Author Affiliations: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China (Zhou L, Rui JA, Wang SB, Chen SG and Qu Q)

 

Corresponding Author: Li Zhou, MD, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China (Tel: 86-10-65296007; Fax: 86-10-65296010; Email: lizhou02@hotmail.com)

 

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60008-9

 

Contributors: ZL proposed the study and wrote the first draft. ZL, RJA, WSB, CSG and QQ analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. ZL is the guarantor.

Funding: This study was supported by a grant from the Beijing Municipal Fund for Key Disciplines, China (100230446).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND:Predictors of poor prognosis of solitary hepatocellular carcinoma (SHCC), a subgroup encompassing most patients with the malignancy, are still controversial. Hence, risk factors for portal vein tumor thrombosis (PVTT) in SHCC are obscure. The present study was designed to address this issue.

 

METHOD: Clinicopathological and follow-up data for 156 consecutive patients with SHCC following curative hepatic resection were analyzed using uni- and multi-variate analyses.

 

RESULTS:Univariate analysis showed that PVTT, tumor-node-metastasis (TNM) stage, Edmondson-Steiner grade and preoperative serum alpha-fetoprotein (AFP) level were associated with the overall and disease-free survival, whereas tumor size only influenced the overall survival. In multivariate Cox regression tests, Edmondson-Steiner grade and TNM stage were independent prognostic markers for both overall and disease-free survival. In addition, the Chi-square test showed that AFP level and Edmondson-Steiner grade were correlated with PVTT. Among them, only Edmondson-Steiner grade was shown to be of independent significance for PVTT in multi-variate logistic regression analysis. Additionally, AFP, the sole preoperative factor for PVTT, was not adequately sensitive and specific.

 

CONCLUSIONS: Factors relating to post-surgical prognosis and PVTT in SHCC are all tumor-related. Of these, Edmondson-Steiner grade and TNM stage might be of particular importance in survival analysis. In addition, accurate prediction of PVTT by clinicopathological parameters before surgery remains difficult.

 

(Hepatobiliary Pancreat Dis Int 2013;12:68-73)

 

KEY WORDS: solitary hepatocellular carcinoma; curative resection; prognosis; portal vein tumor thrombosis

Hepatocellular carcinoma (HCC) is life-threatening because of its high incidence and mortality.^[1-3] So far, the overall clinical outcome of HCC remains unsatisfactory, although some improvements have been achieved in many curative and palliative modalities, such as hepatic resection, liver transplantation, radiofrequency ablation and transcatheter arterial chemoembolization (TACE).^[4] Therefore, much attention has been paid to identify factors affecting the survival of HCC patients, including conventional clinicopathological variables and novel molecular markers.^[5] Among them, tumor number was shown to be an important determinant of prognosis of HCC in patients undergoing several kinds of treatments.^[6-10] Obviously, individuals with solitary HCC (SHCC) had relatively better survival than those with multi-nodular tumor. However, prognostic predictors of SHCC, the main subgroup of HCC according to tumor number,^[7] are still controversial.^{[11, 12]} Thus, further accumulation of more relevant data is required.

 

Portal vein tumor thrombosis (PVTT), a unique disseminating manner of HCC, was found to be associated with poor prognosis of HCC.^[13-15] Currently, imaging examinations including computed tomography (CT) are the main approaches for detection of PVTT, but their sensitivity and specificity are unsatisfactory, especially for small-sized HCC.^[16] Therefore, it is considered whether clinicopathological variables could be helpful in predicting PVTT. To the present, only preliminary of such method has been reported in patients with HCC.^[17] The present study was designed to address the mentioned issue in a cohort of Chinese patients with SHCC who had undergone curative resection of the tumor.

 

 

The medical records of 156 patients with SHCC (defined as single nodular HCC without satellite lesion at the time of diagnosis), who had undergone curative hepatic resection from 1995 to 2002, were reviewed retrospectively. These patients consisted of 137 males and 19 females, with a median age of 47 years (range 15-77). Tumor size was defined as the largest dimension of the tumor mass. PVTT, based on findings in imaging, operation and post-operative examination, indicated gross tumor invasion in the main branches of the portal vein. Tumor-node-metastasis (TNM) staging and Edmondson-Steiner grading were carried out according to the conventional criteria.^{[18, 19]} Written informed consent was obtained from all patients.

