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10.1245/ASO.2005.03.098
Annals of Surgical Oncology 12:289-297 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Prognostic Evaluation of the New American Joint Committee on Cancer/International Union Against Cancer Staging System for Hepatocellular Carcinoma: Analysis of 112 Cirrhotic Patients Resected for Hepatocellular Carcinoma

Giovanni Ramacciato, MD, FACS1, Paolo Mercantini, MD1, Nicola Cautero, MD2, Nicola Corigliano, MD1, Fabrizio Di Benedetto, MD2, Cristiano Quintini, MD2, Giorgio Ercolani, MD1, Giovanni Varotti, MD1, Vincenzo Ziparo, MD1 and Antonio Daniele Pinna, MD, FACS2

1 II° Faculty of Medicine and Surgery, University of Rome "La Sapienza," Azienda Ospedaliera Sant’Andrea, UOC Chirurgia A. Via di Grottarossa 1035, 00189 Rome, Italy
2 Department of Genral Surgery, Liver and Multivisceral Transplantation, University of Modena and Reggio Emilia, Largo del Pozzo 71, Modena, Italy

Correspondence: Address correspondence and reprint requests to: Giovanni Ramacciato, MD, FACS; E-mail: giovanni.ramacciato{at}uniroma1.it.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In 2002, the American Joint Committee on Cancer and the International Union Against Cancer redefined the T-classification for hepatocellular carcinoma, shifting the cutoff value for tumor size from 2 to 5 cm and giving more emphasis to vascular invasion.

Methods: A retrospective cohort study was conducted on 223 consecutive patients with hepatocellular carcinoma observed between 1990 and 2002. One hundred twelve were resected and considered for retrospective analysis. Univariate and multivariate analyses were performed on several clinicopathologic variables. After classification according to each staging system, the long-term survival of different stages was compared. The prognostic value of each staging system was further evaluated by entering each stage, in turn, into the Cox regression model with other clinicopathologic variables. The median follow-up was 19 months.

Results: On multivariate analysis, the viral etiology of cirrhosis and the presence of multiple nodules were independent prognostic factors. When the new staging system was entered into the multivariate analysis, it was the only independent factor (P = .02). When stratified according to the old tumor-node-metastasis system, there were no significant differences in the survival between stage I and II (P = .14) or between stage IIIA and IVA (P = .33); only the survival of stage II and IIIA was different (P < .01). When stratified according to the new tumor-node-metastasis system, there were significant differences between stage I and II (71.7% vs. 54.7%; P = .02).

Conclusions: The new staging system is a more reliable and objective method for T classification. It is easy to use in clinical practice and is better at stratifying curatively resected patients with respect to prognosis.

