levels in early and late recurrence of HCC after curative resection in patients with HBV-related HCC.

Methods

From January 2008 to December 2010, a total of 248 patients underwent curative resection for HBV-related early-stage HCC (solitary tumor; < 5 cm in diameter or multinodular tumor; number of tumors ≤3 and diameter < 3 cm). We analyzed the predictive factors including HBV DNA and HBsAg levels for early recurrence (within 2 years) and late recurrence (after 2 years) of HCC after curative resection.

Results

The median follow-up duration was 33.3 months. Cumulative recurrence rates after resection at 1, 3, and 5 years were 16.6, 34.0, and 46.7 %, respectively. The multivariate analysis showed that risk factors for early recurrence were the presence of microvascular invasion (hazard ratio [HR] 3.86; p < 0.001), preoperative HBV DNA levels ≥ 20,000 IU/mL (HR 2.77; p < 0.001), and des-γ-carboxy prothrombin level ≥ 40 mAU/mL (HR 1.76; p = 0.045). Although, the risk factors for late recurrence by multivariate analysis were preoperative HBsAg levels ≥ 4,000 IU/mL (HR 2.80; p = 0.023) and age at resection ≥ 50 years (HR 3.22; p = 0.032).

Conclusion

The HBV DNA levels were associated with early recurrence, whereas HBsAg levels were associated with late recurrence after curative resection in HBV-related HCC.     

Effects of Genomic Changes in Hepatitis B Virus on Postoperative Recurrence and Survival in Patients with Hepatocellular Carcinoma

Purpose

To determine whether the genomic changes in hepatitis B virus (HBV) affect the clinical outcomes of hepatocellular carcinoma (HCC) in patients with HBV-associated HCC treated with curative surgical resection.

Methods

A total of 247 patients with HBV-associated HCC were treated with curative surgical resection. They were followed regularly for a median of 30 months. The whole X, S, basal core promoter (BCP), and precore regions of HBV were sequenced.

Results

The genomic changes such as the G1896A at precore, the A1762T/G1764A at BCP, the C1653T and the T1753V at X gene, and pre-S2 deletion were not significantly associated with postoperative recurrence of HCC or survival of patients after curative resection. However, in univariate analysis, younger age, elevated serum α-fetoprotein level, elevated serum alanine aminotransferase level, larger tumor size, microvascular invasion, and advanced Cancer of the Liver Italian Program stage were closely associated with shorter survival after surgical resection. In multivariate analysis, only microvascular invasion revealed to be an independent risk factor of postoperative recurrence (relative risk [RR] 5.406; P < 0.001); the independent risk factors of shorter survival appeared to be infiltrative type (RR 5.110; P = 0.032), larger tumor size (RR 1.976; P = 0.047), and microvascular invasion (RR 6.118; P < 0.001).

Conclusions

The postoperative recurrence or survival period may not be affected by the genomic changes at the precore, BCP, X, and pre-S2 regions in HBV of genotype C2 in patients with HBV-associated HCC treated with curative surgical resection. Rather, it may be closely associated with tumor characteristics, such as the size and type of HCC or presence of microvascular invasion.     

Antiviral Therapy Decreases Recurrence of Hepatitis B Virus-related Hepatocellular Carcinoma after Curative Resection: A Meta-analysis

Background

The long-term outcome after curative resection of hepatocellular carcinoma (HCC) remains unsatisfactory because of the high incidence of recurrence. The present study was intended to assess the impact of hepatitis B virus (HBV) DNA level and nucleos(t)ide analog therapy on posthepatectomy recurrence of HBV-related HCC.

Methods

Eligible studies were identified through a computerized literature search. The pooled relative risk ratio (RR) with 95 % confidence interval (CI) was calculated using Review Manager 5.1 Software.

