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© 2001 American Society for Clinical Oncology Clinicopathologic Features of Long-Term Survivors and Disease-Free Survivors After Resection of Hepatocellular Carcinoma: A Study of a Prospective CohortFrom the Center for Study of Liver Disease, Departments of Surgery and Pathology, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong, China. Address reprint requests to Ronnie Tung-Ping Poon, MS, FRCS (Edin), Department of Surgery, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, China; email: poontp{at}hkucc.hku.hk
PURPOSE: This study aims to clarify the clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The clinicopathologic features of 5-year survivors and disease-free survivors were elucidated in a cohort of 230 patients prospectively observed for > 5 years (64 to 192 months) after curative resection of HCC.
RESULTS: The incidence of 5-year overall and disease-free survivors were 37% (85 of 230) and 20% (45 of 230), respectively. Clinicopathologic features associated with 5-year survivors included female sex (P = .024), preoperative serum albumin CONCLUSION: This study shows that long-term disease-free survival > 5 years after resection of HCC can be achieved in patients with favorable tumor characteristics. Early pTNM stage was the most reliable predictor of both long-term overall and disease-free survivors.
HEPATOCELLULAR carcinoma (HCC) is one of the most common malignancies in Asia and Africa.1 The rising incidence of HCC has also become an important issue in Western countries.2,3 Hepatic resection is the treatment of choice for HCC, although liver transplantation has been established as an alternative curative treatment for HCCs less than 5 cm.4,5 During the past decade, hepatic resection for HCC has evolved into a safe procedure with an operative mortality rate close to zero as a result of improved surgical techniques and perioperative care.6,7 However, the long-term prognosis remains unsatisfactory because of a high incidence of recurrence even after curative resection of HCC, with a 5-year actuarial recurrence rate of 75% to 100% reported in the literature.8 The prospect of long-term survival and cure has become a major concern in the selection of patients for hepatic resection, particularly when other treatment options such as liver transplantation, transarterial chemoembolization (TACE), and local ablative therapies are available. The elucidation of prognostic factors of long-term survival not only provides guidance in the choice of treatments but may also help select patients for adjuvant therapy and allow better prognostic counseling. Several recent studies have assessed the survival results and prognostic factors after resection of HCC by use of actuarial analysis.6,9-15 These studies reported estimated 5-year survival rates of 26% to 50% and disease-free survival rates of 13% to 29%.6,9-15 More precise data on the long-term survival outcome and prognostic factors can only be obtained by an analysis of actual long-term survivors (eg, those surviving for > 5 years). A cohort of patients with long enough follow-up and sufficient number of 5-year survivors is required for such a study. Bearing in mind that in many centers, hepatic resection became a standard treatment for HCC only in the last decade or so, it is understandable that reports of such data are scarce in the literature. Although few previous studies have alluded to the features of 5-year or 10-year survivors after resection of HCC,16-19 to our knowledge, none have analyzed the clinicopathologic features of long-term disease-free survivors. The elucidation of the characteristics of the long-term overall survivors is undoubtedly important, but it is of equal interest to clarify the clinicopathologic features of long-term disease-free survivors, who are deemed to have benefited from the curative intent of surgical resection. Both overall and disease-free survival rates are important outcome measures to be considered in deciding the best treatment option for a patient with HCC. We studied a prospective cohort of 230 patients who have been observed for more than 5 years to elucidate the clinicopathologic features of long-term survivors as well as long-term disease-free survivors. On the basis of the results of the study, the role of hepatic resection for HCC in patients with different clinicopathologic characteristics is elaborated, and the implications of our findings on future strategies to improve long-term survival results after resection of HCC are discussed.
Between January 1985 and June 1995, 1,320 patients with HCC were managed in the Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong. A total of 290 (22%) patients underwent hepatic resection. Thirty-three (11%) patients died in the postoperative period within the same hospital admission. The causes of hospital deaths included liver failure (n = 21), intra-abdominal sepsis (n = 7), intra-abdominal hemorrhage (n = 3), myocardial infarction (n = 1), and pericardial effusion (n = 1). The hospital mortality rate has been reduced from 19% (23 of 122) in the period 1985 to 1990 to 5.9% (10 of 168) in the period 1991 to 1995. The 33 patients with hospital mortality were excluded from the present study of long-term survival results. In addition, 19 patients with palliative resection (presence of macroscopic residual tumor) and eight patients without complete follow-up data were also excluded from this study. The remaining 230 patients underwent potentially curative resection, defined as macroscopically complete resection of the tumor, and all have been observed for more than 5 years from the time of resection (median follow-up, 102 months; range, 64 to 192 months). The mean age of the patients at the time of surgery was 53.3 years (SD, 12.4 years; range, 18 to 82 years); 197 patients were men and 33 were women. The majority of HCCs in our locality were related to hepatitis B viral infection, and serum hepatitis B surface antigen (HBsAg) was positive in 178 (77%) patients. None of the HCCs was the fibrolamellar variant.