Key Words: Hepatocellular carcinoma • Liver resection • AJCC/UICC staging system • Retrospective analysis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Until now, the most widely used staging system for evaluating the prognosis of patients who undergo hepatic resection for hepatocellular carcinoma (HCC) in Western countries is the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) tumor-node-metastasis system.1,2 The 5th edition (1997) of tumor-node-metastasis staging for HCC uses pathologic characteristics of tumors—including size, number, and location; presence of vascular invasion; perforation of visceral peritoneum; and invasion of adjacent organs—as criteria for T-staging. However, the prognosis of HCC is unique among gastrointestinal cancers, because it is influenced not only by the tumor characteristics, but also by the underlying liver status. This resulted in the necessity for a new and more accurate staging system. The Cancer of the Liver Italian Program (CLIP) proposed in 1998 a new prognostic system, which was validated by Farinati et al.3 2 years later. More recently, Vauthey et al.,4 analyzing a combined database of 557 patients resected for HCC in 4 centers (2 in the United States, 1 in France, and 1 in Japan), suggested that the 5th edition of the tumor-node-metastasis system is unnecessarily complex and fails to stratify patients adequately with respect to prognosis. According to this consideration, the AJCC/UICC tumor-node-metastasis staging system for primary liver cancer has been revised in the new 6th edition.5 This study evaluates the prognostic value of the new AJCC/UICC tumor-node-metastasis staging system with respect to the old 5th edition in a series of 112 Italian cirrhotic patients who underwent hepatic resection for HCC.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between June 1990 and December 2002, 223 consecutive patients with HCC were observed at the Liver and Multivisceral Transplant Unit, University of Modena, and the Department of Surgery "Pietro Valdoni," University of Rome "La Sapienza." The preoperative diagnosis of HCC was based mainly on computed tomography (CT; or, from 1998, spiral CT), the serum alfa fetoprotein (AFP) level, and hepatic ultrasound-guided fine needle biopsy. The serum AFP level was available in only 55 patients (49%). Needle biopsy was not performed in patients with an increased serum level of AFP, and typical imaging of HCC was performed to avoid needle tract seeding of tumor cells. Clinicopathologic and follow-up data for each patient were recorded in a computerized database, which was regularly updated for tumor recurrence and survival status. The grading system of Child-Turcotte was applied to all patients with cirrhosis. Resection was considered "major" if three or more segments were removed, according to Couinaud’s classification. Intraoperative ultrasound was routinely performed on all patients to detect tumor invasion into the major branches of the portal or the hepatic veins and the presence of lesions in the contralateral lobe. After resection, we routinely performed frozen section investigations; tumor clearance of at least 1 cm at the resection margins was considered adequate to define the surgical procedures as curative (R0). Hospital mortality was defined as death within 30 days after operation, including operative deaths. Tumor recurrence was considered as evidence of hepatic tumoral lesions after a curative resection. All patients discharged were followed up every 3 months in the first year and every 6 months thereafter. The follow-up consisted of physical examination, blood tests, serological liver function tests, detection of serum AFP levels, and liver ultrasound or CT scan. The last follow-up evaluation was performed on June 30, 2003.

The patients were classified separately according to the previous (5th edition) AJCC/UICC tumor-node-metastasis staging system and the new (6th edition; 2002) AJCC/UICC tumor-node-metastasis staging system. Distribution by T-stage for both staging systems is shown in Tables 1GoGoGo to 4Go. Because there is no difference between the UICC and AJCC tumor-node-metastasis classifications, we will refer to this as "AJCC" for brevity.


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  		TABLE 1. International Union Against Cancer Tumor-Node-Metastasis Classification of Primary Liver Cancer, 5th Edition (1997)
 

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  		TABLE 2. Staging system, UICC 5th Edition (1997)
 

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  		TABLE 3. International Union Against Cancer Tumor-Node-Metastasis Classification of Primary Liver Cancer, 6th Edition (2002)
 

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  		TABLE 4. Staging system, UICC 6th Edition (2002)
 
Continuous data were expressed as median and interquartile range. Survival curves were calculated using the Kaplan-Meier method and compared by using the log-rank test. For comparison of survival, continuous variables were dichotomized by using the respective medians as the cutoff values. Only the variables that were significant in the univariate analysis were entered into a Cox regression model to identify the clinicopathologic factors with independent prognostic significance. In the evaluation of these factors with regard to long-term survival and to disease-free survival, the patients with hospital mortality (within 30 days) and those with histological involvement of resection margins were excluded from the analysis. After classification according to each staging system, the long-term survivals of different stages were compared. Concerning the new staging system, because of the lack of a sufficient number of patients classified as stage III and IV, only the difference between stage I and II was evaluated. The prognostic value of each staging system was further evaluated by entering each, in turn, into the Cox regression model with other clinicopathologic variables. All statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL). Differences were considered significant if the P value was <0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifty-eight patients (26%) were judged not suitable for surgical treatment at diagnostic work-up; these patients were referred to radiology units for local ablative therapies or received simple palliative treatment. Twenty-five patients (11%) fulfilled the criteria for liver transplantation; among these, 15 were treated with orthotopic liver transplantation, and 10 underwent living related liver transplantation. One hundred forty patients (63%) underwent surgery, and 112 of them could be resected (resectability rate, 80%). This group of patients was considered for the retrospective analysis.

