AIM: To comprehend the risk factors of recurrence of hepatocellular carcinoma (HCC) and its relationship with the infection patterns of hepatitis B virus (HBV).

METHODS: All materials of 270 cases of postoperative HCC were statistically analyzed by SPSS software. Recurrence and metastasis were classified into early ( ≤2 years) and late phase (>2 years). Risk factors for recurrence and metastasis after surgery in each group were analyzed.

RESULTS: Out of 270 cases of HCC, 162 cases were followed up in which recurrence and metastasis occurred in 136 cases. There were a lot of risk factors related to recurrence and metastasis of HCC; risk factors contributing to early phase recurrence were serum AFP level, vascular invasion, incisal margin and operative transfusion, gross tumor classification and number of intrahepatic node to late phase recurrence. The HBV infective rate of recurrent HCC was 94.1%, in which “HBsAg, HBeAb, HBcAb” positive pattern reached 45.6%. The proportion of HBV infection in solitary large hepatocellular carcinoma (SLHCC) evidently decreased compared to nodular hepatocellular carcinoma (NHCC) (P<0.05).

CONCLUSION: The early and late recurrence and metastasis after hepatectomy of HCC were associated with different risk factors. The early recurrence may be mediated by vascular invasion and remnant lesion, the late recurrence by tumor’s clinical pathology propert, as multicentric carcinogenesis or intrahepatic carcinoma de novo. HBV replication takes a great role in this process. From this study, we found that SLHCC has more satisfactory neoplasm biological behavior than NHCC.

Because of the advances in surgical techniques and perioperative management, hepatectomy of hepatocellular carcinoma (HCC) has become a safe operation with low operative mortality. However, the long-term prognosis remains poor due to a high incidence of recurrence and metastasis of HCC, ranging from 50% to 80%[1-3]. The effect of HCC’s therapy is also unpleasant; the high rate of recurrence and metastasis after HCC resection has always disturbed clinical surgeon nowadays. There are lots of reports based on the fact that intrahepatic recurrence or multicentric carcinogenesis de novo were found after resection of HCC[4,5]. Because different risk factors for recurrence and metastasis have been identified in previous articles[6], it is a controversy regarding the way of recurrence and metastasis, which need us continue to disclose its mechanism.

Hepatitis B virus (HBV) is a hepadnavirus, discussed worldwide as resulting in viral hepatitis in humans. HBV gets distributed at various ages, the infectious rate of HBV has reached 10% in China. Once it infects the human body, the HBV gets replicated and proliferated into hepatocytes, induces hepatocyte lesion and develops into chronic hepatitis. It has been reported that HBV is the prime cause for the development of HCC. In order to discuss the relationship between HBV and the recurrence and metastasis of HCC, we studied the clinical data of postoperative HCC and its follow-up.

Recurrence and metastasis of HCC could divide into intrahepatic recurrence and extrahepatic metastasis, but 90% of recurrence were intrahepatic, which could be expressed in mono-, poly- and omni-hepatic dissemination. Extrahepatic metastasis means primary lesion of HCC spreading to distant location, it can also accompany with intrahepatic recurrence. Multi-center carcinogenesis of HCC was closely related to postoperative recurrence. It has reported that recurrent rate reach to peak amongst 2 year, about 62-82%. This time after hepatectomy was the most risky period for recurrence and metastasis[11]. Therefore, we divided the recurrent time into early and late phase according to the point of 2 years postoperatively. In this study, recurrent risk factors at early phase were serum AFP level, vascular invasion, incisal margin and operative transfusion. Serum AFP was synthesized on embryo hepatocyte, it was not expressed on normal hepatocytes, but was expressed specifically on hepatic cancer cells. Now serum AFP level usually assayed as utility data contributing to judgment of operative effect on whether it descents to normal level (<20 μg/L). It has reported that serum AFP level would be descended to negative in 18% postoperative patients, and obvious descended in 40%[12]. Nowadays image examination such as B-US, CT scan, magnetic resonance imaging and digital subtraction angiography are limited, even the LR-CT with ultra-iodized oil image through hepatic artery can only find tumor >0.5 cm, and it is difficult to find the micro carcinoma <0.3 cm. So it is important for the surveillance of the recurrence and metastasis of postoperative HCC. Serum AFP level will be changed pre- and post-operation at HCC patients. Our material shows 85 cases occurred positive expression.

