|Year : 2016 | Volume
| Issue : 1 | Page : 20-28
The safety and adequacy of liver resection for large hepatocellular carcinoma: A retrospective single institute study
Amr Mostafa Aziz, Hazem Zakaria, Islam Ayoub, Hossam Eldeen Soliman, Maher Osman
Department of Hepato-Pancreatico-Biliary Surgery, National Liver Institute, Menoufia University, 32511 Shebin El kom, Menoufia, Egypt
|Date of Web Publication||5-May-2016|
Amr Mostafa Aziz
Department of HPB Surgery and Liver Transplant, National Liver Institute, Menoufia University, 32511 Shebin El-kom, Menoufia
Source of Support: None, Conflict of Interest: None
Background: Most major hepatocellular carcinoma (HCC) staging systems recommend hepatic resection only for patients with early-stage of HCC. Still there is controversial about resection of patients with large HCC (defined as >5 cm). The aim of this retrospective study is to investigate the clinicopathological features that impacted the long-term outcomes of 1 year after hepatectomy of large HCC >5 cm in cirrhotic patients. Materials and Methods: From February 2012 to December 2015, a total of 92 patients with resection of large HCC on liver cirrhosis were reviewed retrospectively and considered for clinicopathological features that impacted the long-term outcomes. Time to recurrence (recurrence-free survival) and overall survival (OS) were determined by Kaplan-Meier analysis. Results: Twenty-nine (31.5%) patients developed tumor recurrence. The mean time until tumor recurrence was 12.4 ± 6.6 months. The cumulative 1-, 2-, and 3-year disease-free survival rates were 73%, 28%, and 18%, respectively. On multivariate analysis, male gender, α-fetoprotein >400, bilobed tumors, patients with portal hypertension, plasma transfusion, and absence of tumor capsule remained independent predictors for recurrence of HCC. The OS rates at 1, 2, and 3 years were 73%, 31%, and 16%, respectively. On multivariate analysis, α-fetoprotein >400 and plasma transfusion remained independent predictors for death. Conclusions: Liver resection is suggested in patients with large HCC and can be performed with acceptable overall and disease-free survival and morbidity rates. Identification of risk factors and close postresection follow-up with early detection are mandatory measures for prompt treatment of tumor recurrence which is reflected by a beneficial survival rate for this group of patients.
Keywords: Large hepatocellular carcinoma, liver cirrhosis, liver resection
|How to cite this article:|
Aziz AM, Zakaria H, Ayoub I, Soliman HE, Osman M. The safety and adequacy of liver resection for large hepatocellular carcinoma: A retrospective single institute study. Saudi Surg J 2016;4:20-8
|How to cite this URL:|
Aziz AM, Zakaria H, Ayoub I, Soliman HE, Osman M. The safety and adequacy of liver resection for large hepatocellular carcinoma: A retrospective single institute study. Saudi Surg J [serial online] 2016 [cited 2022 Jan 28];4:20-8. Available from: https://www.saudisurgj.org/text.asp?2016/4/1/20/181811
| Introduction|| |
In Egypt, hepatocellular carcinoma (HCC) is the 2 nd most common cancer in men and the 6 th most common cancers in women.  HCC was reported to account for about 4.7% of CLD patients. The rising incidence of HCC in Egypt could be also explained through improvements in screening programs and diagnostic tools. 
Hepatic resection (HR) is widely regarded as the first-line treatment for selected patients with HCC. The prognosis of cancer patients is solely related to tumor stage. However, this is not the case in HCC patients. Cirrhosis underlies the neoplasm in most individuals and thus, their outcome is related to these two entities that simultaneously determine the applicability and efficacy of treatments. Accordingly, prognostic modeling in HCC patients has a high complexity and should consider four tightly related aspects: Tumor stage, degree of liver function impairment, patient's general condition, and treatment efficacy. ,
Most major HCC staging systems recommend HR only for patients with early-stage HCC (Barcelona clinic liver cancer stage A) , Many medical centers also routinely categorize patients with single large tumors (>5 cm) as stage B although some experts recommend classifying them as stage A. , However, according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system for HCC, tumor size of HCC does not affect the surgical outcome if the tumor does not have satellite nodules or major vascular invasion, and a single HCC without vascular invasion is presently classified as T1 regardless of tumor size. , Practice guidelines for HCC treatment that have been published in the USA by the American Association for the Study of Liver Disease , and in Japan  recommended surgical resection for patients who have a single HCC without major vascular invasion and well-preserved liver function regardless of tumor size.