The demographic and clinicopathologic characteristics of the 112 patients in the study cohort are listed in Table 5Go. Data regarding hepatitis and serology were available for all patients. There was more hepatitis C–positive serology (61 patients; 54.5%) compared with hepatitis B–positive serology (22 patients; 19.6%). Among 112 patients, liver cirrhosis was present in 101 patients (90%); most of them were classified as Child class A or B.


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  		TABLE 5. Clinicopathologic characteristics of 112 patients
 
The overall morbidity rate was 26% (29 patients). The most frequent complications were infections (abdominal abscess, pleural effusion, and broncho-pneumonia), liver failure, hemorrhage, ascites, and mild lower limb edemas. The overall hospital mortality rate was 10.7% (12 patients). According to preoperative Child classification, hospital mortality rates were 10.3%, 12%, and 11% for Child A, B, and C patients, respectively. According to the extension of the resections, hospital mortality rates were 20% (7 of 34 patients) and 6.4% (5 of 78 patients) for major and minor resections, respectively. The most frequent causes of hospital death were postoperative liver failure and massive hemoperitoneum with disseminated intravascular coagulation. At the final pathologic examination, 79 patients (70%) had a trabecular HCC, 1 (1%) had the fibrolamellar type, 10 (9%) had the mixed trabecular/acinar type, and 22 (20%) had an undifferentiated necrotic bulk. Microscopic vascular invasion was found in 23 patients (21%), and a peritumoral fibrous capsule was present in only 10 patients (9%).

The median follow-up was 19 months (interquartile range, 10–36 months). The 1-, 3-, and 5-year overall survival rates were 86.6%, 70.3%, and 60.6%, respectively (Fig. 1Go). Tumor recurrence appeared in 27 patients (32.5%) and was the leading cause of death in 21 patients (18.8%). The 1-, 3-, and 5-year disease-free survival rates were 86.3%, 58.1%, and 40.7%, respectively. A total of 32 patients (28.6%) died during the follow-up period. Five patients (4.5%) were lost to follow-up at 2, 11, 12, 34, and 45 months, respectively. Up to the last follow-up date, 63 patients (56.3%) were alive: 45 (40.2%) are disease free.



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  		FIG. 1. Overall survival rates for 12, 36, and 60 months.

 
Table 6Go shows the prognostic influence of clinicopathologic characteristics on univariate analysis in patients curatively resected for HCC. Whenever we included patients not curatively resected into the statistical analysis, the involvement of resection margins became a very strong prognostic factor and made the other clinicopathologic variables statistically not significant regarding long-term survival. Among the factors evaluated, viral etiology of cirrhosis (P = .03), presence of multiple nodules (P = .02), and vascular invasion (P = .05) were found to be related to a worse long-term survival. When entered into the multivariate analysis, only the viral etiology of cirrhosis and the presence of multiple nodules were confirmed as independent prognostic factors.


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  		TABLE 6. Overall survival: univariate analysis of prognostic clinicopathologic factors
 
Concerning disease-free survival, none of the analyzed clinicopathologic factors resulted in statistical significance. Stage migrations resulting from reclassifying the resected HCC from the old to the new staging system are listed in Table 7Go. All 10 patients classified as stage I (T1N0) according to the old staging system were confirmed as stage I in the new classification. However, among 66 patients classified as stage II (T2N0) in the old system, 61 (92.4%) were downstaged to stage I (T1N0) in the new system, and the remaining 5 patients (7.6%) were confirmed as stage II (T2N0) in the new classification. Among 24 patients classified as stage IIIA in the old system, downstaging was observed in 23 patients (96%): 22 became stage II, and 1 became stage I according to the new classification. The only patient classified as stage IIIB in the old classification was downstaged as stage II in the new classification. Regarding the 11 patients classified as stage IVA in the old system, all patients (100%) were downstaged: 8 (73%) became stage II, 2 (18%) became stage IIIA, and 1 (9%) became stage IIIC. In conclusion, a global downstaging of the population analyzed was observed: according to the new edition of the tumor-node-metastasis system, most patients (64%) are classified as T1 (stage I), 36 patients (32%) are T2 (stage II), and only 4 patients (4%) belong to stages IIIA and IIIC (Table 7Go).