Results

Twenty studies with a total of 8,204 participants were included for this meta-analysis. Pooled analysis showed that high viral load was significantly associated with risk of recurrence (RR: 1.85, 95 % CI: 1.41–2.42; P < 0.001), poorer disease-free survival (DFS) (RR: 1.96, 95 % CI: 1.62–2.38; P < 0.001), and poorer overall survival (OS) (RR: 1.47, 95 % CI: 1.22–1.77; P < 0.001) of HBV-related HCC after surgical resection. Nucleos(t)ide analog therapy significantly decreased the recurrence risk (RR: 0.69, 95 % CI: 0.59–0.80; P < 0.001) and improved both DFS (RR: 0.70, 95 % CI: 0.58–0.83; P < 0.001) and OS (RR: 0.46, 95 % CI: 0.32–0.68; P < 0.001).

Conclusions

High DNA level is associated with posthepatectomy recurrence of HBV-related HCC. Nucleos(t)ide analog therapy improves the prognosis of HBV-related HCC after resection.     

Recurrence and Poor Prognosis Following Resection of Small Hepatitis B-Related Hepatocellular Carcinoma Lesions Are Associated with Aberrant Tumor Expression Profiles of Glypican 3 and Osteopontin

Background

Early detection and following appropriate treatments of hepatocellular carcinoma (HCC) is still the gold standard for favored outcome of HCC patients; nevertheless, a small portion of hepatitis B virus (HBV)-related small HCC (<5 cm) patients got poor prognosis. Furthermore, the study for small HBV–HCC was limited. Therefore, the aim of this study was to explore the potential genetic signature for HBV-related small HCC as novel prognostic factors.

Methods

We examined expression profiles of HBV-related small HCC using an Affymetrix U133A GeneChip, evaluated differential gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), and finally validated these expression patterns by immunohistochemistry (IHC).

Results:

A total of 57 genes were differentially expressed between tumor and normal parts (n = 20 pairs) using Affymetrix U133A chip, and 16 genes were further evaluated by qRT-PCR. The result was compatible with the finding of oligonucleotide microarray (Pearson’s correlation, r = 0.87). Furthermore, the expression pattern in HCC tissue by IHC in another group of small HBV–HCC (n = 100) showed overexpression of either osteopontin (OPN) or glypican 3 (GPC3) is an independent prognostic factor for disease-free survival (DFS) in HBV-positive small HCC (P < 0.01 and 0.03, respectively). Long-term DFS and overall survival (OS) for small HBV–HCC patients with high risk (both elevated GPC3⁺/OPN⁺) were DFS 0%, OS 0%, respectively; on the other hand, DFS and OS in patients with moderate (only 1 gene elevated) or low (OPN^?/GPC3^?) risk were 35.0 and 46.5%, respectively.

Conclusions

Elevation of both OPN and GPC3 may act as an adverse indicator for HBV-related small HCC patients after curative resection.

     

Single HCC in Cirrhotic Patients: Liver Resection or Liver Transplantation? Long-term Outcome According to an Intention-to-treat Basis

Background

Compensated cirrhotic patients with single hepatocellular carcinoma (HCC) ≤5 cm may benefit from both liver resection (LR) and liver transplantation (LT); however, the better 10-year actuarial survival of the two treatments remains unclear. We aimed to assess the long-term outcome of cirrhotic patients with single HCC ≤5 cm treated either with LR or LT on an intention-to-treat basis.

Methods

A total of 217 cirrhotic patients with single HCC ≤5 cm were evaluated at our department: 95 were treated with LR (LR group), and 122 were included on the waiting list for LT (LT group). Patients in the LR group were divided into very early HCC (tumor size ≤2 cm) and early HCC (tumor size >2 cm). Median follow-up was 5.3 (range 0.1–18) years.

Results

Tumor recurrence was 72 % in the LR group versus 16 % in the LT group (p < 0.001). 1-, 5-, and 10-year cumulative risk of recurrence was 18, 69, and 83 % in the LR group versus 4, 18, and 20 % in the LT group (p < 0.001). Ten-year actuarial survival was 33 % in the LR group versus 49 % in the LT group (p = 0.002). At HCC recurrence, 27.3 % were included on the waiting list for salvage transplantation (very early HCC group) versus 15.1 % (early HCC group) (p = 0.2). After salvage transplantation, HCC recurrence was 0 % (very early HCC group) versus 40 % (early HCC group) (p = 0.2). No significant differences were observed in 1-, 5-, and 10-year actuarial survival between the very early HCC group and the LT group (95, 55, and 50 % vs. 82, 62, and 50 %).