 

The criteria of curative resection for patients with HCC were as follows: (1) Tumors (no more than three) were limited with at least two segments free of lesion; (2) No evidence of tumor thrombus in the trunks of the portal vein, hepatic vein and bile duct; (3) Child-Pugh grading was not worse than class B. Ten host and tumor-related variables were evaluated by survival analyses: age, gender, hepatitis B surface antigen (HBsAg), hepatitis C virus C virus (HCV), Child-Pugh grade, preoperative alpha-fetoprotein (AFP) level, tumor size, PVTT, TNM stage and Edmondson-Steiner grade. For PVTT, TNM stage was excluded from the analyses, because PVTT was involved in the system.^[18]

 

After the resection, the patients, especially those with recurrent tumors, received multi-modal serial therapies including TACE, local ablation therapy and biological therapy. These patients were followed up every one month up to three months. Regular imaging (Fig. 1) and testing of serum AFP levels were performed to detect tumor recurrence and metastasis. Later, the patients were followed up from 3 to 108 months (median 19).

 

A statistical software package, SPSS11.5 (SPSS Inc., Chicago, IL., USA) was used for all analyses. The survival rate of the patients was calculated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was performed for prognostic factors by using the Cox regression test. The Chi-square and stepwise logistic regression test were adopted to evaluate risk factors of PVTT. P values of less than 0.05 were regarded as statistically significant.

 

 

The overall 1-, 3-, and 5-year survival rates of patients with SHCC were 82.9%, 54.7% and 47.8%, respectively (56±4 months; 95% confidence interval (CI) 48-65) (Fig. 2). Correspondingly, the 1-, 3-, and 5-year disease-free survival rates were 70.3%, 36.4% and 22.5%, respectively (38±3 months; 95% CI: 31-44).

 

Univariate analysis showed that Edmondson-Steiner grade, TNM stage, serum AFP level and PVTT were predictive for the overall and disease-free survival of SHCC patients, whereas tumor size influenced the overall survival (P<0.05; Table 1). Other parameters were not statistically significant (Table 1). In the Cox regression test, Edmondson-Steiner grade and TNM stage were independent prognostic markers for the overall and disease-free survival of the patients (P<0.05; Table 2).

 

PVTT was preliminarily diagnosed by imaging examinations in 13 patients and pathologically confirmed in 17. By the Chi-square test, serum AFP level (χ²=6.528, P=0.011) and Edmondson-Steiner grade (χ²=7.373, P=0.007) were associated with PVTT (Table 3), whereas gender, age, HBsAg, HCV, liver cirrhosis, Child-Pugh grade and tumor size were not significant (Table 3). Of the significant factors, AFP, the single preoperative variable, carried a sensitivity of 64.7% (11/17), a specificity of 66.9% (93/139), a positive predictive value of 19.3% (11/57), and a negative predictive value of 93.9% (93/99). In stepwise logistic regression analysis, Edmondson-Steiner grade was of independent predictive power for PVTT in SHCC (RR=3.467, 95% CI: 1.032-11.65, P=0.044), whereas marginal significant difference for AFP level was also shown (RR=2.685, 95% CI: 0.894-8.065, P=0.078).