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  		TABLE 7. Stage migration from the old to the new staging system
 
The median survival and the 5-year survival rate of patients by the 1997 T-stage were 63 months and 67.5% for T1, 90 months and 74.8% for T2, and 47 months and 40.0% for T3, respectively. According to the new 2002 T-stage, the median survival and the 5-year survival rate were 90 months and 71.7% for T1 and 61 months and 54.7% for T2, respectively. The corresponding survival curves are shown in Figs. 2Go and 3Go. Comparisons of survival by tumor-node-metastasis stage for stages I and II show a more homogeneous relationship in each stage group when defined by the 2002 tumor-node-metastasis classification. When stratified according to the old tumor-node-metastasis system, there were no significant differences in survival between stage I and II (P = .14) and between stage IIIA and IVA (P = .33); only the survival of stage II and IIIA was significantly different (P < 0.01). When stratified according to the new tumor-node-metastasis system, there were significant differences between stage I and II (71.7% vs. 54.7%; P = .02). Comparisons between stage II and III and between stage III and IV according to the new classification were not possible because there were too few patients.



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  		FIG. 2. Survival curves of patients stratified according to the American Joint Committee on Cancer/International Union Against Cancer Staging System (5th edition). When patients were stratified according to the old tumor-node-metastasis system, no difference in survival was observed between stage I and II (P = .14) or between stage IIIA and IVA (P = .33).

 


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  		FIG. 3. Survival curves of patients stratified according to the American Joint Committee on Cancer/International Union Against Cancer Staging System (6th edition). When patients were stratified according to the new tumor-node-metastasis system, significant differences were observed between stage I and II (71.7% vs. 54.7%, respectively; P = .02).

 
To determine whether tumor size was likely to influence the survival rate, patients in the new stage I were divided into three subcategories: tumor size <2 cm, 2 to 5 cm, and >5 cm. Among 72 patients classified as new stage I, the 5-year survival rate was 68.2%, 70.7%, and 75.8%, respectively, for a tumor size of <2 cm, 2 to 5 cm, and >5 cm, respectively, with no statistically significant difference (P = .10). Size does not affect prognosis for these categories. Furthermore, the new stage II was explored to examine the survival rate of two distinct categories. A similar survival rate was observed between single tumors with microvascular invasion (60%) and multiple tumors, none of which was >5 cm (71%; P = .52).

The prognostic value of each staging system was further evaluated by entering, in turn, the respective staging into the Cox regression model in addition to the significant prognostic factors obtained by univariate analysis. When the old staging system was entered into the multivariate analysis, viral etiology of cirrhosis (P = .05) and solitary tumor (P = .01) were confirmed as prognostic independent factors, whereas the staging system was not significant (P = .35). The new staging system was the only prognostic independent factor when entered into the multivariate analysis (P = .02).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The prognosis of HCC is unique among gastrointestinal cancers because it is influenced not only by the tumor characteristics, but also by the underlying liver status.6–9 There is wide recognition that the conventional tumor-node-metastasis staging system has its limitations in stratifying patients with HCC into different risk groups, because host-related factors are not included, although they are important in prognosis. Therefore, both tumor-related and host-related factors, such as liver function status, should be included in a good staging system.