In Egypt, not all patients with solitary HCC >5 cm had the option of liver transplantation either due to organ shortage or financial inability, so those patients need another modality for treatment.
Our aim in this study was to retrospectively investigate the clinicopathological features that impacted the long-term outcomes after hepatectomy of large HCC >5 cm in cirrhotic patients.
| Materials and Methods|| |
From February 2012 to December 2015, 134 curative liver resections for large HCC on top of cirrhosis were performed at the National Liver Institute, Department of HPB Surgery and Liver Transplantation, Menoufia University, Egypt. A total of 42 patients were excluded from the study analysis because of early hospital mortality (3 patients 2.2%), lost follow-up (29 patients 21.6%), and defective filing system in (10 patients 7.5%). Therefore, a total of 92 patients with resection of large HCC on liver cirrhosis were reviewed retrospectively and considered for clinicopathological features that impacted the long-term outcomes.
After hospital discharge, patients were followed-up weekly in the 1 st month, biweekly in the 2 nd -3 rd months following discharge and every month thereafter for the 1 st year. Follow-up was done at the outpatient department of our institution. Ultrasonography and liver function tests were performed whenever needed during the regular visits while a computed tomography and alpha-fetoprotein (AFP) level were performed after the 1 st month and similarly on 3-month basis during the 1 st year. Disease-free recurrence was defined as the time calculated from HR to the time of detection of tumor recurrence. Survival duration was defined as the time from HR to the date of death or last contact.
All values were expressed as median with range. The relationships between categorical variables were tested using Chi-squared analysis. Patient survival was calculated using the Kaplan-Meier method, and comparison of survival curves was made with the log-rank test. Potential predictors of survival and disease-free recurrence were calculated using the Kaplan-Meier method. Statistically, significant differences were indicated by P < 0.05. All statistical analyses were conducted using SPSS version 21 software (SPSS Inc. by IBM, Chicago, USA).
| Results|| |
Ninety-two patients were included in this study, with 79 (86%) were males and 13 (14%) females, with the overall mean age of the patients was 56.5 ± 9.4 years, with a range of 20-70 years. Hepatitis C virus was shown to represent the most common cause of cirrhosis in 89 (96.7%) patients, with only 3 (3.3%) patients were negative for HCV. Twenty-nine (31.5%) patients had comorbidities; diabetes mellitus in 24 (26%) patients, and hypertension in 19 (20.7%) patients. All patients were child A class with a mean model for end-stage liver disease (MELD) score of 7.7 ± 1.7 (rang from 6 to 13). The mean value of serum α-fetoprotein was 556 ± 1734 ng/dl (range from 2 to 13,019 ng/dl). Forty-three (46.6%) patients had portal hypertension as defined by its surrogate markers such as splenomegaly, platelet count <100,000/cumm, and esophageal varices.
All tumors resected were >5 cm, with the mean diameter was 6.7 ± 3 (range from 5 to 24 cm), and according to UCSF criteria, tumors >6.5 cm occurred in 63 (68.5%) patients and <6.5 cm occurred in 29 (31.5%) patients. Seven patients had bifocal lesions; the second focal lesion was <2.5 cm in diameter. These seven patients were managed by resection plus intraoperative RF ablation in five patients, plus alcohol injection in one patient, and in the last patient by two resections.
