Clinical Analysis of the Risk Factors of Early and Late Phase Recurrence after Surgical Excision of Hepatocellular Carcinoma: Experience of One Center with 345 Patients

Research Article

Ann Hematol Oncol. 2019; 6(9): 1266.

Clinical Analysis of the Risk Factors of Early and Late Phase Recurrence after Surgical Excision of Hepatocellular Carcinoma: Experience of One Center with 345 Patients

Tailai A1, Tianxing D1, Zhenyu Y2, Wei L3, Yingcai Z1 and Guoying W1,3*

1Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, China

2Organ Transplantation Institute, The Third Affiliated Hospital of Sun Yat-sen University, China

3Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, China

*Corresponding author: Wang Guoying, Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, China

Received: June 22, 2019; Accepted: July 18, 2019; Published: July 25, 2019


Background: Resection excision operation is an important treatment alternative for respectable HCC (hepatocellular carcinoma); unfortunately, many patients undergo the experience of early or late phase recurrence after surgical excision of the tumor lesion. Our study here aims to investigate the risk factors associated with early and late phase recurrence after surgery as well as to establish a predictive model to facilitate improving our predictive ability about HCC recurrence and accumulating the comprehensive treatment experience.

Methods: We conducted a retrospective analysis of 345 patients who received surgical excision of the tumor lesions in our hospital. Patients were divided into three classes: no recurrence, early phase recurrence and late phase recurrence. Risk factors of early and late recurrence were analyzed statistically. On the basis of the risk factors associated with early and late phase recurrence, the mathematics models for early and late phase recurrence were established.

Results: The cumulative survival rates without recurrence at 1,2,3,4, and 5 years were 68.8%, 40.1%, 35.7%, 30.2%, and 27.5% respectively. According to the widely accepted definition: early phase recurrence occurs within 2 years after the surgery and late phase recurrence happens 2 years after the resection. 197 patients had early phase recurrence and 25 ones had late phase recurrence. Cox multivariate proportion hazard model suggested that multiplicity of tumor lesions, high preoperative serum fibrinogen level, high preoperative serum GGT level and too much blood transfused are independent risk factors significantly correlated with early phase recurrence. In contrast with the risk factors associated with early phase recurrence, multiplicity of tumor lesions, severe liver cirrhosis and portal vein hypertension, high preoperative serum CHE level and high preoperative serum GGT level were identified as risk factors associated with late phase recurrence. Patients with at least two of the four early phase recurrence risk factors were much more likely to have early phase recurrence and patients with three or more late recurrence risk factors were prone to experience late phase recurrence.

Conclusions: Different kinds of risk factors are associated with early and late phase recurrence. Early phase recurrence occurs due to metastases within the liver while late phase recurrence happens as a result of impaired liver function reserve and carcinogenesis de novo from the cirrhotic liver.

Keywords: Hepatocellular carcinoma; Early and late phase recurrence; Surgical excision; Risk factors; Prognosis; High-risk group and low-risk group; Cut-off value


As a common kind of malignant tumor, HCC (hepatocellular carcinoma) causes about 1 million deaths due to its increasing incidence annually and poor 5-year survival rate of less than 5% without treatment [1-4]. Surgery, which includes keratectomy and liver transplantation, is still believed by most surgeons to be the most effective treatment alternative for the patients with respectable HCC lesions. Although liver transplantation is the most curative treatment, it also has its own shortcomings. The lack of donor livers, long waiting time, higher perioperative morbidity and long-term or even lifetime immunosuppression therapy still restrict the wide application of the liver transplantation in the treatment of HCC. Over the last several decades surgical techniques and perioperative management of patients undergoing keratectomy have become more and more sophisticated which makes the procedure of resection of HCC much safer than that of several decades ago [1,3,4,5]. The safety of the surgical procedure is indicated by much lower mortality and morbidity rates than those of several decades ago [1,3,4,5]. Even after a safe surgical resection of the HCC, the long-term prognosis of patients with HCC remains poor due to the high incidence of recurrence (68%-96%) [1,4,5,7,9]. Thus it is critical to develop effective therapeutic methods to control tumor recurrence with an ultimate goal of prolonging the life of HCC patients. By now, various kinds of risk factors associated with HCC recurrence have been reported. These factors include tumor-related ones, background liver status, the type of the surgery and even some molecular and immunological markers [1-8,12,14,17,20]. However, the exact causes and mechanism of recurrence still remain mysterious. In this study, we investigated the pattern of recurrence time and a few potential risk factors that may help us predict the early and late phase recurrence of HCC after a hepatectomy for HCC.



