Histological evaluation of intracapsular venous invasion for discrimination between portal and hepatic venous invasion in hepatocellular carcinoma

Background and Aim:  Histological criteria for intracapsular venous invasion (IVI) that would allow its discrimination between portal and hepatic venous invasion in hepatocellular carcinoma (HCC) have not been established.
Methods:  We evaluated IVI immunohistochemically to discriminate between portal and hepatic venous invasion in 89 resected specimens from patients with HCC. IVI was defined as the microscopic involvement of the vessels within the fibrous capsule of HCC. The hepatic venous system was subdivided into the central vein and the sublobular/hepatic vein. Immunohistochemical analysis with the D2-40 monoclonal antibody revealed lymphatic vessels.
Results:  In non-neoplastic liver tissues, the portal veins ( n  = 4355) were accompanied by lymphatic vessels (99.7%), bile ductules (100%) and arteries (96%), whereas the central veins ( n  = 3932) and sublobular/hepatic veins ( n  = 662) were rarely accompanied by lymphatic vessels (0% and 17%, respectively) and bile ductules (12% and 33%, respectively). In total, 29 IVI foci were detected; three foci were clearly visible within vessels that contained a distinct layer of connective tissue fibers, signifying sublobular/hepatic venous invasion. As the remaining 26 foci were accompanied by lymphatic vessels (26/26 [100%]), bile ductules (21/26 [81%]) and arteries (10/26 [38%]), these foci were considered to reflect intracapsular portal venous invasion rather than venous invasion of the central vein. Intracapsular portal venous invasion was significantly associated with extratumoral portal venous invasion ( P  < 0.001).
Conclusions:  D2-40 immunoreactivity for the histological evaluation of IVI in HCC allows discrimination between portal and hepatic venous invasion for cases in which portal venous invasion predominates.     

Clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse: a retrospective study of patients undergoing hepatic resection

Background This study was carried out to clarify the etiology and clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse.Methods HCC patients who underwent resection were divided into three groups: a non-B non-C (NBNC) group (n = 13), who were seronegative for hepatitis B surface antigen (HBs Ag) and anti-hepatitis C antibody (HCV Ab), excluding a history of alcohol abuse; a B group (n = 25), who were seropositive for HBs Ag only; and a C group (n = 116), who were seropositive for HCV Ab only. We analyzed the features of tumor- and host-related factors and the outcome of the NBNC group.Results Hepatic inflammation and fibrosis were less severe in the NBNC group than in the other groups. There were no significant differences in tumor-related factors, except for higher serum levels of -fetoprotein in the NBNC group. Recurrence rates and disease-free survivals were comparable among the three groups. The NBNC group comprised a greater population with one or two recurrent hepatic lesions (P < 0.05), and indocyanine green retention rates and fibrosis scores were preserved after the initial hepatectomy. The NBNC group had higher resection rates for intrahepatic recurrences (75.0%) than the other groups (21.1% and 22.2% in groups B and C, respectively; P < 0.05 and P < 0.05). The survival rate after the initial hepatectomy or detection of the recurrent lesions was significantly better in the NBNC group (both 100% at 5 years) than those in groups B and C (P < 0.05).Conclusions NBNC patients maintained good liver function following the initial hepatectomy, and tended to have one or two recurrent lesions. These biological advantages provided NBNC patients more opportunities for repeat resection of intrahepatic recurrences, which may lead to a favorable outcome.     

Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma

AIM：To clarify the effect of a high des-gamma-carboxy prothrombin （DCP） level on the invasiveness and prognosis of small hepatocellular carcinoma.
METHODS： Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors.
RESULTS： The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion （P = 0.03） and serum DCP ≥ 400 mAU/mL （P = 0.02） were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free （P = 0.02） and overall survival （P = 0.0005）. In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free （P = 0.02） and overall survivals （P = 0.01）. In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically.
CONCLUSION： For small hepatocellular carcinoma, a high preoperative DCP level appears indicative fortumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body.     

Assessment of safety in hepatic resection for hepatocellular carcinoma focusing on indirect hyperbilirubinemia

Background/purpose

The indications for hepatic resection for hepatocellular carcinoma (HCC) patients with total bilirubin (T-Bil) equal to or higher than 1.2 mg/dl remain controversial. The aim of this study was to investigate the safety of hepatic resection for HCC patients who showed high T-Bil (≥1.2 mg/dl) with low direct bilirubin (D-Bil ≤ 0.5 mg/dl).