Preoperative portal vein embolization (PPVE) was done in five patients; three on the right side where one patient underwent transarterial chemoembolization (TACE) 3 weeks earlier and two other patients underwent PPVE on the left side. As regards to the type and extent of resection, anatomical resection (formal RT, LT, or left lateral resection) was done for 27 (29.3%) patients, monosegmentectomy in 41 (44.6%) patients, and nonanatomical resection in 24 (26.1%) patients [Figure 1] and [Figure 2].
|Figure 2: A large exophytic hepatocellular carcinoma in the right lobe liver|
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Of the 92 patients, 48 (52.2%) developed one or more complications. Postoperative ascites developed in 43 (46.7%) cases, which has been controlled by diuretics. Those patients who suffered postoperative ascites were those who had significant preoperative portal hypertension (PH). Furthermore, 2 (2.2%) of the portal hypertensive patients developed hematemesis which was controlled endoscopically. Postresection bleeding in the form of primary hemorrhage was detected in one patient and treated by relaparotomy and control of bleeding or in the form of mild blood oozing from the abdominal drain in 3 (3.3%) patients and treated conservatively. Other complications include abdominal collection in 5 (5.4%) patients who had been treated by US-guided pigtail drainage, bile leak in one (1.1%) case treated conservatively, wound infection in 9 (13.2%) cases with wound dehiscence in two of them, and chest infection in 3 (3.3%) cases.
The mean follow-up period was 18.8 ± 10 months (range 6-46 months) for the entire cohort. The mean time until tumor recurrence was 12.4 ± 6.6 months (range from 3 to 27 months). The cumulative 1-, 2-, and 3-year disease-free survival rates were 73%, 28% and 18% respectively [Figure 3]. Twenty-nine (31.5%) patients developed tumor recurrence in the liver; four of them had concomitant extrahepatic metastasis, one case in the adrenal gland, and the other three cases to the bone. Radiofrequency ablation was commonly applied in the treatment of recurrent HCC in 16 (17.4%) cases, followed by TACE in 8 (8.7%) and molecular targeted treatment (sorafenib) in 4 (4.3%) while repeated HR was done for 1 (1.1%) case.
|Figure 3: Recurrence free survival curve of 92 cases of liver resections for hepatocellular carcinoma on cirrhosis|
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The overall survival (OS) rates at 1, 2, and 3 years were 73%, 31%, and 16%, respectively [Figure 4]. Twenty patients (21.7%) died from tumor recurrence and tumor dissemination in 14 (70%) patients and because of liver failure in 6 (30%) patients.
|Figure 4: Overall survival curve of 92 cases of liver resections for hepatocellular carcinoma on cirrhosis|
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The previously described patients' outcomes (recurrence-free survival [RFS] and OS) were analyzed in comparison with various clinical and pathological parameters to detect factors that can impact outcomes [Table 1] and [Table 2]. On univariate analysis, the factors with the greatest influence on disease-free survival were male gender, α-fetoprotein > 400, MELD score > 9, tumor size >6.5 cm and bilobed tumors, absence of tumor capsule, patients with portal hypertension and plasma transfusion. On multivariate analysis, male gender, α-fetoprotein >400, bilobar tumors, patients with portal hypertension, plasma transfusion, and absence of tumor capsule remained independent predictors for recurrence of HCC.
|Table 1: Clinical and pathological characteristics of patients in relation to recurrence |
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|Table 2: Clinical and pathological characteristics of patients in relation to survival |
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The association of various clinicopathological factors with survival was evaluated [Table 2]. In univariate analysis, male gender, α-fetoprotein >400, and plasma transfusion were statistically significant for the incidence of death. On multivariate analysis, α-fetoprotein >400 and plasma transfusion remained independent predictors for death.
| Discussion|| |
Treatment of HCC on top of liver cirrhosis is a very challenging issue because a precise balance must be maintained between radical tumor excision and maximal parenchymal preservation.  The ideal test of the benefit of any treatment is a randomized prospective trial, but such studies are limited for patients with HCC.  The existing treatment strategies have been based on theoretical analyses and several cohort investigations. ,, Liver resection remains the mainstay of potentially curative treatment for HCC as a destination therapy in some patients with adequate liver function or potentially serving as a bridge to liver transplantation. Nevertheless, liver resection is considered the only curative and feasible therapeutic option for giant HCC, especially whenever little parenchyma would be resected (e.g., in exophytic large tumors).