The criteria for resectability were absence of extrahepatic metastasis, absence of main portal vein tumor thrombus, anatomically resectable unilobar or bilobar disease, and adequate liver function reserve. Liver function was assessed by liver biochemistry and Child’s grading, and after 1987, the indocyanine green clearance test was also used. We performed major hepatic resection (resection of All patients were prospectively observed in a HCC clinic and regularly monitored for recurrence by assessment every 3 months for serum alpha fetoprotein level and ultrasonography or CT scan. Diagnosis of recurrence was based on a combination of elevated serum alpha fetoprotein level and typical imaging findings in CT scan, hepatic angiography, or postlipiodol CT scan. Percutaneous fine-needle aspiration cytology was performed to confirm diagnosis in uncertain cases. Intrahepatic recurrence was managed aggressively with a policy of repeating resection if possible, and TACE or percutaneous ethanol injection if unresectable. The details of our policy of management for recurrent tumors have been reported previously.21 With an aim of constantly monitoring the postoperative and survival results in the patients we studied, the clinicopathologic, operative, and follow-up data of all patients with hepatic resection of HCC in our unit have been prospectively collected as computerized data during the study period. For the purpose of this study, the pathologic tumor-node-metastasis (pTNM) stage of each patient has been reclassified according to the latest (1997) edition of the International Union Against Cancer (UICC) tumor-node-metastasis classification (Table 1).22
Comparisons of clinicopathologic features between 5-year survivors and those who died within 5 years after resection of HCC, and between 5-year disease-free survivors and those who developed recurrent disease within 5 years, were performed by the  2 test with Yates’ correction (or where appropriate, Fisher’s exact test). Multivariate analysis via a logistic regression model was performed to identify the independent factors predictive of 5-year survivors and 5-year disease-free survivors, respectively. All statistical analyses were performed with SPSS for Windows 9.0 software (SPSS, Chicago, IL). P < .05 was considered statistically significant.
Long-Term Overall and Disease-Free Survival Results Eighty-five (37%) of the 230 patients survived for more than 5 years after hepatic resection (survival range, 64 to 192 months by the time of analysis). The other 145 patients died within 5 years after resection; 136 (94%) patients died as a result of intrahepatic (n = 107) or extrahepatic (n = 29) recurrent disease, and nine (6%) patients died as a result of complications of cirrhosis without evidence of recurrent disease. Of the 85 patients who survived for 5-years, 45 were free of disease at 5 years, comprising 20% of the total 230 patients. The other 40 patients had developed recurrence at a median of 24 months (range, 4 to 55 months) after initial resection of HCC but lived for more than 5 years. Thirty-three of these 40 patients had intrahepatic recurrences, which were solitary in 24 and multifocal in nine patients (seven patients with two nodules and two patients with three nodules). The intrahepatic recurrences were treated by repeat resection (n = 3), TACE (n = 26), or percutaneous ethanol injection (n = 4). The other seven patients had lung recurrences, which were solitary in four patients and were treated by surgical excision, whereas the other three patients had multiple lesions and were treated with systemic chemotherapy. Eight of the 45 patients who were 5-year disease-free survivors subsequently developed intrahepatic recurrence at a follow-up period of 64 to 132 months (median, 71 months), whereas the other 37 patients remained disease-free after a follow-up of 64 to 180 months (median, 92 months). Apart from the nine patients who died of cirrhotic complications, another 28 patients who were initially assigned to Child’s grade A status had deterioration of liver function into Child’s grade B status during the follow-up period of the study, including 24 patients who subsequently developed recurrent disease and four patients who remained disease-free by the time of analysis. Eighty-five patients underwent surgery before June 1990 and have been observed for more than 10 years, of whom 16 (19%) have survived for more than 10 years after resection of HCC, and 10 patients (12%) have survived without recurrence for more than 10 years. Six patients developed recurrence at a median of 34 months (range, 6 to 101 months) after initial surgery but survived for more than 10 years. Five of these six patients had solitary intrahepatic recurrence and were treated with repeat resection (n = 2) or TACE (n = 3), whereas the other patient had a solitary lung recurrence treated by surgical excision. Table 2 lists the clinicopathologic features of 10-year disease-free survivors. Five of the 10 disease-free survivors had tumors of 10 cm or more, and pathologic features of invasive tumors, such as the presence of venous invasion and microsatellite tumor nodule, were observed in some of these 10-year disease-free survivors. One patient with positive histologic resection margin has survived without recurrence for more than 12 years. This patient received adjuvant transarterial chemotherapy after surgery. The only pathologic feature that definitely precluded 10-year disease-free survival was pTNM stage IVA disease.