Between March 2005 and May 2013, 475 patients received surgical excision of HCC at the department of hepatobiliary surgery and liver transplantation of The Third Affiliated Hospital of Sun Yat Sen University. Of all these patients, 130 were excluded from the study. 57 patients received other treatment options prior to the resection surgery and 73 ones had simultaneous intraoperative microwave ablation because of the multiple lesions within the liver. 345 patients were included in the present study. Curative resection includes the complete removal of the tumor and the visible portal vein tumor thrombus with a negative microscopic margin. Patients receiving anti-HBV before and after the hepatectomy are recorded in the study and we analyzed the relationship between the anti-HBV therapy and late phase recurrence. The procedures and the related methods of this study and using human sample had received approval by the Ethics Committee of our hospital before the implementation and all the patients involved in this research had signed written informed consent.

Surgical modalities

If 3 or more segments (according to the Coined classification were resected, the procedure was called a major hepatectomy. 180 (52%) patients underwent major hepatectomies, of whom 27 (5%) were resected 3 or more discontinuous segments. The resection operation of 165 patients were minor ones that include non-anatomical wedge resections (no more than two segments) or enucleations (50, 14.3%) and left lateral segmentectomy (44, 12.8%). The average number of resected hepatic segments is 3.2 0.4 (range 0-6). Anatomical resection, defined as any type of systematic resection of the portal region based on the Coined classification system, was performed in 299 patients (75.1%), while 99 patients underwent non-anatomical resections (24.9%. In this study we classified incomplete removal of tumor-bearing portal region such as wedge resection or enucleation as non-anatomical resection while discontinuous segments resection was defined as anatomical resection as long as each resection of the patient was anatomical resection.

Diagnosis of HCC

Nowadays most HCC patients were detected and evaluated using contrast ultrasonography, contrast CT and MRI. If the lesion is larger than 2cm in diameter, a single imaging modality with arterial hypervascular and venous washout characteristic is suggestive of HCC; otherwise 2 or more kinds of imaging modalities with arterial hypervascular and venous washout characteristic are needed to confirm the diagnosis of HCC. The diagnosis of HCC patients were confirmed by histopathological investigation after the resection. Pathological grading was based on the Edmodson-Steiner criteria.


All the follow-up processes of the patients after resection were carried out in the outpatient or inpatient department of our hospital and the recurrence of HCC was closely monitored prospectively. The follow-up protocol was made up of monthly serum AFP (alpha-fetoprotein) monitoring and contrast ultrasonography, contrast CT or MRI once every 3 months after the resection of the HCC lesion. The changes of the serum tumor markers before and after the surgical operation as well as those at the confirmation of the recurrence were assessed. Tumor recurrence was confirmed according to the same criteria applied to the initial diagnosis of HCC and if hepatic re-resection was done, the recurrence was diagnosed by histopathological investigation. The number, size and location of recurrence (intrahepatic or extrahepatic) were then recorded. Recurrences outside of the liver (i.e metastases) were investigated by contrast ultrasonography, CT, MRI or PET-CT using 18F-FDG.

Statistical analysis

Descriptive statistics had several parameters including mean, range, standard deviation and proportion. For the continuous variables that have been previously widely used by the clinicians, the widely accepted cut-off values of these variables were directly used, otherwise the cut-off values were calculated by the ROC curve method. In univariate analysis, χ2 test was adopted to determine the variables significantly associated with early and late phase recurrence. The multivariate analysis of prognostic factors for HCC early and late phase recurrence was done using the Cox’s proportional hazards model. All the 23 variables were entered into a backward stepwise regression model. Step selections were based on the maximal likelihood ratio tests and only significant variables were reserved in the multivariate Cox’s proportional hazards model analysis. The Kaplan-Meir method was used to evaluate survival rates and the logrank test was applied to compare survival rates. SPSS18.0 for Windows (Chicago IL, USA) was used to to perform all the statistical evaluation. For ROC (receiver operating characteristic) curve analysis, we used the Medcalc (version120 to calculate the sensitivity, specificity, area under the curve and to select the optimal cut-off value for predicting HCC recurrence. A variable was considered statistically significant when its P value was lower than 0.05.


Patient characteristics

306 men (88.7%) and 39 women (11.3%) were incorporated in the present study with a mean age of 50.01±11.62 years. Assessed by the Child-Pugh classification system, all the patients belonged to grade A or B. 317 patients (92.2%) belonged to Child-Pugh A and 28 patients (7.8%) belonged to Child-Pugh B. At the start of the hepatectomy, 237 patients (68.7%) had only one tumor lesion and 108 patients (31.3%) had multiple tumors. The median nodule diameter was 5.38 cm (range 1.0-18.2cm). Regarding the etiology of the HCC, 310 (77.9%) of all the patients were HBV-positive while only 3 were confirmed HCV-positive. All the patients had liver fibrosis of different grades and 272 patients (68.3%) had cirrhosis background. Table 1 shows the demographics of all the patients that contain preoperative, intraoperative and tumor-related parameters pertain to the initial hepatectomy.