During long-term clinical investigations, Yang et al. had observed that there is one specific type of HCC which is large in size but exhibits a low invasive and metastatic potential and a good outcome after resection. This type of HCC typically has just a solitary node >5 cm in diameter and grows expansively within an intact capsule or pseudocapsule.  Many literature data suggest that relatively good biological behaviors and outcomes have been observed in some individuals with larger-sized HCC, thus making a definition of solitary large HCC, a new subtype of HCC. ,,
In our study, the mean time of recurrence was 12.4 ± 6.6 months (range from 3 to 27 months), with the cumulative 1-, 2-, and 3-year disease-free survival rates were 73%, 28%, and 18%, respectively while the OS rates at 1, 2, and 3 years were 73%, 31%, and 16%, respectively.
On multivariate analysis, the factors with the greatest influence on disease-free survival were male gender, α-fetoprotein >400, bilobed tumors, patients with portal hypertension, plasma transfusion, and absence of tumor capsule remained independent predictors for recurrence of HCC. Further, the factors with the greatest influence on survival were α-fetoprotein >400 and plasma transfusion remained independent predictors for death. Our study is one between few studies which focused on tumor recurrence in relation to PH, MELD score, and interestingly with plasma transfusion.
In the current study, α-fetoprotein >400 confirmed a negative effect on disease-free survival after curative resection. In many other studies, AFP levels predict poor OS for patients with large HCC. ,, The Liver Cancer Study Group of Japan and the Cancer of the Liver Italian Program reports have stressed the importance of preoperative AFP levels by incorporating the AFP level in their clinical prognostic scores. , The 2009 HCC Medical Guidelines reduced the serum AFP value for HCC diagnosis from 400 to 200 ng/mL.  The mechanism by which AFP levels may worsen prognosis remains unknown, AFP induces the suppression of cytotoxic T-lymphocytes activity and antibody responses of B lymphocytes, as well as contains epitopes, which activate the expansion of inducible transforming growth factor-B producing regulatory T-cells and evading tumor control. ,, Um et al. showed that AFP appears to affect antigen-presenting cells as in HCC patients with high levels of AFP; their antigen-presenting cells are dysfunctional and the role of the dendritic cells is impaired.  In a study by Yamamoto et al., they demonstrated an interaction between AFP and the innate immune system and hypothesized that elevation of AFP in cirrhosis patients impairs innate immunity, which results in the promotion of HCC development. 
In our study, MELD score >9 was statistically significant for recurrence of HCC after resection which may reflect advanced cirrhosis. Many reports have pointed out that chronic active hepatitis and cirrhosis are the most significant risk factors for intrahepatic recurrence through multicentric carcinogenesis, the so-called "multicentric occurrence." ,,,
In the present report, tumors >6.5 (exceeding UCSF criteria) had a negative impact on disease-free survival. Our findings are in consistence with the observations of other recent single center studies demonstrating that tumor size is an important prognostic factor of surgically resected solitary HCC. ,, On contrast, tumor size has been omitted as a prognostic factor for solitary HCC in the latest editions (6 th and 7 th ) of the AJCC tumor-node-metastasis classification systems. , However, several large cohort studies have demonstrated the importance of tumor size as a prognostic marker for solitary HCC and challenged the rationale for its omission as an important prognostic factor. ,,, The findings in this study have potentially important implications as it provides further supporting evidence that the current AJCC staging system for T2 solitary HCC should be revised.
Besides being a large tumor, the bilobar lesions further significantly reduce the RFS as shown in the univariate analysis, and the presence of multiple tumors was an important prognostic factor for a lower RFS in the multivariate analysis. The number of HCC lesions may reflect the overall tumor burden and thus acts as a negative prognostic factor. ,,,, Multiple nodules result from either multicentric carcinogenesis or transportal vein metastasis. The presence of microsatellites had a significant negative influence on the long-term outcome of patients after HR of HCC. ,, The AJCC staging system stratifies patients with multiple tumors >5 cm to the T3 category, and thus a worse prognosis. 