Surgery-related vascular invasion, incisal margin and operative transfusion were immediate causes for postoperative recurrence and metastasis at early phase, it means the HCC incision was not radical, and remnant carcinoma continues to grow after operation. As the way of enlarged incisal margin peremptory to prevent postoperative recurrence and metastasis is undesirable, it could not reduce the recurrence and metastasis but lead the patient to liver function failure or death[13-15]. Our experiences are to adopt limited hepatectomy, incisal margin is kept in 1-2 cm especially for the tumor with capsule or pseudocapsule. Owing to abundant liver blood supply, operative transfusion is usually inevitable even though there are lots of hemostasia measures to manipulate hepatic hemorrhage on operation. Investigation has made clear that operative hetero-transfusion could bring out many troubles[16,17]. Our study detected the recurrent rate obviously increased in whom accepted transfusion compared to non-transfusion (P = 0.012), indicated operative transfusion is auxo-action for recurrence and metastasis at the early phase of postoperation. The mechanism maybe: Thrombosis is the advantage of cancer cell implantation, growth factors are released to reinforce cancer cell growth directly or indirectly, to inhibit the NK cell’s activity and result in the function of NK immunocytes decreased, to accelerate the growth of remnant cancer cells. Therefore surgeon should weigh the merits and demerits while performing HCC hepatectomy, adopt acrobatic hepatectomy technique, reduced operative hepatic bleeding and blood transfusion as far as possible, to adopt self-transfusion when necessary. Preoperative vascular invasion or carcinoma thrombosis are fundamental cause for postoperative recurrence and metastasis, leading to decrease of postoperative survival rate. Above all, the micro vascular invasion under microscopy could not be judged, which directly lead to recurrence and metastasis at early phase after hepatectomy[18].

The clinical classification of HCC was the independence related risk factor during the late phase of postoperation. On the basement of previous abundant basic and clinical research, we divided HCC into small HCC (SHCC), solitary large HCC (SLHCC) and nodular HCC (NHCC) according to its clinical pathology propert. Analyzed 29 cases of recurrent data at late phase in contrast with 107 cases at early phase, we found the proportion of SLHCC decreased obviously than NHCC (58.9% vs 48.3%), there was a significant difference (χ² = 3.929, P = 0.047). It indicated SLHCC has more satisfactory neoplasm biological behavior than NHCC, which coincided with the results of our prophase research[10].

Chronic HBV infection is the main cause of HCC genesis in China. We statistically analyzed the materials of in-patients accepted hepatectomy at our hospital, the HBV infective rate reached 90%. The closed relation between HBV infection and HCC could manifest in the concordance on their epidemiologic character, such as local distribution, sex, age and family history[19]. The main HBV infective pattern of 270 patients was positive “HBsAg, HBeAb, HBcAb” viral markers. Positive HBsAg shows those patients existing with HBV infection, positive HBeAb and HBcAb shows HBV replicated in hepatocytes at lower level. If HBeAb presented long-term positive, the HBV-DNA has been integrated with host hepatocyte chromosome DNA, kept latentiation ever since[20,21]. Our data on 136 cases of recurrence and metastasis shows that the pattern of positive HBcAb was distinctly enhanced. We could explain that the HCC patients with HBV infection have lower immunological function, with decreased resistant ability, HBV promoted recurrence and metastasis by various kinds of pathway as activating HBx function, integrating host cell DNA, destructing apoptosis of normal hepatocyte, inactivating P53 gene, facilitating extracellular matrix degradation[22-24].

Among the recurrent HCC, the HBV infective pattern of NHCC was evidently different from that of SLHCC, furthermore, the proportion of NHCC with HBV infection was evidently increased (P<0.05). It is interpreted that NHCC more easily combines with HBV reproduction than SLHCC in the course of recurrence and metastasis. So the prognosis that NHCC is worse than SLHCC could be elucidated from another point of view.

In conclusion, this study provides an epidemiological evidence that intrahepatic recurrence and metastasis of HCC after hepatic resection has two obvious etiologies. The early recurrence may be mediated by vascular invasion and remnant lesion, the late recurrence by tumor’s clinical pathology propert, as multicentric carcinogenesis or intrahepatic carcinoma de novo. So we could prevent recurrence and metastasis of HCC in the following way: to adopt limited hepatectomy and acrobatic hepatectomy technique, to reduce operative hepatic bleeding and blood transfusion as far as possible, to control HBV infection in HCC patients. In this way, we can increase postoperative survival rate of HCC on whole.