Methods

Thirty-four HCC patients showing high T-Bil with low D-Bil were treated with mono- to tri-segmentectomy between January 2000 and December 2010. The perioperative clinical parameters and prognosis of the high T-Bil/low D-Bil patients were compared with those of 253 HCC patients showing normal T-Bil. In addition, complication rates of the patients with high T-Bil/high D-Bil (n = 4) were analyzed.

Results

The prothrombin time activity, indocyanine green clearance test, asialo-scintigraphy, and platelet count were similar in the two groups. The mean serum albumin in high T-Bil/low D-Bil patients was significantly higher than that of normal T-Bil patients (4.2 ± 0.5 vs. 4.0 ± 0.4 g/dl, P = 0.004). There were no significant differences in operation time, intraoperative bleeding, red cell concentrate transfusion rate, postoperative complication rate, and disease-free and overall survivals between the two groups. Postoperative hyperbilirubinemia (T-Bil >5 mg/dl) with ascites was observed in one of four high T-Bil/high D-Bil patients (25 %).

Conclusions

Mono- to tri-segmentectomy can be performed in patients with low D-Bil (≤0.5 mg/dl) similarly to patients with low T-Bil (<1.2 mg/dl), even in HCC patients showing high T-Bil (≥1.2 mg/dl).     

Fibrosis and inflammatory activity in noncancerous tissue and mitotic index of cancer tissue in patients with hepatocellular carcinoma: relationship to clinicopathological factors and prognosis after hepatic resection

This study was designed to provide a histopathological analysis focusing on fibrosis (staging) and necroinflammatory reaction (grading, hepatitis activity index: HAI) in noncancerous liver tissue, and mitotic index (MI) in cancerous liver tissue to predict prognosis in 81 patients with chronic hepatitis or cirrhosis who underwent hepatectomy for hepatocellular carcinoma (HCC). The incidence of grade 2/3 and higher HAI was higher in patients with viral hepatitis C. The incidence of grade 2/3 was associated with vascular invasion of HCC, postoperative liver dysfunction, and cancer recurrence. Higher MI (5) was significantly associated with vascular invasion, poor histological differentiation, and recurrence rate (P < 0.05). Multivariate analysis showed that higher grade was the factor strongly associated with cancer recurrence (odds ratio: 10.621, P = 0.006). Higher MI correlated with overall patient survival (P < 0.05) by univariate analysis. Grading and MI are the useful prognostic markers for predicting tumor recurrence and patient survival.     

Effective hepatic artery chemoembolization for advanced hepatocellular carcinoma with extensive tumour thrombus through the hepatic vein

BACKGROUND AND AIMS: Advanced hepatocellular carcinoma (HCC) with extensive tumour growth through the hepatic vein still has an extremely poor prognosis, even after cancer chemotherapy and/or transarterial embolization. Although aggressive surgical treatments using extracorporeal circulation and liver transplantation have been performed by some authors, the reported results were still unsatisfactory. In this study, we report the favourable result of hepatic artery chemoembolization and subsequent surgical resection in three patients with advanced HCC with extensive tumour thrombus through the hepatic vein. METHODS AND RESULTS: Three irresectable patients with HCC with extensive tumour thrombus through the hepatic vein underwent hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam. After the reduction of tumour extent with hepatic artery chemoembolization, two of the three patients underwent surgical resection. These two patients are still alive at 59 and 21 postoperative months, respectively. In the other case, the extent of the tumour and functional reserve of the liver prevented us from performing surgical resection, but the patient is doing well 62 months after the initial treatment. CONCLUSIONS: Hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam might be an effective treatment for irresectable advanced HCC with extensive tumour thrombus into the inferior vena cava or the right atrium through the hepatic vein. Radical surgical resection might be applicable for selected patients without high surgical risk after reducing tumour extent by hepatic artery chemoembolization.     

Prognostic factors in patients with advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy

Background The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor. We aimed to clarify the prognostic factors in patients with advanced HCC receiving hepatic arterial infusion chemotherapy (HAIC).Methods Forty-four HCC patients were treated with HAIC, using low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) with/without leucovorin (or isovorin). Of these 44 patients, 15 received low-dose CDDP and 5-FU, and 29 received low-dose CDDP, 5-FU, and leucovorin or isovorin. Prognostic factors were evaluated by univariate and multivariate analyses of patient and disease characteristics.Results Of all patients, 5 and 12 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, 38%). The response rate (48.3%) in the low-dose CDDP and 5-FU with leucovorin/isovorin group was significantly better than that (20%) in the low-dose CDDP and 5-FU group (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative survival rates of the 44 patients were 39%, 18%, 12%, and 9%, respectively. The regimen using low-dose CDDP and 5-FU with leucovorin/isovorin tended to improve survival rates (P = 0.097). Univariate and multivariate analyses showed the same variables—the Child-Pugh score (P = 0.013, P = 0.018), -fetoprotein (AFP) level (P = 0.010, P = 0.009), and therapeutic effect after HAIC (P = 0.003, P = 0.01), respectively, to be significant prognostic factors.Conclusions Patients who had advanced HCC with favorable hepatic reserve capacity and a lower AFP level were suitable candidates for HAIC. Moreover, the regimen using low-dose CDDP and 5-FU with leucovorin/isovorin may be suitable for advanced HCC patients, because of the improvement in the response rate and survival compared with the low-dose CDDP and 5-FU regimen without leucovorin/isovorin.     

Immunohistochemical analysis of tumor biological factors in hepatocellular carcinoma: relationship to clinicopathological factors and prognosis after hepatic resection

Background The relationship between patient prognosis and various tumor biological factors has been reported previously, and prognostic factors of tumor biology may improve predictions of prognosis after hepatectomy for hepatocellular carcinoma (HCC) and may contribute to a new staging classification. This study was designed to provide an immunohistochemical analysis of tumor biological factors in patients who underwent hepatectomy for HCC.Methods Factors analyzed included p53 overexpression, microvessel counts, proliferating cell nuclear antigen, and expression of nm23. We examined 81 HCCs from patients with chronic liver diseases.Results In patients who underwent chemoembolization before surgery, or those a who had confluent multinodular tumor, p53 expression tended to be higher than in patients without chemoembolization (33% vs 11%) or those with a simple nodular tumor (28% vs 10%), but the difference was not statistically significant (P = 0.051 and P = 0.092, respectively). A lower tumor microvessel count and negative nm23 expression were significantly associated with poor disease-free survival by univariate analysis (P 0.01 and P 0.05, respectively). A lower tumor microvessel count was found to be a significant prognostic factor for disease-free and overall survivals (risk ratios, 2.44 and 3.13, respectively; P 0.05), in addition to tumor size, vascular invasion, and longterm ascites, by Coxs multivariate analysis.Conclusions Tumor microvessel count appears to be a useful prognostic marker for predicting HCC recurrence and patient survival.     

Alpha-fetoprotein and tumour size are associated with microvascular invasion in explanted livers of patients undergoing transplantation with hepatocellular carcinoma

Background:

To determine factors associated with outcomes and microvascular invasion (MVI) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC).

Methods:

Between July 1996 and August 2008 at the Universities of Kentucky or Tennessee, LT recipients were retrospectively analysed.

Results:

One hundred and one patients had HCC in the explanted liver; one patient was excluded because of fibrolamellar histology. Seventy-nine (79%) were male and 81 (81%) were older than 50. HCC was incidental in 32 patients (32%). Median follow-up was 31 months. Ten patients (10%) developed recurrence, which was associated with poor survival (P= 0.006). Overall 1-, 3-, and 5-year survival rates were 87%, 69% and 62%, respectively. Excluding patients with lymph node metastasis (LNM) or MVI yielded 91%, 81% and 75% survival at the same time points. MVI was independently associated with recurrence (OR 28.40, 95% CI 1.77–456.48, P= 0.018) and decreased survival (OR 4.70, 95% CI 1.24–17.80, P= 0.023), and LNM with decreased survival (OR 6.05, 95% CI 1.23–29.71, P= 0.027). Tumour size (OR 4.1, 95% CI 1.2–13.5, P= 0.013) and alpha-fetoproptein (AFP) > 100 (OR 5.0, 95% CI 1.4–18.1, P= 0.006) were associated with MVI.

Conclusions:

MVI greatly increases the risk of recurrence and death after LT for HCC, and is strongly associated with tumour size and AFP > 100.     

Risk factors for early death after liver resection in patients with solitary hepatocellular carcinoma

Background/Purpose

Although most patients who receive hepatectomy for a solitary hepatocellular carcinoma (HCC) have a relatively fair result, some have a poor prognosis. The aim of this study was to evaluate the risk factors for early death after hepatectomy in patients with a solitary HCC.

Methods

Eligible patients (n = 110) who had undergone hepatectomy for solitary HCC between 1990 and 2002 and were able to be followed up for more than 2 years after the hepatectomy were divided into two groups, those who died of cancer recurrence within 2 years (early-death group; n = 18) and those who survived for more than 2 years after the surgery (survival group; n = 92). Risk factors for early death after liver resection were evaluated by univariate and multivariate analyses.

