Immunohistochemical study of the relationship between 8-hydroxy-2'-deoxyguanosine levels in noncancerous region and postoperative recurrence of hepatocellular carcinoma in remnant liver.

Hepatocellular carcinoma (HCC) frequently develops in patients with chronic viral hepatitis and cirrhosis. In these chronic liver disorders, an increased production of reactive oxygen species (ROS) causing oxidative DNA damage has been reported. In this study, we immunohistologically (LSAB method) demonstrated the presence of 8-hydroxy-2'-deoxyguanosine (8-OHdG) that was generated when oxidative DNA damage was caused by active oxygen species in noncancerous region obtained at hepatectomy for HCC, and investigated the relationship between 8-OHdG and remnant liver recurrence. We found that the 8-OHdG labeling index (LI) for noncancerous region at the time of hepatectomy was significantly higher in recurrent (31.1+/-10.2%) than in nonrecurrent (20.6+/-8.0%) patients (P<0.01). The high 8-OHdG LI (>/=30%) group showed a significantly higher recurrence rate, compared with the low LI (<30%) group (P<0.01). The cancer-free survival curves also showed that the high 8-OHdG LI (>/=30%) group had a significantly poorer prognosis because of remnant liver recurrence than the low 8-OHdG LI (<30%) group (P<0.05). The 8-OHdG LI showed a significant correlation with the histopathologic evaluation of noncancerous region based on the New Inuyama Classification: a higher pathologic Staging and a higher pathologic Grading were associated with a higher 8-OhdG LI. Analysis by Grading and Staging showed that the high 8-OHdG LI group (>/=30%) of Grade A2, Stage F3, or Stage F4 had a significantly higher recurrence rate compared with the low 8-OHdG LI group (<30%) of Grade A2, Stage F3, or Stage F4, respectively. In addition, using multivariate analysis, we compared the influence on recurrence of the histological features that, at the time of hepatectomy, showed significant differences in the rate of remnant liver recurrence, that is, the number of tumors and the presence or absence of portal involvement, and three variables of the Grading, Staging, and 8-OHdG LI of noncancerous regions. The results suggested that 8-OHdG LI (P=0.02) and portal involvement (P=0.04), in this order, were useful as independent prognostic factors for recurrence. From this, we consider that, if patients with high 8-OHdG LI (>/=30%) in noncancerous region at the time of hepatectomy are regarded as being at high risk for remnant liver recurrence (heterochronous multicentric carcinogenesis) and are given careful follow-up treatment with preventive therapy for remnant liver recurrence, the prognosis will be improved.