Conclusions

LR should be the treatment of choice for cirrhotic patients with very early HCC.     

Serum Antibody Titers Against Hepatitis C Virus and Postoperative Intrahepatic Recurrence of Hepatocellular Carcinoma

Background

Hepatocellular carcinoma (HCC) is the seventh most common cancer and the third leading cause of cancer deaths worldwide. Hepatitis C virus (HCV) infection is a major risk factor for HCC recurrence after curative resection. This study evaluated anti-HCV antibody (Ab) titer as a prognostic indicator of HCC recurrence after curative hepatic resection.

Methods

A total of 82 patients with HCC (anti-HCV Ab positive and hepatitis B surface antigen negative) who underwent curative hepatic resection were evaluated. Anti-HCV Ab titers were measured using a third-generation enzyme immunoassay, and patients were divided into high (n = 41) and low (n = 41) titer groups to compare their clinicopathological characteristics and disease-free survival. Univariate and multivariate analyses were conducted to identify risk factors for early or late recurrence.

Results

Multivariate analysis showed that anti-HCV Ab titer and vascular invasion were independent prognostic factors of disease-free survival [odds ratio (OR) 1.9, p = 0.03, and OR 1.8, p = 0.04, respectively]. Subgroup analysis identified only vascular invasion as an independent prognostic factor for early recurrences that were considered residual intrahepatic metastases. Subgroup analysis identified anti-HCV Ab titer and fibrosis grade as independent prognostic factors of late recurrences that were considered to be metachronous multicentric liver carcinogenesis (OR 4.8, p = 0.04, and OR 5.2, p = 0.03, respectively).

Discussion

Anti-HCV Ab titer is a predictive factor for HCC recurrence, especially the risk of late recurrence due to multicentric carcinogenesis. Prevention of liver carcinogenesis after hepatic resection for HCC might be appropriate for patients with high anti-HCV Ab titers.     

Influence of Nonclinical Factors on Choice of Therapy for Early Hepatocellular Carcinoma

Background

Initial therapy for early hepatocellular carcinoma (HCC) with well-compensated cirrhosis is controversial. While we previously reported on the effect of clinical factors and surgeon specialty on choice of therapy for early HCC, other nonclinical factors also may impact decision-making.

Methods

Surgeons who treat HCC were invited to complete a web-based survey that included ten case scenarios. Choice of therapy—liver transplantation (LT), liver resection (LR), or radiofrequency ablation (RFA)—was analyzed using regression models.

Results

There were 336 responses for analysis. Most respondents were in academic centers (86 %) that offered LT (71 %). The median number of patients annually evaluated for HCC was 30. Both practice type and HCC case volume were associated with choice of therapy, but these associations were not independent of surgeon specialty. LT surgeons who did not also perform RFA were less likely than those LT surgeons who did offer RFA to choose RFA over LT (relative risk ratios (RRR) 0.38, P < 0.001). Non-LT surgeons were more likely than LT surgeons who also offered RFA to choose RFA over LT (RRR 2.24, P < 0.001). Surgeons who worked at hospitals where LT was performed were much more likely to choose LT over LR and RFA even if they did not personally perform LT (RRR 1.27 and RRR 3.33, P < 0.001).

Conclusions

Surgeon- and institution-related factors impact choice of therapy for early HCC even after adjustment for differences in clinical presentation. These data suggest that choice of therapy for patients with early HCC varies across providers independent of case selection.     

Infection with Hepatitis C Virus is an Adverse Prognostic Factor after Liver Resection for Early-stage Hepatocellular Carcinoma

Introduction

Recent data support liver resection (LR) as first-line approach in patients with preserved liver function who have resectable/transplantable hepatocellular carcinoma (HCC). This study was designed to evaluate the outcome of LR in patients with transplantable HCC.