 

 

SHCC, compared with multiple nodular HCC, is strongly suggested to have better prognosis.^[6-10] Satisfactory five-year overall and disease-free survival rates (79.6% and 41.1%, respectively) were achieved in a Japanese cohort of patients with SHCC who had undergone hepatic resection.^[12] However, the present series presented a relatively poorer prognosis (the five-year overall and disease-free survival rates of 47.8% and 22.5%, respectively). Demographic characteristics such as smaller tumor size (3.13 cm) and higher HCV positivity (66.5%) in the Japanese patients might account in part for the observed difference, because the two features were shown to be associated with better prognosis of HCC.^{[5, 20, 21]} However, the variables influencing the prognosis of SHCC, which were deemed controversial in previous studies,^{[11, 12]} remain to be elucidated. The significant risk factors for early death included gross tumor classification, tumor diameter, macroscopic portal vein invasion, microscopic growth pattern, microscopic vascular invasion and the width of surgical margin.^[11] However, tumor-related factors do not influence the prognosis of SHCC after partial hepatectomy.^[12] Univariate analysis in our study revealed that Edmondson-Steiner grade, TNM stage and preoperative serum AFP level were significant markers for the overall and disease-free survival of patients, along with vascular invasion, tumor size and PVTT (Table 1). The present study is the first to identify these newly introduced factors as prognostic indicators for SHCC, although they were reported to be prognostic in other subsets of HCC.^[22-24] Among these factors, Edmondson-Steiner grade and TNM stage were of independent prognostic implications, suggesting that the two variables might be particularly important. Another phenomenon that should be noted is that all the prognosticators were tumor-related, strongly indicating the pivotal role of tumor characteristics in the prognosis of SHCC, and supporting the finding of Kondo et al.^[11]

 

PVTT, arising from the invasion of HCC cells into the portal vein, is well acknowledged as a special type of metastasis in HCC.^[25] The presence of PVTT is associated with unfavorable prognosis of HCC.^[13-15] Recently, some investigators reported that tumor response after TACE was significantly affected by PVTT,^[26] which is consistent with our finding. Currently, imaging examinations remain the gold standard in the diagnosis of PVTT. However, the diagnostic power, especially the sensitivity, is unsatisfactory.^[16] Studies^[27-31] found that some cancer-related molecules such as platelet-derived endothelial cell growth factor (PD-ECGF), vascular endothelial growth factor (VEGF), thrombomodulin, angiopoietin 2, ephrin B2 and low molecular weight protein have the potential to serve as biomarkers of PVTT in HCC. However, the predictive power of conventional clinical and pathological parameters is less well evaluated. Another study^[17] demonstrated the significant association of age, gamma-glutamyltransferase, number of segmental invasion, microvascular invasion, and segment location of S2, S3, S4 and S6. In our study, serum AFP level and Edmondson-Steiner grade were associated with PVTT. It was reported that tumor differentiation is closely related to vascular invasion and proliferation in HCC.^{[32, 33]} The finding that poorly differentiated HCC carries an increased expression of angiogenic factors and high microvessel density might account, at least in part, for this correlation.^{[32, 34]} Therefore, the relation of PVTT and Edmondson-Steiner grade in SHCC might be easily understood. However, data regarding the aforementioned factors could not be obtained before surgery. In addition, we identified serum AFP level as a potential significant marker of PVTT by univariate analysis. Researchers^[35-38] observed that AFP could promote proliferation, mediate escape of immune surveillance and inhibit apoptosis in human HCC cells, via regulation of the expression of c-Fos, c-Jun, N-Ras, Fas/FasL and caspase-3. Other experiments using specific stealth RNAi of AFP also confirmed its impact on the proliferation and apoptosis of HCC cells.^[39] Currently, there has been no direct evidence for the role of AFP in invasion/metastasis of HCC cells. However, high AFP value (>400 ng/mL) was found in well, moderately and poorly differentiated HCC.^[40] There was a relationship between differentiation and vascular invasion.^[33] Thus AFP may be associated with PVTT, an important manner of vascular invasion of HCC. Of course, AFP, the sole preoperative parameter, in the present study did not show a sensitivity and a specificity for PVTT. It was not superior to those previously reported for CT scanning,^[16] indicating that the predictive power of this variable was limited in this cohort. In future, more in-depth investigations with larger sample sizes might be necessary for a final conclusion.

 

In summary, our data indicate that factors relating to post-surgical prognosis and PVTT in SHCC are all tumor-related. Edmondson-Steiner grade and TNM stage might be of particular importance in survival analysis, whereas the accurate preoperative prediction of PVTT by clinicopathological parameters remains difficult.

 

 

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