Table 3 lists the incidences of 5-year overall and disease-free survivors in subgroups of patients stratified by tumor size or pTNM stage. A breakdown analysis of the survival results by tumor size revealed that the best outcome was observed in patients with tumors less than 5 cm. Among the 59 patients with HCC less than 5 cm, four had macroscopic portal or hepatic venous invasion. Excluding these four patients, the 5-year survivor rate of patients with HCC less than 5 cm and without macroscopic venous invasion was 64% (35 of 55), and the 5-year disease-free survivor rate was 35% (19 of 55). There was progressive decrease in 5-year survivor and disease-free survivor rates with increasing tumor size. However, even among patients with tumor size more than 10 cm, 20% patients survived for more than 5 years, and 10% patients survived disease-free for more than 5 years.
Analysis of survival results stratified by pTNM stage indicated a progressive decrease in 5-year overall and disease-free survivor rates from stage I to stage IVA. Notably, there were no 5-year disease-free survivors amongst the 45 stage IVA patients, including five with multiple bilobar tumors, 17 with tumor involvement of a major branch of portal or hepatic vein, four with direct invasion into adjacent organs, and 19 with preoperative or intraoperative tumor rupture. However, five patients with stage IA disease, who all developed intrahepatic recurrence within 1 year after surgery and were managed by TACE, survived for more than 5 years (range, 64 to 123 months).
Clinicopathologic Features of 5-Year Survivors and 5-Year Disease-Free Survivors
Table 5 shows a comparison of the clinicopathologic features between 5-year disease-free survivors and patients who developed recurrence within 5 years after resection of HCC. Nine patients who died of complications of cirrhosis without evidence of recurrence were excluded from this analysis. One host factor (serum AST < 50 U/L) and five tumor factors (tumor size < 5 cm, presence of tumor capsule, absence of venous invasion, absence of microsatellite tumor nodule, and pTNM stage I or II) were significant factors associated with 5-year disease-free survivors. Neither cirrhosis nor resection margin width had significant influence on the 5-year disease-free survival results, although there was a trend toward a higher proportion of patients with histologically negative resection margin among the 5-year disease-free survivors. Two patients with positive microscopic resection margin survived disease-free for more than 5 years (96 and 132 months, respectively), and both received postoperative adjuvant transarterial chemotherapy. By multivariate analysis, only tumor pTNM stage was identified as an independent factor predictive of 5-year disease-free survival (IIIA/IVA v I/II; risk ratio, 15.40; 95% confidence interval, 5.80 to 45.40; P < .001).