After Okuda et al.10 suggested a clinical staging system in 1995, CLIP proposed in 1998 a new prognostic system by a retrospective evaluation of 435 Italian patients. All four parameters involved in the Child-Pugh staging system plus macroscopic tumor morphology, AFP levels, and the presence or absence of portal thrombosis were included in the analysis.11 This new prognostic system, compared with the Okuda staging system, seems to be more efficient in giving prognostic information.12 However, in these studies, only 12 of 435 patients were resected: therefore, surgery was seldom advocated as treatment for HCC. Two years later, Farinati et al.3 confirmed these results, analyzing 154 patients with HCC, 17 of whom underwent surgical treatment. Thus, the CLIP score is able to predict survival better than the tumor-node-metastasis staging system, especially in the subgroup of patients undergoing alternative treatments, and, therefore, it may be applied to patients with unresectable disease. Only Zhao et al.13 tried to evaluate the CLIP score in patients resected for HCC. In this study, the CLIP score seemed to have a unique superiority for predicting recurrence. However, the survival analysis showed that the CLIP score was associated with prognosis in the univariate analysis and was not associated with that in the multivariate analysis. Otherwise, the tumor-node-metastasis stage was associated with prognosis in the both univariate and multivariate survival analyses.

The controversy is ongoing over the value of the AJCC tumor-node-metastasis system for staging of HCC. The tumor-node-metastasis staging system is still one of the most widely used staging systems for HCC treated by resection, but studies from different centers on its prognostic value have suggested that the 5th edition is not accurate and is too complicated to be used routinely.4,14–16 It also results in a non-homogeneous stratification in patients classified as stage I and II. For these reasons, universal acceptance of the tumor-node-metastasis system for the staging of HCC has been stifled by disagreement over the definition of tumor characteristics.

An approach to simplify and to obtain a better homogeneity between T-groups has been achieved with the 6th edition of the AJCC tumor-node-metastasis staging system for HCC. Principally, the definition of T-stage was reviewed. The most important changes from the old edition are that the cutoff value for tumor size in the prognostic classification was modified from 2 to 5 cm and that the influence of tumor size is related only to patients with multiple tumors. The basis of the new classification was suggested by Vauthey et al.4 in an analysis conducted on 557 patients resected for HCC. In this study, better survival results were found for patients with ≤5-cm HCC compared with those with tumors >5 cm, whereas similar survival was observed for tumors ≤2 cm and those that ranged from 2 to 5 cm. On this basis, the new AJCC system for HCC was constructed by limiting the size factor to ≤5 vs. >5 cm. The recognition that the shifting of the cut-off value of the size variable from 2 to 5 cm may provide more reliable prognostic implications has been recently confirmed by Poon and Fan.17 These authors found no significant difference in prognosis between patients with tumors ≤2 cm and those with tumors of 2 to 5 cm (5-year survival of 69% vs. 62%, respectively; P = .238), whereas there was a significant difference between patients with tumors ≤5 cm and those with tumors >5 cm (62% vs. 34%; P < .0001). In our study, tumor size alone failed to reach statistical significance in the univariate analysis (P = .45), thus suggesting that the effect of size status on outcome should be evaluated together with the other clinicopathologic factors.

Therefore, in the assessment of the T-factor in the last edition of the AJCC tumor-node-metastasis staging system, major emphasis was given to vascular invasion as a potential factor predictive of poor prognosis. The finding that microscopic vascular invasion affects the prognosis of patients resected for HCC is not new.18–20 Fong et al.,21 in a series of 412 HCC cases, reported a poorer survival rate in a subset of patients positive for this pathologic finding compared with those who had negative findings (3-year survival, 58% vs. 41%; 5-year survival, 48% vs. 23%, respectively; P = .02). The presence of vascular invasion has been advocated as the common method of intrahepatic spread that is at the origin of early intrahepatic recurrence.22,23 This type of dissemination is usually known as intrahepatic metastasis. Unfortunately, this finding can be investigated only in resected specimens and not during the pre-operative work-up. In accordance with previous authors, our study found that vascular invasion is a strong predictor of outcome (P = .05).

