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10.1245/ASO.2003.03.072
Annals of Surgical Oncology 10:1070-1076 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Hepatic Resection and Prognosis for Patients With Hepatocellular Carcinoma Larger Than 10 cm: Two Decades of Experience at Chang Gung Memorial Hospital

Chun-Nan Yeh, MD, Wei-Chen Lee, MD and Miin-Fu Chen, MD, FACS

From the Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Correspondence: Address correspondence and reprint requests to: Chun-Nan Yeh, MD, Department of Surgery, Chang Gung Memorial Hospital, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan; Fax: 886-3-328-5818; E-mail: ycn{at}adm.cgmh.org.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Although screening programs in high-risk populations have facilitated the detection of small hepatocellular carcinoma (HCC), some HCC patients continue to present with advanced, large tumors. However, reports of hepatic resection for HCC larger than 10 cm (L-HCC) are limited. This study aims to determine the clinicopathologic factors that influence the prognosis of hepatic resection for L-HCC.

Methods: The clinical features of 211 L-HCC patients undergoing hepatic resection were reviewed. Clinical features and factors influencing the outcome of 985 patients with HCC smaller than 10 cm (S-HCC) were used for comparison.

Results: Of 1196 surgically resected HCCs, 211 (17.6%) were L-HCC. Multivariate logistic regression analysis showed that the presence of dull abdominal pain, a low indocyanine green retention rate value, a high percentage of alfa fetoprotein (AFP) >400 ng/mL, major hepatectomy, absence of tumor capsule formation, satellite lesions, and vascular invasion were the seven main independent factors differentiating L-HCC from S-HCC patients. Significantly worse overall survival was noted in L-HCC patients, especially those with tumor rupture, satellite lesions, AFP >400 ng/mL, and blood loss of >1 L during surgery.

Conclusions: Hepatic resection, when feasible, is safe and is the preferred treatment for L-HCC patients. However, overall and disease-free survival for L-HCC are worse than for S-HCC. Disease-free survival for L-HCC patients undergoing hepatic resection is significantly influenced by a high value of alkaline phosphatase and by AFP. Overall survival for L-HCC patients undergoing hepatic resection is significantly influenced by a high value of AFP, blood loss, tumor rupture, and satellite lesions.

Key Words: Hepatocellular carcinoma • Hepatic resection • Prognosis • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is a common disease in Taiwan, with an annual age-adjusted incidence of 27.7 per 100,000 population. It is the leading cause of cancer-related deaths among men and is second among women in Taiwan.1

Advances in diagnostic imaging and the widespread application of screening programs in high-risk populations have facilitated the detection of small HCC (S-HCC). However, some patients with HCC present with advanced, large tumors. Liver transplantation is contraindicated with HCC larger than 5 cm,2,3 as is local regional treatment, such as percutaneous ethanol or acetic acid injection.4–6 The only nonsurgical treatment option for HCC larger than 10 cm (L-HCC) is transarterial chemoembolization, but the response rate is generally poor.7,8 Hepatic surgeons thus must perform hepatic resection on patients with potentially curable L-HCC. Large HCC may have more risk of postoperative liver failure than S-HCC, and large tumor size also suggests a significantly higher risk of recurrence. Therefore, reports of hepatic resection for L-HCC are limited,9–15 and the role of hepatic resection for L-HCC is unclear. This study evaluated the safety and efficacy of hepatic resection for L-HCC and examined the clinicopathologic factors influencing overall and disease-free survival after resection for L-HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1982 to 2001, 1196 consecutive HCC patients underwent surgery at the Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan. One hundred seventeen patients were excluded from the survival study, including 54 HCC patients with incomplete follow-up records and 63 HCC patients who died within a month of surgery (surgical mortality rate, 5.27%; 63 of 1196). The 1196 HCC patients were divided into L-HCC (n = 211) and S-HCC (n = 985) groups. The mean diameter of the tumors in the L-HCC and S-HCC groups was 13.9 ± 3.4 cm (range, 10.2–30 cm) and 4.5 ± 2.4 cm (range, .4–10 cm), respectively. Laboratory tests were performed on the day before surgery. Demographics, symptomatology, physical examination, laboratory data, presence of cirrhosis, Child-Pugh grade, operative findings, pathologic features, disease-free survival, and long-term survival were compared between the L-HCC and S-HCC groups. Clinical features were considered as present or absent; age, >65 vs. <65 years; blood urea nitrogen (BUN), <21 vs. >=21 mg/dL; prothrombin time, <4 vs. >=4 seconds; aspartate aminotransferase (AST), <34 vs. >=34 IU/L; alkaline phosphatase (ALP), <94 vs. >=94 IU/L; indocyanine green (ICG) retention rate at 15 minutes, <10% vs. >=10%; alfa fetoprotein (AFP), <400 vs. >=400 ng/mL; and blood loss, <1 vs. >=1 L.