Methods

Between 1998 and 2009, 75 patients (65 men, mean age 61 ± 11 years) with HCC eligible for liver transplantation (LT) underwent LR. The underlying hepatic disease was related to hepatitis C (HCV) in 30 (40 %) patients, hepatitis B (HBV) in 15 (20 %) patients, alcohol abuse in 26 patients (36 %) and other in 10 patients (13 %). Fifty-five (73 %) patients had cirrhosis. Intermittent clamping of the hepatic pedicle was used in 41 (55 %) patients. Treatment of recurrence by salvage LT was performed in 6 (8 %) patients.

Results

Operative morbidity and mortality rates were 37 and 5  % respectively. At 1, 3, and 5 years, overall (OS) and disease-free (DFS) survival rates were 81, 69,55 and 56, 31, and 21 %, respectively. On multivariate analysis, HCV infection was the only independent factor associated with decreased OS (p = 0.02). On multivariate analysis, HCV infection (p = 0.05) and intermittent hepatic pedicle clamping (p = 0.003) were associated with decreased DFS. The 1-, 3-, and 5-year OS and DFS rates in patients with HCV-related HCC were 69, 53, 38 and 50, 18, and 9% respectively.

Conclusions

Overall and disease-free survival after liver resection in patients with HCV-related HCC and preserved liver function is poor. Primary LT should be offered to these patients.     

Impact of Viral Hepatitis on Outcomes after Liver Resection for Hepatocellular Carcinoma: Results from a North American Center

Background

Hepatitis B (HBV) and hepatitis C (HCV) are well-recognized risk factors for hepatocellular carcinoma (HCC). The characteristics and clinical outcomes of HCC arising from these conditions may differ. This study was conducted to compare the outcomes of HCC associated with HBV and HCV after liver resection.

Methods

Of 386 liver resections for HCC performed between July 1992 and April 2011, 181 patients had HBV and 74 patients had HCV. Patients with HBV/HCV coinfections (n = 20), non-HBV/HCV etiology (n = 94), and postoperative death within 3 months (n = 17) were excluded. Patient, tumor characteristics, and perioperative and oncologic outcomes were compared between patients with HBV and HCV.

Results

The patients with HBV had better overall survival (OS) than patients with HCV (68 vs. 59 months, p = 0.03); however, there was no difference in recurrence-free survival (RFS) between the groups (44 vs. 45 months, p = 0.1). The factors predictive of OS based on multivariate analyses included: vascular invasion [p < 0.01, hazard ratio (HR) = 3.4], Child-Pugh Score (p < 0.01, HR = 4.8), and underlying liver disease (HCV vs HBV) (p = 0.01, HR = 1.9). Vascular invasion and tumor number (p < 0.01, HR = 2.3 and p < 0.01, HR = 2.1) were independent predictors of RFS.

Conclusions

OS but not RFS after liver resection for HCC is better in patients with HBV than HCV. This survival advantage for HBV patients may be due to differences in tumor biology and outcomes after disease recurrence.     

γ-Glutamyltranspeptidase is a Prognostic Marker of Survival and Recurrence in Radiofrequency-Ablation Treatment of Hepatocellular Carcinoma

Purpose

Serum γ-glutamyltranspeptidase (GGT) level, which is often elevated in hepatocellular carcinoma (HCC), has now been found to be an oxidative stress marker which correlates with inflammation in the extracellular hepatic microenvironment. The aim of this study was to investigate the prognostic significance of GGT serum levels in patients undergoing radiofrequency ablation (RFA) therapy for the treatment of HCC.

Methods

This retrospective study included 254 patients with small liver cancer (tumor of ≤5 cm in diameter and nodule of ≤3 cm) who had been treated with RFA. Baseline serum GGT was examined before therapy, and overall survival (OS) and recurrence-free survival were evaluated by the Kaplan–Meier method. Univariate and multivariate analyses were used to analyze the significance of GGT and other serum markers as prognostic factors.

Results

After a median follow-up of 27 months, 51 patients had died and 123 had hepatic recurrence. After treatment with RFA, HCC patients with elevated GGT had a shorter OS versus those with normal GGT level (p = 0.001); they also had higher recurrence (p = 0.001). On multivariate analysis, albumin (p = 0.003), GGT (p = 0.035), and tumor size (p = 0.027) were independent risk factors for survival, and GGT (p = 0.010) and tumor size (p = 0.026) were significant risk factors for recurrence.