Hepatic resection and liver transplantation are currently the only potentially curative treatments available for HCC. The 5-year overall and disease-free survival results have been widely accepted as the measures of the efficacy of these surgical treatments in achieving long-term survival and cure.5,23 This study of a prospective cohort of patients with follow-up for more than 5 years revealed an absolute 5-year survivor rate of 37% and disease-free survivor rate of 20%, which could serve as more precise reference data for future studies pertaining to the prognosis after resection of HCC. Among 85 patients observed for more than 10 years, the 10-year overall survivor rate of 19% and the disease-free survivor rate of 12% were observed. The 10-year survivor rate in this study was higher than that of 7.7% reported in a Japanese study.19 However, it is important to note that 77% of our Chinese patients had hepatitis B–related HCC, whereas only 16% of patients in that Japanese study were HBsAg positive.19 In fact, in the latter study, HBsAg positivity was identified as a significant factor in favor of long-term survivors, and the authors suggested that patients with hepatitis B–related HCC might have a lower incidence of multicentric occurrence than patients with chronic hepatitis C infection.19 The subgroup analyses help clarify the role of hepatic resection in patients with different tumor sizes and stages. It is necessary to consider tumors of size less than and more than 5 cm separately because liver transplantation is an alternative curative treatment for the former group, provided macroscopic venous invasion is absent.4 For patients with HCC less than 5 cm with Child’s C cirrhosis, there is no doubt that transplantation is the treatment of choice. However, for patients with small HCC associated with Child’s A cirrhosis or with a noncirrhotic liver, it remains controversial whether hepatic resection or transplantation should be offered.24 No data on the incidence of actual 5-year survivors after transplantation for HCC have been reported yet. The estimated actuarial 5-year survival rates after transplantation for HCC less than 5 cm in size without macroscopic venous invasion have been reported to be 60% to 70% in recent series.15,25-27 In the patients we studied with similar tumor characteristics, the 5-year survivor rate of 64% after resection was comparable, although the 5-year disease-free survivor rate was inferior to the actuarial disease-free survival rates after transplantation.15,25-27 In view of the shortage of organ donors, it seems reasonable to consider resection as the initial treatment for small HCC in patients with preserved liver function, and reserve transplantation as a salvage treatment for intrahepatic recurrence or progressive liver failure.28,29 The role of hepatic resection for large HCC has remained controversial because of poor survival results previously documented.30 Even in a recent review article, it has been suggested that surgical resection should be restricted to patients with tumors 5 cm or less in size.1 It is generally accepted that tumor size more than 5 cm is a contraindication for liver transplantation or local ablative therapy such as percutaneous ethanol injection,1,4 and the 5-year actuarial survival rate after TACE for HCC more than 10 cm was less than 10%.31 The current study shows that for tumors more than 5 cm in size, surgical resection resulted in a 5-year survivor rate of 29% and a 5-year disease-free survivor rate of 15%. Even for patients with tumor larger than 10 cm, 20% survived for more than 5 years, and 10% survived disease-free for more than 5 years. As listed in Table 2, five of the ten 10-year disease-free survivors had HCC of 10 cm or more. Hence, large tumor size should not be regarded as a contraindication to surgical resection, which is currently the only potentially curative treatment for patients with large HCC. Both long-term overall and disease-free survivor rates were closely related to pTNM stage. It is noteworthy that there were no 5-year disease-free survivors among 45 stage IVA patients. We have reclassified all tumors by means of the criteria provided in the latest edition of the UICC pTNM classification, in which tumors with invasion into adjacent organs or perforation of visceral peritoneum were included in stage IVA in addition to bilobar multiple diseases and invasion into a major portal vein or hepatic vein branch. A previous study failed to demonstrate the prognostic significance of the UICC pTNM stage in patients undergoing resection of HCC.32 Our study demonstrates that the revised UICC pTNM classification is a reliable staging system for patients with HCC undergoing surgical resection and should be used more widely for stratifying patients’ prognosis. A recent study has proposed surgical resection as an effective and standard therapy for stage IVA HCC.33 In that study, the actuarial 5-year survival rate of stage IVA patients was 15%, but the disease-free survival rate was not evaluated. Our data suggest that hepatic resection should not be regarded as curative in stage IVA disease. However, five patients (11%) with stage IVA disease survived for more than 5 years despite early recurrence. The recurrent tumors in these five patients were treated with TACE, which has been shown to contribute to prolonged survival after recurrence of HCC.21,31 Because no other effective treatments are currently available for this group of patients, resection followed by aggressive management of recurrence seems to be the best option for stage IVA disease. A comparison of the clinicopathologic features between 5-year survivors and nonsurvivors in the patients we studied revealed that features related to tumor invasiveness were the main factors predictive of long-term survivors. We found by multivariate analysis that tumor stage was the only significant prognostic factor predictive of long-term survivors. Our results were in contrast to a Japanese study that found that such host factors as viral status and liver function were