Similarly, the absence of tumor capsule was statistically significant for shortened RFS in the present analysis. Reported incidence of tumor encapsulation ranges from 3.6% to 86.4%. ,,, Encapsulation of HCC is reported to be more common in Asian countries. However, two recent studies from European Centers showed that encapsulation in HCC and in cirrhotic livers was not infrequent and was found in 73.6% and 76.9% of cases, respectively. , A clear relationship was shown between tumor encapsulation and a lower tumor invasiveness, including less frequent direct liver invasion, tumor microsatellites, and venous permeation. ,,
The European Association for the Study of the Liver guidelines considers PH as a relative contraindication to liver resection because of the high risk of postresection bleeding and/or liver failure. , Other studies confirmed a correlation between PH and increased mortality and complications. ,,,,,, Our study is one of a few reports in the literature to demonstrate a relationship between RFS and PH. PH may reflect the degree of cirrhosis severity, which has been shown as the most significant risk factor for intrahepatic recurrence through multicentric carcinogenesis.
It has been reported that blood transfusions are significantly associated with increased the incidence of tumor recurrence, especially in patients with early tumor stages I or II  and HCC without angioinvasion.  These studies suggest that the impact of blood transfusions on tumor recurrence is pronounced in patients with relatively early stages of HCC.  On the other hand, other reports on HR for HCC described that intraoperative blood transfusion adversely affected OS rates but not RFS. , Another study on HCC reported that a large number of perioperative blood transfusions adversely affected OS.  In the present study, a large volume of perioperative plasma transfusions significantly associated with both decreased disease-free and OS in multivariate analysis. Packed red blood cells transfusion was, in contrast, not significantly affecting the recurrence or survival in our study. This finding may be due to the small number of patients who needed blood transfusion during surgery as a result of improved surgical technique and modern transaction tools and hemostatic measures.
HCC is characterized by its propensity for vascular invasion. Numerous previous studies have demonstrated that the presence of either microscopic or macroscopic vascular invasion is the key risk factor for recurrence. , Intrahepatic metastasis via the portal venous system is generally accepted as an important mechanism for intrahepatic recurrence. , Our study did not show any significant for RFS or OS.
In the present study, the type of resection had no impact on RFS or OS. These results have similarly been demonstrated by Abdel Wahab et al.  as there was no significant influence on tumor recurrence rate after major resection or minor or localized resection of the liver. Likely, Cho et al. in their study concluded that there were no significant disease-free or OS differences between anatomical and nonanatomical liver resection. A tumor >5 cm and the presence of cirrhosis were statistically significant risk factors for recurrence, irrespective of the extent of resection. 
The etiology of HCC recurrence is multifactorial. Studying these risk factors of recurrence is very important to create a scoring system, so one can predict RFS and OS. Identification of patients who are at high risk for recurrence after liver resection raises the question whether this group of patients should receive additional therapy before or after resection, especially most patients with vascular invasion have microscopic invasion that is identified only after postoperative pathologic examination. Yet, adjuvant treatment for HCC is still unmet need. A proposed algorithm for the treatment of recurrences after resection by Shah et al. who suggested that recurrences within 1 year and pathologic vascular invasion on initial resection were poor prognostic factors for recurrence. This has guided their approach to consider liver transplant as salvage treatment for patients who experience recurrence after 1 year after resection.  However, the optimal therapy for recurrences should be individualized depending on the liver status, the location and size of recurrence, and the availability of grafts. Radiofrequency ablation has been our preferred approach with acceptable results.
| Conclusion|| |
With recent advances in preoperative planning, risk assessment, and better surgical techniques, liver resection for large HCC can be performed safely with minimal morbidity and mortality outcomes in high-volume centers. Liver resection is suggested in patients with large HCC and can be performed with acceptable overall and disease-free survival and morbidity rates. Identification of risk factors and close postresection follow-up with early detection are mandatory measures for prompt treatment of tumor recurrence which is reflected by a beneficial survival rate for this group of patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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