All solitary tumors with vascular invasion (again, regardless of size) are combined with multiple tumors <5 cm and classified as T2 because of a similar prognosis. The fact that vascular invasion commonly begins as the tumor diameter approaches 5 cm24,25 likely justifies the shifting of the tumor size cutoff value from 2 to 5 cm and explains the correlation between tumor diameter >5 cm and an unfavorable prognosis.

In this study, we evaluated the accuracy of the new tumor-node-metastasis staging system and compared this classification with the earlier version. Our data show a remarkable effect on the stage distribution of our patients according to the former T-status of the tumor-node-metastasis system and on the more recent T-class according to the new tumor-node-metastasis system. Of the 66 patients classified as T2 by the old staging system, 61 (92.4%) were downstaged to stage I (T1N0) with the new classification, and among 24 patients classified as stage IIIA in the old system, down-staging was observed in 23 patients (96%). Twenty-two became stage II, and 1 became stage I (Table 7Go). Stage migration, evident from the number of patients belonging to each T-group, resulted in a change in the survival comparison. The difference between the two systems become apparent when survival was analyzed from the earlier stages according to the old tumor-node-metastasis system. In fact, the difference in 5-year survival between the old stage I and II was not significant, whereas a significant difference was observed only between stage II and III (74.8% vs. 40%; P < .01). When the tumors were classified according to the new AJCC tumor-node-metastasis staging system, there was a significant difference between stage I and II (P = .02); this resulted in a better stratification of patients. Furthermore, survival analysis that stratified in subcategories the stage I and stage II patients showed no significant difference, thus confirming the strong prognostic value of these two distinct stages. Therefore, the 5-year survival rate of stage I patients increased with the new classification compared with the old, from 67.5% to 71.7%, and decreased from 74.8% to 54.7% for stage II.

Poon and Fan17 have already compared the new staging system with the previous edition in a careful analysis of 542 patients resected for HCC. They found, as we did, significant differences between stage I and II (P < .01) and between stage II and IIIB (P < .001) when the patients were classified according to the new tumor-node-metastasis staging system. However, 5-year survival rates were essentially similar for stages I and II when the previous staging system was applied.

In this series, the viral etiology of cirrhosis (P = .03) and the presence of multiple nodules (P = .02) were also found to be related to a worse long-term survival rate on univariate and multivariate analysis. The importance of chronic liver disease in the prognosis of patients undergoing resection for HCC is well known. Patients with hepatitis B or C virus--related cirrhosis had a worse prognosis when compared with patients who had cirrhosis due to other causes (alcoholic, in most patients).26–28 Several authors have investigated the effect of viral infection on recurrence and survival. Japanese reports have pointed out that chronic active hepatitis and cirrhosis are the most significant risk factors for intrahepatic recurrence through multicentric occurrence after liver resection for HCC. This can be explained by an enhanced proliferating activity and, thus, an increased rate of genetic mutations and promotions induced by the repeated inflammation and cellular necrosis in patients with chronic hepatitis or cirrhosis.29,30

Regarding multiple tumors, it is well known that almost all patients with two or more HCCs develop intrahepatic recurrence within 5 years, because they might have HCCs of a multicentric origin. Most authors report an increased risk of recurrence and worse long-term survival associated with multiple tumors.31,32 Although the multivariate analysis shows that patients with solitary tumors have a better prognosis compared with those who have multiple tumors, we analyzed the survival rate of the two distinct categories of patients belonging to the new stage II and found similar survival rates between patients with a single tumor with microvascular invasion (60%) and those with multiple tumors, none of which was >5 cm (71%; P = .52).

In conclusion, the evaluation of the prognostic value of the 6th edition of the AJCC tumor-node-metastasis staging system has provided encouraging results. Our results suggest that the new classification achieves an accurate stratification of patients (in particular, for stage I and II) and is simpler than the previous edition. It is also a more reliable comparative analysis of outcome after hepatic resection for HCC. Further studies have to be conducted to validate this new staging system with unresectable HCC.

Received for publication March 29, 2004. Accepted for publication November 22, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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