Resections included segmentectomy, lobectomy, extended lobectomy, subsegmentectomy, and wedge resection. Segmentectomy is a resection of one of the four segments (lateral, medial, anterior, or posterior) of the liver as classified by Healey and Schroy.16 Meanwhile, subsegmentectomy is a resection of a Couinaud segment.17 Histopathologic findings of HCC were divided into four grades according to Edmondsen and Steiner’s system.18 Grades I and II were conditioned as low-grade HCC, and grades III and IV were conditioned as high grade.

All data are presented as percentages of patients or mean with SD. Numerical data were compared by independent two-sample t-tests. Nominal data were compared by Pearson {chi}2 tests or multiple forward stepwise logistic regression, when appropriate. Survival was calculated and plots were constructed according to the Kaplan-Meier method. Nineteen clinicopathologic variables were selected for analysis, including demographic data, clinical features, laboratory data, operative findings, and pathologic features. All parameters were dichotomized on the basis of the most significant parametric factors to examine their influence on survival. Meanwhile, the log-rank test was performed for a statistical univariate analysis of prognostic variables. Multivariate analysis was conducted with Cox’s proportional hazard model by using stepwise selection of variables. All statistical analyses were performed with the SPSS computer software package (Version 10.0; SPSS Inc., Chicago, IL). A value of P <= .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The L-HCC group contained 164 men and 47 women, with a mean age of 47.8 ± 14.3 years (range, 6–88 years). The L-HCC group had younger age distributions and a higher rate of symptoms (dull abdominal pain) than the S-HCC group but had a similar sex ratio (Table 1). Furthermore, the L-HCC group also had a higher percentage of hepatitis B infection and a lower percentage of hepatitis C infection compared with the S-HCC group. Finally, the rate of cirrhosis was lower in the L-HCC group than the S-HCC group, but the percentage of Child-Pugh grade A was similar in both groups. (Table 1)


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  		TABLE 1. Demographic data of 1196 HCC patients with tumor size larger than 10 cm (L-HCC) and smaller than 10 cm (S-HCC)
 
Table 2 lists the results of all preoperative laboratory tests. L-HCC patients revealed increased platelets, AFP, and AST and lower international normalized ratio, direct bilirubin, BUN value, and ICG 15-minute retention ratios compared with S-HCC patients.


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  		TABLE 2. Laboratory data of 1196 HCC patients with tumor size larger than 10 cm (L-HCC) and smaller than 10 cm (S-HCC)
 
Table 3 summarizes the operative, macroscopic, and microscopic findings and outcomes. L-HCC patients received more major hepatectomies, had more intraoperative blood loss, and had greater blood transfusion requirements. Furthermore, compared with S-HCC patients, L-HCC patients had a lower percentage of capsular formation of the tumor and had higher incidences of satellite lesions, vascular invasion, tumor rupture, and tumor recurrence. However, L-HCC patients had tumor grading, tumor clearance margin, postoperative complications, and length of hospital stay similar to those of S-HCC patients (Table 3). The overall mortality rate was 5.2% (63 of 1196) and did not differ between the L-HCC group (4.3%) and the S-HCC group (5.5%; P = .473). Univariate analysis showed younger patients; more dull abdominal pain; higher rates of hepatitis B infection; lower rates of hepatitis C infection; lower rates of cirrhosis; lower ICG values; more prothrombin time <4 seconds; more AST >34 IU/L; more ALP >94; more AFP> 400 ng/mL; more BUN >21 mg/dL; more major hepatectomy; more intraoperative blood loss; greater blood transfusion requirements; absence of tumor capsule formation; and a higher incidence of vascular invasion, satellite lesions, and tumor rupture in L-HCC patients compared with S-HCC patients. However, multivariate logistic regression analysis demonstrated that the presence of symptoms (dull abdominal pain), a lower ICG value, a higher percentage of AFP >400 ng/mL, more major hepatectomy, more absence of tumor capsular formation, a higher incidence of satellite lesions, and vascular invasion were the seven main independent factors that differentiated L-HCC patients from S-HCC patients (Table 4).