the main factors associated with long-term survivors, and none of the tumor factors were found to have significant prognostic influence.19 The disparity may be related to different patient populations in terms of viral etiology of HCC, as mentioned above. Although patients with hepatitis C infection are more prone to multicentric recurrence, patients with hepatitis B–related HCC may have a higher incidence of metastatic recurrence related to tumor invasiveness.34 In a study of predominantly hepatitis C–related HCC, patients with cirrhosis were found to have poorer survival results than patients without cirrhosis because of a higher incidence of multicentric recurrence.35 In the current study, the presence of cirrhosis did not seem to jeopardize the chance of long-term survival or disease-free survival. As noted in Table 2, five of the 10-year disease-free survivors had a cirrhotic liver. This observation corroborates the finding of our previous study that actuarial survival of patients with cirrhosis was comparable to patients without cirrhosis after resection of hepatitis B–related HCC.36 In patients with hepatitis B–related HCC, new approaches of inhibiting intrahepatic metastasis, such as intra-arterial lipiodolized 131-iodine and adoptive immunotherapy,37,38 may be essential to enhance the long-term survival results. On the other hand, strategies that aim at suppression of multicentric recurrence, such as the use of acyclic retinoid or interferon,39,40 may be more applicable to patients with hepatitis C–related HCC. This study clearly demonstrates that tumor recurrence, especially intrahepatic recurrence, is the main cause of death in the long term after hepatic resection. Pathologic features related to tumor invasiveness were the main determining factors of long-term disease-free survival. Among the host factors, only a low preoperative serum AST level was predictive of 5-year disease-free survivors. A high serum transaminase level may reflect active hepatitis activity in the nontumorous liver, but it may also be due to necrosis of tumor cells in advanced HCCs.41 Multivariate analysis indicated that pTNM stage was the only factor predictive of 5-year disease-free survivors. Except for stage IVA disease, other pathologic features of invasive disease were not absolutely exclusive of 5-year or even 10-year disease-free survival. It is particularly noteworthy that positive histologic margin did not preclude the prospect of 5-year or 10-year disease-free survival. Some surgeons considered a clear histologic margin a necessary criterion for curative resection of HCC,42 whereas others defined curative resection simply as complete macroscopic resection of HCC.11,12,43 Although such definitions are somewhat arbitrary, our finding suggests that a positive histologic margin should not be regarded as incompatible with cure. Both of the 5-year survivors with positive histologic margin in this study received postoperative adjuvant regional chemotherapy. Future prospective studies should clarify whether postoperative regional chemotherapy is of benefit in patients with positive histologic margin. This study shows that cure in terms of disease-free survival for more than 5 or even 10 years can be expected in a proportion of patients after resection of HCC, especially in those with favorable tumor characteristics. However, it should be noticed that some patients could develop recurrence after 5 or even 10 years of disease-free survival. In a strict sense, the concept of cure may not be applicable to resection of HCC because late recurrence can occur because of multicentric tumors in the liver remnant. Hence, it is important to continue long-term surveillance of the patients for recurrence. As illustrated by the data in this study, aggressive management of recurrent disease by surgical resection if possible, or otherwise by nonsurgical modalities such as TACE, could result in prolonged survival in patients with recurrent tumors. Treatment of recurrence may also have benefit to patients in terms of quality of life. A recent study by the authors has shown that hepatic resection of HCC improved patients’ quality-of-life scores, and the scores remained better than preoperative scores even in patients whose disease recurred.44 Eradication or effective control of recurrent tumors can play an important role in maintaining quality of life among patients whose disease recurs. In conclusion, this study of a cohort of patients with extended follow-up helps clarify the long-term prognosis after resection of HCC by providing valuable data on the actual incidence of 5-year and 10-year survivors and disease-free survivors. It must be emphasized that the long-term survival results in this study were predominantly those of hepatitis B–related HCC. The clinicopathologic features of long-term overall survivors and disease-free survivors have been elucidated in detail, and early pTNM stage was identified as the most reliable predictor of both long-term overall and disease-free survivors in this group of patients. Stage IVA disease was found to be the only pathologic feature that precluded long-term disease-free survival. To improve the long-term survival results after resection of HCC, it is imperative that effective postoperative adjuvant therapies are developed to prevent recurrence in patients with advanced HCC.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 g/L (P = .033), AST < 50 u/L (P = .001), tumor < 5 cm (P = .001), solitary tumor (P = .035), encapsulated tumor (P = .021), no venous invasion (P = .001), no microsatellite nodule (P = .001), and early pathologic tumor-node-metastasis (pTNM) stage (I or II, P < .001). Features favoring 5-year disease-free survivors were preoperative serum AST < 50 u/L (P = .007), tumor < 5 cm (P = .005), encapsulated tumor (P = .007), no venous invasion (P < .001), no microsatellite nodule (P = .001), and early pTNM stage (I or II, P < .001). By multivariate analysis, pTNM stage was the only significant predictive factor for both overall and disease-free survival. 