Conclusions

Serum GGT is a convenient prognostic biomarker related to OS and recurrence in HCC patients undergoing RFA treatment.     

The Clinical Behavior of Transplantable Recurrent Hepatocellular Carcinoma After Curative Resection: Implications for Salvage Liver Transplantation

Background

This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT).

Methods

The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for ≥12 months or control of a recurrent tumor within the MC by active locoregional treatment.

Results

After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P < 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age >50 years and an indocyanine green retention at 15 min >10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence.

Conclusions

The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.     

Early Viral Suppression Predicts Good Postoperative Survivals in Patients with Hepatocellular Carcinoma with a High Baseline HBV-DNA Load

Purpose

To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC).

Methods

A retrospective study was conducted on patients with a baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined.

Results

Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival.

Conclusions

Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.     

Combination of Morphologic Criteria and α-Fetoprotein in Selection of Patients With Hepatocellular Carcinoma for Liver Transplantation Minimizes the Problem of Posttransplant Tumor Recurrence

Background

Serum α-fetoprotein concentration (AFP) might be a useful addition to morphologic criteria for selecting patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). The aim of this study was to evaluate the role of AFP in selecting HCC patients at minimal risk of posttransplant tumor recurrence in the setting of existing criteria.

Methods

This retrospective cohort study was based on 121 HCC patients after LT performed at a single institution. AFP was evaluated as a predictor of posttransplant tumor recurrence with respect to fulfillment of the Milan, University of California, San Francisco (UCSF), and Up-to-7 criteria.

Results

There was a nearly linear association between AFP and the risk of HCC recurrence (p < 0.001 for linear effect; p = 0.434 for nonlinear effect). AFP predicted HCC recurrence in patients (1) beyond the Milan criteria (p < 0.001; optimal cutoff 200 ng/ml); (2) within the UCSF criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.015; optimal cutoff 200 ng/ml); and (3) within the Up-to-7 criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.023; optimal cutoff 100 ng/ml) but not in patients within the Milan criteria (p = 0.834). Patients within either UCSF and Up-to-7 criteria with AFP level <100 ng/ml exhibited superior (100 %) 5-year recurrence-free survival—significantly higher than those within UCSF (p = 0.005) or Up-to-7 (p = 0.001) criteria with AFP levels higher than the estimated cutoffs or beyond with AFP levels less than the estimated cutoffs.

Conclusions

Combining the UCSF and Up-to-7 criteria with an AFP level <100 ng/ml is associated with minimal risk of tumor recurrence. Hence, this combination might be useful for selecting HCC patients for LT.     

Predictor for Histological Microvascular Invasion of Hepatocellular Carcinoma: A Lesson from 229 Consecutive Cases of Curative Liver Resection

Background

Microscopic vascular invasion is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. To predict microscopic portal venous invasion, the following two questions were examined retrospectively: Is it possible to detect microvascular invasion preoperatively? What are the characteristics of a group of early HCC recurrences even with no microvascular invasion?

Methods

Study 1 included 229 patients with HCC who underwent curative liver resection between 1991 and 2008; 127 had HCC without microscopic portal venous invasion, and 52 had HCC with microscopic portal venous invasion (MPVI). These two distinct groups were analyzed with regard to various clinicopathologic factors. Subsequently, we specifically investigated if HCCs <5 cm with vascular invasion (n = 32) have some characteristics that would allow detection of latent microvascular invasion. Study 2 included 127 HCC patients without MVPI; 42 had a recurrence within 2 years, and 85 patients were recurrence-free for at least 2 years. These two distinct groups were analyzed with regard to various clinicopathologic factors.

Results

HCC diameter of >5 cm, the macroscopic appearance of HCC, and high levels of preoperative des-γ-carboxyprothrombin are significant prognostic factors in identifying microvascular invasion of HCC. The strongest predictor of early recurrence (within 2 years) was the serum α-fetoprotein level in patients without clear microvascular invasion.