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  		TABLE 3. Operative findings, pathological features, and outcomes of 1196 HCC patients with tumor size larger than 10 cm (L-HCC) and smaller than 10 cm (S-HCC)
 

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  		TABLE 4. Univariate and multiple forward stepwise logistic regression analysis of clinicopathological features in 1196 HCC patients with L-HCC and S-HCC
 
All of the 1079 patients who underwent hepatic resection were followed up regularly until death; follow-up ranged from 1.1 to 213.5 months (median, 16.4 months). The 1-, 3-, 5-, and 10-year disease-free survival rates were 32.9%, 18.8%, 12.7%, and 12.7%, respectively, for L-HCC patients and 61.2%, 40.7%, 32.1%, and 15.7%, respectively, for S-HCC patients. Moreover, the 1-, 3-, 5-, and 10-year overall survival rates of L-HCC patients were 48.1%, 24.0%, 16.7%, and 13.1%, respectively, and those for S-HCC patients were 81.4%, 57.3%, 39.5%, and 17.9%, respectively. Compared with the S-HCC group, the L-HCC patients had significantly worse overall and disease-free survival (P = .00001; Fig. 1). Univariate log-rank analysis identified the following as adverse influences on disease-free survival: abnormally increased ALP, AFP, the presence of satellite lesions, and vascular invasion (Tables 5 and 6Go). Meanwhile, multivariate Cox proportional hazard analysis demonstrated that abnormally increased ALP and AFP levels were the only two independent prognostic factors that adversely influenced disease-free survival (Table 7).



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  		FIG. 1. (A) Disease-free and (B) overall survival of 190 patients with hepatocellular carcinoma larger than 10 cm versus that in 889 patients with hepatocellular carcinoma smaller than 10 cm.

 

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  		TABLE 5. Univariate analysis of influence on disease-free survival for HCC patients with tumor > 10 cm (n = 190)
 

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  		TABLE 6. Univariate analysis of influence on disease-free survival for HCC patients with tumor > 10 cm (n = 190)
 

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  		TABLE 7. Cox regression analysis
 
Significant negative influences on overall cumulative survival for L-HCC included a high AST level, a high serum AFP level, blood loss >1 L, tumor rupture, absence of capsule formation, presence of satellite lesions, and vascular invasion (Tables 8 and 9 Go). Multivariate Cox proportional hazard analysis indicated that four independent significant factors adversely influence the overall survival: increased AFP level, blood loss >1 L, tumor rupture, and satellite lesions (Table 7).


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  		TABLE 8. Univariate analysis of influence on overall survival for HCC patients with tumor > 10 cm (n = 190)
 

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  		TABLE 9. Univariate analysis of influence on overall survival for HCC patients with tumor > 10 cm (n = 190)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The L-HCC group differed from the S-HCC group in many respects, including demographics, laboratory data, operative findings, pathologic features, and prognosis. This study also used univariate and multivariate analysis to calculate survival rates for L-HCC in terms of numerous clinicopathologic factors. To our knowledge, this study presents the largest series reported thus far, consisting of >200 patients with resection of L-HCC.

Similar to a previous Hong Kong study, this study demonstrated that L-HCC patients had similar sex ratios, younger age distributions, lower rates of cirrhosis, and a higher frequency of increased AFP.14 This study also showed that L-HCC patients had higher percentages of the presence of symptoms and hepatitis B infection and lower percentages of hepatitis C infection. The younger age distribution among the L-HCC patients may be the main explanation for the demographic differences between the L-HCC and S-HCC groups. Our previous study, a Japanese study, and the Hong Kong study have shown that high positive rates for hepatitis B surface antigen, low positive rates for hepatitis C virus, a low proportion of cirrhosis, and a high frequency of increased AFP levels were noted among the younger HCC patients compared with older HCC patients, suggesting a possible difference in the carcinogenesis of HCC between young and elderly patients.19–22 Hepatitis B virus may be important in HCC development without associated liver cirrhosis.19 This investigation reached similar findings. However, multivariate logistic regression analysis did not reveal any difference between the L-HCC and S-HCC groups in terms of age, hepatitis status, or cirrhosis. Significant dull abdominal pain was the only independent factor relating to patients with L-HCC. Such symptoms should lead physicians to a diagnosis of HCC, particularly for high-risk patients in an endemic area.

Major differences in preoperative laboratory data were noted between the two groups; however, AFP >400 ng/mL and lower ICG values were the only two of the seven independent factors that differentiated L-HCC from S-HCC patients. The lower portion of cirrhosis in the L-HCC group compared with the S-HCC group explains the lower ICG value in that group.

