Liver resection for young patients with large hepatocellular carcinoma: a single center experience from China

Background To investigate retrospectively the clinicopathological characteristics and outcomes of young patients with large hepatocellular carcinoma after hepatectomy. Methods From January 2003 to December 2012, a total of 153 patients with large hepatocellular carcinoma (HCC) who received liver resection were included in the study. The clinicopathological features were analyzed retrospectively. The perioperative data were compared between those aged <40 years (the young group) and those aged >40 years (the older group). Prognostic factors and long-term survival were evaluated. Results The young group had more hepatitis B virus-related HCC than the older group (87.2% vs 66.3%, P = 0.031). In the young group, 15 patients (21.5%) were overweight (body mass index 25 to 29.9 kg/m2) or obese (body mass index ≥30 kg/m2), and 38 patients (45.8%) were overweight or obese in the older group (P = 0.032). Other clinicopathological characteristics were similar between the two groups. The perioperative data showed that the older group had more pulmonary infection after hepatectomy. Vascular invasion and high Edmondson-Steiner grade were the independent prognostic factors for long-term survival. There was no statistical difference between the young group and the older group in overall survival and disease-free survival (P = 0.109 and P = 0.087, respectively). Conclusions Liver resection for young patients with large HCC was safe and efficacious and should be recommended.


Background
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China. HCC ranks second as a cause of cancer death overall in China [1][2][3][4]. Many studies have reported that hepatectomy could be performed satisfactorily for large HCC (>5 cm) with acceptable mortality [5][6][7]. However, there are few reports about the clinicopathological features and outcomes in young patients with large HCC after hepatectomy, and the significance of hepatectomy for these patients therefore remains unknown.
In USA and Europe, which are not hepatitis B endemic areas, patients younger than 40 years of age with large HCC are reported to be rare;however, young patients with large HCC are not uncommon in China. To investigate the clinicopathological features as well as the long-term outcomes after hepatectomy of young patients with large HCC, we performed a retrospective study of patients with large HCC undergoing hepatectomy whose ages were younger than 40 years (the young group), compared to those patients aged above 40 years (the older group).

Methods
From January 2003 to December 2012, 153 patients with large HCC (>5 cm) were treated surgically in the Affiliated Hospital of Zhejiang University School of Medicine. Patients younger than 40 years of age (n = 70) were defined as the young group And patients aged above 40 years (n = 83) were defined as the older group. Preoperative evaluation protocol included blood biochemistry, chest radiography, liver and renal function tests, ultrasonography, contrast computed tomography and indocyanine green clearance test.
Liver resection was undertaken in the patients with good cardiopulmonary and renal function, Pugh-Child's grades A and B, and indocyanine green test at 15 min <15%.
All intraoperative and postoperative complications were reviewed retrospectively through medical records. Complications (Clavien-Dindo gradesI-V) contained ascites, wound infection, pleural effusion, pulmonary infection, biliary fistula, liver failure and bleeding. Follow-up data were obtained by direct communication with patients after they underwent hepatic resection. All patients were examined for recurrence by clinical examination, alphafetoprotein (AFP) and ultrasonography. The follow-up period was calculated from the date of surgery to the date of either death or last follow-up. Prior informed consent was obtained from all patients and the study was approved by the Ethics Committee of Yiwu affiliated hospital of zhejiang university school of medicine.
Continuous variables were expressed as mean ± SD and compared using the independent-samples t test. Categorical data analysis used the rank test or chi-square test. Survival analysis, including overall survival and diseasefree survival, was estimated by the Kaplan-Meier survival method and compared using the log-rank test. Univariate and multivariate analysis by the Cox proportional hazard regression model was used to identify independent prognostic factors. All statistical analyses were performed using

Clinicopathologic features of patients with large hepatocellular carcinoma
The clinicopathologic parameters of the 153 patients with large HCC who underwent liver resection are shown in Table 1. The age of the young group was 32 ± 5 years compared to 55 ± 9 years in the older group.

Postoperative complications
There was no significant difference in the overall postoperative complication rate between the two groups (23% vs 22.9%, P = 0.928; Table 3). The common complications of the two groups were ascites, wound infection, pleural effusion, pulmonary infection, biliary fistula, liver failure and bleeding. The most common complication in the young group was bleeding (8.6%), and the most common complication in the older group was pulmonary infection (13.3%). Pulmonary infection showed a significant difference between the two groups (P = 0.041). The only postoperative death was caused by liver failure in the older group (Table 3).

Long-term survival and prognostic factors of patients with large hepatocellular carcinoma after hepatectomy
The 1-, 3-, and 5-year overall survival rates in the young group were 93%, 79% and 47%. The 1-, 3-, and 5-year disease-free survival rates in the young group were 87%, 28% and 17%. The 1-, 3-, and 5-year overall survival rates in the older group were 85%, 75% and 40%. The 1-, 3-, and 5-year disease-free survival rates in the older group were 65%, 36% and 11%. Overall survival and disease-free survival in the young group and the older group were similar (P = 0.109 and P = 0.087, respectively; Figure 1). Variables that might affect overall survival of young patients with large HCC after hepatic resection were also analyzed in this study (Table 4). Univariate analysis of the prognostic factorsfound that patients with liver cirrhosis (P = 0.045), vascular invasion (P = 0.017) and high Edmondson-Steiner grade (P = 0.036) had poorer overall survival than those without these variables. However, using multivariate analysis of the prognostic factors that predicted overall survival status, only presence of vascular invasion (P = 0.031) and high Edmondson-Steiner grade (P = 0.042) was significant (Table 4).

Discussion
Young patients with large HCC, who are rare in USA and Europe, are not uncommon at diagnosis in China. Astudy showed that 30% of HCC patients were younger than 40 years old [8]; in our cohort this ratio reached 47%. The high liver cancer rates in young patients in China largely reflect the prevalence of chronic hepatitis B virus (HBV) infection [9][10][11]. In this study, the young group had more HBV-related HCC than the older group (87.2% vs66.3%, P = 0.031). This implied that HCC in most young patients was caused by HBV infection. This infection may even have happened in infancy and has caused liver cirrhosis after many years. HBV infection leads to HCC [12][13][14][15]; therefore, regular examination of AFP and B ultrasound is very important for young patients with a history of hepatitis B infection. It is key for an early diagnosis and early operative treatment to improve the survival rate of young HCC patients. In the older group, there may be other factors involved. In the young group, 15 patients (21.4%) were overweight (BMI 25 to 29.9 kg/ m 2 ) or obese (BMI ≥30 kg/m 2 ), compared to 38 patients (45.8%) in the older group (P = 0.032). It is implied that non-alcoholic fatty liver diseases, which are associated with obesity, may participate in the development of HCC, especially in older patients [16][17][18][19]; therefore, we must pay more attention to the older patients who are overweight or obese.
Our study showed that hepatic resection for large HCC could be performed with an acceptable mortality rate and postoperative complication rates. The perioperative data   were similar between two two groups, except that the older group had more pulmonary infection after hepatectomy. This implies that hepatectomy for young patients with large HCC is safe. We also found that the cumulative overall and disease-free survival curves after hepatectomy showed no statistical difference between the young and the older groups. This implies that hepatic resection for young patients with large HCC is efficacious.

Conclusion
In conclusion, the clinicopathologic characteristics and the outcome for young patients with large HCC after liver resection were similar to that of the older patients, except for differences in infection through HBV and BMI. Liver resection for young patients with large HCC is safe and efficacious and should be recommended.