Conclusions

Tumor size, macroscopic appearance, and high tumor marker levels are important elements in identifying the group of patients with a low HCC recurrence rate after curative liver resection.     

Analysis of the Risk Factors of Untransplantable Recurrence After Primary Curative Resection for Patients with Hepatocellular Carcinoma

Purpose

To determine the prognostic factors that predict recurrence of hepatocellular carcinoma (HCC) exceeding the University of California at San Francisco (UCSF) criteria after primary resection.

Methods

HCC patients who underwent curative liver resections between 2001 and 2007 and who were within the UCSF criteria (n = 716) were examined. Independent prognostic factors were examined by the Cox proportional hazard model.

Results

A total of 285 patients (39.8 %) developed recurrences. Of the patients who developed recurrences, 180 had HCC still within the UCSF criteria (63.2 %), and 105 developed HCC beyond this criteria (36.8 %). Among the population with primary transplantable HCC, patients with larger primary tumor sizes, serum α-fetoprotein (AFP) levels over 400 ng/mL, satellite nodules, vascular invasion, or undifferentiated HCC had a risk of untransplantable recurrence, as shown by univariate analysis. In multivariate analysis, undifferentiated HCC and vascular invasion were identified as the significant predictors with adjusted hazard ratios of 9.25 [95 % confidence interval (CI) 2.13–40.21] and 2.19 (95 % CI 1.34–3.58), respectively. When only preoperative factors were considered in multivariate analysis, primary tumor size and serum AFP levels over 400 ng/mL were identified as significant predictors with adjusted hazard ratios of 1.24 (95 % CI 1.07–1.45) and 1.72 (95 % CI 1.05–2.82), respectively.

Conclusions

For primary HCC patients within the UCSF criteria, larger tumor sizes and AFP levels over 400 ng/mL were associated with postresection recurrence of HCC exceeding the UCSF criteria. Because these are clearly markers for aggressive tumor biology, whether early primary transplant will alter the aggressive tumor behaviors warrant further investigation.     

Prognosis After Resection of Hepatitis B Virus-Related Hepatocellular Carcinoma Originating from Non-cirrhotic Liver

Background

Long-term prognosis after resection of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) originating from non-cirrhotic liver is not fully clarified.

Methods

A total of 183 patients who underwent curative hepatectomy for HCC without cirrhosis were classified into two groups: HBV infection group (n = 124) and non-HBV infection group (n = 59). Long-term postoperative outcomes were compared between the two groups.

Results

The 5-year postoperative overall survival (OS) and disease-free survival (DFS) were 42.6 and 39.0 %, respectively, in the HBV infection group versus 52.3 and 46.5 % in the non-HBV infection group (both p > 0.05). When patients were subdivided according to TNM stages, OS in stages II or III HCC patients was similar between the two groups. In contrast, OS and DFS were significantly worse in stage I patients with HBV infection than those in stage I patients without HBV infection (p = 0.041 and 0.038, respectively). Preoperative serum HBV DNA >4 log₁₀ copies/mL and vascular invasion were independent factors associated with poor prognosis (p = 0.034 and 0.017, respectively) for patients with HBV infection.

Conclusions

After hepatic resection for HCC in non-cirrhotic liver, patients with HBV infection with early-stage tumors had worse prognosis than patients without HBV infection, possibly due to the carcinogenetic potential of viral hepatitis in the remnant liver. Antiviral therapy should be considered after hepatectomy in patients with high HBV DNA levels.     

Response to Therapy as a Criterion for Awarding Priority to Patients With Hepatocellular Carcinoma Awaiting Liver Transplantation

Background

How to prioritize patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) remains controversial. This study was designed to assess the effectiveness of a policy for prioritizing HCC patients according to their response to pre-LT therapy.

