| Background:Hepatocellular carcinoma (HCC) is a major health problem of worldwide significance,being the sixth most common cancer with more than749,000new cases diagnosedannually, and the third leading cause of cancer-related death. Almost90%of HCCs areassociated with a known risk factor. As an underlying cause for HCC, hepatitis B virus(HBV) plays a pivotal role in hepatocarcinogenesis, and the incidence of HCC is thehighest in areas such as Asia and Africa where chronic HBV infection is endemic. ChronicHBV infection is responsible for approximately54%of the total cases.70%-90%of suchHBV-related HCC arises from cirrhosis, and most of them experienced progressive chronicliver disease, which appears as hepatitis, fibrosis, cirrhosis and finally HCC. Viralreplication is now recognized as the key driver of liver injury and disease progression.Recent studies have identified a significant association between serum HBV-DNA level,the reflection of the level of intrahepatic viral replication, and liver injury, progression tocirrhosis as well as liver failure in patients with CHB infection. And higher serumHBV-DNA level is also found to be associated with the increased incidence of HCC.Antiviral therapy to lower the HBV viral level is found to be associated with improvementof disease progression clinically and histologically. Besides, the incidence of HCC inpatients with CHB can even be reduced by antiviral therapy, as suggested by ameta-analysis.Interestingly, serum HBV viral levels and liver histology regarding inflammation andfibrosis in noncancerous liver tissue were identified as independent risk factors to predictthe prognosis after curative hepatectomy for HCC respectively. However, whether there isa link between HBV viral load and liver histology in noncancerous liver tissue isunderreported. On the other hand, although elevated HBV-DNA levels were linked toincreased incidence of HCC, and even recurrence after hepatectomy for HCC, most studiesare based on determinations of serum HBV-DNA levels at a single time point at study entryrather than at multiple time points, which is considered more appropriate, as the fluctuationof HBV-DNA levels is common during the natural course of chronic HBV infection, not tomention the vast application of antiviral therapy nowadays, such as nucleoside ornucleotide analogues. And the REVEAL-HBV study does demonstrate that persistentlyelevated serum HBV-DNA levels documented at two different time points is associated with the highest risk of HCC.Objective:We conduct this present study to determine the influence of serum HBV-DNA levelfluctuation between the primary and repeat hepatectomy on liver histology regardinginflammation and fibrosis in the noncancerous liver tissue, and prognosis after repeatcurative hepatectomy for recurrent HBV-related HCC.Methods:From January2002to December2009, a total of385consecutive recurrent HBV-relatedHCC patients without extrahepatic metastasis before surgeries underwent both the first andsecond curative hepatectomy by the same surgical team at our unit. All patients wereseropositive for hepatitis B surface antigen (HBsAg) before the initial hepatectomy with apathological diagnosis of HCC confirmed after every hepatectomy. On the basis ofHBV-DNA fluctuation between the primary and repeat hepatectomy for every patient, theywere divided into four groups. Group A:122patients were confirmed with persistently lowHBV-DNA replication (＜2000IU/mL) verified in the blood tests before first and secondhepatectomy. Group B:62patients had low HBV-DNA levels (＜2000IU/mL) before thefirst hepatectomy and high HBV-DNAlevels (≥2000IU/mL) before the second. Group C:71patients had persistently high HBV-DNAreplication (≥2000IU/mL) verified in theblood tests before first and second hepatectomy. Group D:130patients had highHBV-DNAlevels (≥2000IU/mL) before the first hepatectomy and low HBV-DNA levels(＜2000IU/mL) before the second. The baseline characteristics of patients in differentgroups were compared. And the disease progression regarding inflammation and fibrosiswere investigated. Disease free survival and overall survival were estimated by theKaplan-Meier method. Variables with p＜0.05in univariate analysis were subjected tomultivariate Cox regression modeling.Results：1. Compared with the primary hepatectomy, there were more serum HBeAg negativepatients（P=0.002），more minor operations（P＜0.001），longer operation duration（P＜0.001），more hemorrhage in the operation（P＜0.001） and smaller tumor size（P＜0.001）in the repeat hepatectomy.2. In the noncancerous tissue from the primary hepatectomy, no significant differenceregarding the Knodell inflammation score amd Ishak fibrosis score was found between theA group and B group as well as the C Group and D group. However, in the noncancerous tissue from the repeat hepatectomy, there was a significant difference regarding theKnodell inflammation score amd Ishak fibrosis score between the A group and B group （P＜0.001）as well as the C Group and D group（P＜0.001）.3.In the Kaplan-Meier survival analysis for the four groups of A group, B group, Cgroup, and D group, a significant difference was found regarding disease free survival （P=0.001）and overall survival（P=0.002）. In the comparison of survival between twogroups, both the disease free survival and overall survival of A group was higher than thatof B group, and the difference was significant（P=0.003、P=0.007）; the disease freesurvival of C group was higher than that of the D group（P=0.006）, but no significantdifference was found between the overall survival of the two groups（P=0.018）.4. The multivariate analysis of risk factors for disease free survival after the repeathepatectomy determined the significant risk factors including the disease free intervalbetween the primary and repeat hepatectomy（P=0.009）, HBV-DNA before the repeathepatectomy（P=0.002）, tumor number in the repeat hepatectomy（P=0.011）,microvascular invasion in the repeat hepatectomy（P＜0.001） and the Ishak score＞3regarding fibrosis in the noncancerous tissue from the repeat hepatectomy（P=0.042）.5. The multivariate analysis of risk factors for overall survival after the repeathepatectomy determined the significant risk factors including the disease free intervalbetween the primary and repeat hepatectomy（P=0.025）, HBeAg positive before therepeat hepatectomy（P=0.035），HBV-DNA before the repeat hepatectomy（P=0.021）,tumor number in the repeat hepatectomy（P=0.035）, microvascular invasion in the repeathepatectomy（P＜0.001） and the Ishak score＞3regarding fibrosis in the noncanceroustissue from the repeat hepatectomy（P=0.022）.Conclusions:1. The fluctuation of HBV-DNA levels may influence the disease progression regardinginflammation and fibrosis of the noncancerous liver tissue in HCC patients. Thedeterminations of serum HBV-DNA levels at multiple time points may better estimateprognosis after hepatectomy than at a single time point.2. The serum HBV-DNA of HCC patients should be monitored regularly. Antiviraltherapies may improve the inflammation and fibrosis of the noncancerous liver tissue inHCC patients, and it may be crucial in improving prognosis after hepatectomy. |
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