A previous report from Hong Kong has shown that L-HCC patients may experience more major hepatectomy, more blood loss, more blood transfusion, less capsule formation, and a higher frequency of recurrence, satellite lesions, vascular invasion, and tumor rupture.14 Larger tumor size, greater technical challenges, absence of liver cirrhosis, and better liver function reserve increase the likelihood of major hepatectomy, as well as increasing blood loss and blood transfusion and increasing the frequency of recurrence in L-HCC patients. Tumor capsule formation is less common in L-HCC patients. Tumor capsule formation is considered as occurring at an early stage of tumor development. The higher the percentage of well-encapsulated tumor, the lower the incidence of tumor emboli and the better the tumor cell differentiation.23 L-HCC patients also displayed more tumor rupture, satellite lesions, and vascular invasion. HCC is characterized by its propensity for vascular invasion. Notably, Yamagata et al.24 claimed that increased intratumoral pressure with a high incidence of venous invasion was the main reason for HCC with rupture; this would explain the higher rates of tumor rupture in L-HCC patients. The present study confirmed this observation. However, multivariate logistic regression analysis in this study showed that a higher incidence of major hepatectomy, a lower incidence of tumor capsular formation, and a higher incidence of vascular invasion and satellite lesions differentiated L-HCC from S-HCC. Moreover, operative morbidity, mortality, and hospital stay were similar between the L-HCC and S-HCC groups, suggesting that resection is a safe and rational treatment in selected patients with L-HCC.

This study confirmed a poor prognosis for L-HCC patients undergoing hepatectomy compared with S-HCC patients in terms of overall and disease-free survival. Applying multivariate Cox proportional hazard analysis to data from this investigation revealed that long-term disease-free survival depends on preoperative liver function tests (ALP) and tumor marker levels. Meanwhile, long-term overall survival depends on preoperative tumor markers, blood loss, tumor rupture, and tumor multiplicity.

Our previous studies have demonstrated that an increased ALP level adversely influences long-term overall and disease-free survival for HCC patients with cirrhosis.25 This study showed only that an increased ALP level adversely affected disease-free survival for L-HCC patients undergoing hepatectomy. An increased ALP level may indicate the presence of liver disease and bile duct obstruction. Furthermore, a high preoperative ALP level may be correlated with increased mortality after hepatectomy for metastatic disease.26

AFP >400 ng/mL also predicts poor disease-free and overall survival for L-HCC patients. From the world literature on factors affecting the prognosis of surgically treated patients, previous European and Japanese reports emphasize the importance of the preoperative AFP value.27,28 The Italian group proposed the Cancer of the Liver Italian Program scoring system for the staging for HCC, based partly on the AFP value.27 The specific reason for the increased AFP level worsening the prognosis is uncertain. AFP may be a unique biological variable that expresses grade of malignancy and has suppressive effects on the immunological reaction directed against tumor cells.29,30 Some authors suggest that a high serum AFP level is closely related to the growth and development of hepatitis virus–related HCC.31

All previous studies on the effect of intraoperative blood loss after HCC resection have demonstrated that lower perioperative blood loss contributes to long-term recurrence-free survival.32 Perioperative blood transfusion is related to a shorter disease-free survival due to the immunosuppressive effect of transfusion.33 However, this study indicated that blood loss exceeding 1 L during surgery was a negative factor for long-term overall survival for L-HCC patients who received hepatectomy. To reduce bleeding during hepatic resection and avoid the need for transfusion, highly skilled surgery is mandatory, especially for L-HCC. Such highly skilled surgery includes portal triad clamping, central venous pressure reduction, and the selective anterior approach with or without thoracic extension during hepatic resection.34 The quality of surgical performance directly influences the long-term prognosis of HCC resection patients. Our previous study demonstrated that hepatic resection for ruptured HCC can achieve comparable long-term overall and disease-free survival to elective surgery in selected cases.35 However, this work revealed that L-HCC patients with rupture who underwent hepatic resection had significantly worse overall survival compared with the S-HCC group. Multivariate analysis has consistently identified tumor multiplicity as the main factor that adversely affects the prognosis for L-HCC patients. Multiple nodules result from either multicentric carcinogenesis or intrahepatic metastasis. The presence of microsatellites had a significant negative influence on the long-term outcome of patients after hepatic resection of HCC.27,28,36

In conclusion, hepatic resection, when feasible, is safe and is the preferred treatment for L-HCC patients. However, the overall and disease-free survival for L-HCC are worse than for S-HCC. Disease-free survival for L-HCC patients undergoing hepatic resection is significantly influenced by a high value of ALP and AFP. Overall survival for L-HCC patients undergoing hepatic resection is significantly influenced by a high value of AFP, blood loss, tumor rupture, and satellite lesions.


   FOOTNOTES
 
Disease-free survival for patients with hepatocellular carcinoma larger than 10 cm (L-HCC) undergoing hepatic resection is significantly influenced by a high value of alkaline phosphatase and by alfa fetoprotein (AFP). Overall survival for L-HCC patients undergoing hepatic resection is significantly influenced by a high value of AFP, blood loss, tumor rupture, and satellite lesions.

Received for publication March 11, 2003. Accepted for publication July 3, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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