Methods

The study period was from 2000 to 2008. Dropout criteria included macroscopic vascular invasion, metastases, and poorly differentiated grade at pre-LT biopsy. A specific treatment algorithm was adopted to treat HCC before LT, and the effect of treatment was evaluated 3 months after listing or after the diagnosis of HCC for patients diagnosed while already on the waiting list. Patients were divided into two groups: group 1, patients with disease that completely or partially responded to therapy; and group 2, patients with stable, progressive, or untreatable disease. Group 2 patients were prioritized for LT unless full restaging and repeat biopsy identified dropout criteria.

Results

At the 3-month visit, 62 HCC patients (42%) were assigned to group 2 and 85 (58%) to group 1. Eleven of 12 dropouts due to tumor progression came from group 2 (P < 0.01). Response to therapy was the sole predictor of dropout probability, independent of tumor stage (competing risk analysis). The 42 patients in group 2 who were transplanted had much the same 3-year post-LT survival rate as the 57 transplanted patients in group 1 (with survival rates of 82% and 83%, respectively; P > 0.05), but a slightly higher risk of post-LT HCC recurrence (13% and 2%, respectively; P = 0.04).

Conclusions

Response to therapy is a potentially effective tool for prioritizing HCC patients for LT.     

Combination of Osteopontin with Peritumoral Infiltrating Macrophages is Associated with Poor Prognosis of Early-Stage Hepatocellular Carcinoma after Curative Resection

Background

Crosstalk between a tumor and the microenvironment plays a key role in tumor progression and metastasis. This study was performed to elucidate the prognostic significance of combining tumor-secreted osteopontin (OPN) with microenvironment-associated peritumoral macrophages (PTMs) in hepatocellular carcinoma (HCC), especially for those with early-stage disease.

Methods

Tissue microarray-based immunohistochemistry was used to investigate OPN and PTMs expression in two independent cohorts consisting of 374 patients with HCC who underwent radical resection. The prognostic value for the two factors alone or in combination was investigated in these patients.

Results

OPN combined with PTMs was an independent prognostic factor for both overall survival (OS; p < 0.0001) and time to recurrence (TTR; p = 0.003) from the learning cohort (n = 96). Their combined value for prognosis was validated in early-stage HCCs using another independent cohort (n = 278; OS, p < 0.001; TTR, p = 0.001). This combination remained significant in HCCs with low α-fetoprotein levels in both cohorts, and was predictive for early recurrence/death risk (<2 years) compared with a single marker. Only OPN+HCCs had a significant correlation of PTMs levels with OS (p = 0.01) or TTR (p = 0.011).

Conclusions

Tumor OPN combined with PTMs is a promising predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. The interplay of OPN and PTMs represents a new insight into tumor progression and therapeutic targets for HCC.     

Recurrence of Hepatocellular Carcinoma in Noncirrhotic Liver After Hepatectomy

Background

Hepatocellular carcinoma in noncirrhotic liver (HCCNC) is rare. This tumor has a particular epidemiology and presentation, and it requires specific treatment, compared with HCC in cirrhotic liver. The aims of this study were to determine the survival and recurrence rates, prognostic factors, and optimum treatment of HCCNC and to propose a follow-up protocol for patients who have undergone surgery for HCCNC.

Methods

This study included 131 patients who underwent surgical treatment for HCCNC from January 1992 to December 2010. Survival and recurrence rates were evaluated, and the prognostic factors and characteristics of recurrence were analyzed. Pathologic characteristics of the tumors and the nontumoral liver were examined.

Results

The mean survival time was 67.9 months. The 5- and 10-year overall survival rates were 72.9 and 36.7 %, respectively. In all, 54 patients (41.2 %) developed recurrence at a median interval of 30.96 months. Of these recurrences, 31.5 % occurred during the first year, and 24.1 % occurred more than 5 years after surgery. Macro- or microvascular invasion and tumor size >5 cm were significantly associated with a poor survival rate. The predictive factors for recurrence were multiple tumors, tumor diameter >5 cm, and satellite nodules. Patients who underwent surgical treatment for recurrence had a significantly longer survival time than those who did not (p < 0.0292).

Conclusions

Recurrence is the most common cause of death after hepatectomy for HCC, and patients should undergo careful, long-term follow-up. Early detection and treatment of recurrence with curative intent should improve the prognosis of these patients.