Results

The gross tumor classification, tumor diameter, macroscopic portal vein invasion, microscopic growth pattern, microscopic vascular invasion (MVI), and the width of the surgical margin were significant (P < 0.05) factors by univariate analysis. Multivariate analysis showed that the presence of MVI was an independent and significant risk factor for early death of recurrence.

Conclusions

Among patients with solitary HCC, the presence of MVI indicates a poor prognosis. These patients need adjuvant chemotherapy in the early period after hepatectomy.     

Complete resection of hepatocellular carcinoma with direct invasion to the stomach remnant

A 61-year-old man presented with anemia (hemoglobin, 5.9?mg/dl) and a history of alcoholic liver disease. The patient also had a past history of a distal gastrectomy and Billroth II reconstruction, due to a gastric ulcer, performed 20 years previously. Endoscopic gastroscopy revealed a hemorrhagic ulcerative tumor at the gastrojejunostomy site. Computed tomography and angiography demonstrated a 10-cm tumor and a 2-cm tumor in the left lateral segment of the liver, suggestive of hepatocellular carcinoma (HCC). The larger tumor showed extrahepatic growth, with invasion of the stomach remnant. Because transcatheter arterial embolization of the tumor failed to control the bleeding, we carried out an en-bloc resection of the left lateral segment of the liver and the stomach remnant. Direct invasion of HCC into the gastrointestinal tract is rarely encountered. Here we report a case of HCC that invaded the stomach remnant and present a review of the literature.     

Combined AFP-CRUT with microvascular invasion accurately predicts mortality risk in patients with hepatocellular carcinoma following curative liver resection

Aims: To establish and validate an equation of α-fetoprotein (AFP) change rate over unit time (AFP-CRUT) as a potential predictor of survival after resection in patients with hepatocellular carcinoma (HCC). Methods: The AFP-CRUT was constructed based on dynamic variation in AFP over time and then categorized into quintiles. The area under the receiver operating characteristic (ROC) curve showed the performance for survival prediction. Results: As independent risk factors associated with mortality, microvascular invasion (MVI) (p = 0.003) and AFP-CRUT quintiles (p = 0.048) were combined to enhance the predictive effect. The highest 5-year overall survival rate following curative liver resection (93%) was observed in patients with MVI absent and AFP-CRUT in quintile 1 (49.64 to 209.61). In contrast, the lowest 5-year overall survival (7%) was obtained in quintile 5 (?469.29 to 6.45) with MVI present. In validation cohorts at both 12 and 24 months, AFP-CRUT performed well as a potential prognostic biomarker. Conclusions: Combining AFP-CRUT quintiles with MVI may predict significantly improved outcomes and enhance the predictive power for patient responses to therapeutic intervention.     

Treatment and prognostic factors in patients with hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma is a leading cause of death from cancer worldwide. Survival of patients depends on tumor extension and liver function, but yet there is no consensual prognostic model. AIMS: To evaluate the influence on survival of pretreatment parameters (clinico-laboratorial, liver function, tumor extension, Okuda and Cancer of the Liver Italian program (CLIP) staging) and treatment modalities. METHODS: We retrospectively analyzed 207 patients, diagnosed between 1993 and 2003. The initial treatment was: surgery--six patients; radiofrequency ablation--21; percutaneous ethanol injection--29; transarterial chemoembolization--49; tamoxifen--49; supportive care alone--53. Factors determining survival were assessed by Kaplan-Meier method and Cox regression models. RESULTS: Median survival was 24 months. In univariate analysis, Child-Pugh classification and Model for end-stage liver disease (MELD) score, portal vein thrombosis (PVT), tumor size, number of lesions, Okuda and CLIP scores were all associated with prognosis (P < 0.001). Alpha-fetoprotein levels were not predictive of survival. Independent predictors of survival were ascites, bilirubin, PVT and therapeutic modalities (P < 0.001). In early stage hepatocellular carcinoma (HCC), survival was similar for both percutaneous ablation modalities, either radiofrequency or ethanol injection (P = NS). In advanced HCC, survival was better in patients receiving tamoxifen than supportive care alone (P < 0.001). CONCLUSION: This study reinforces the importance of baseline liver function (Child-Pugh classification and MELD score) in the survival of patients with HCC, although staging systems allowed the stratification of patients in different prognostic groups. Ascites, bilirubin and PVT were independent pretreatment predictors of survival. All treatments influenced the patient's outcome, whether in early or advanced stages.