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Simplified Staging for Hepatocellular Carcinoma

From the International Cooperative Study Group on Hepatocellular Carcinoma; Departments of Surgical Oncology, Biostatistics and Biomathematics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology, Massachusetts General Hospital, Boston, MA; Department of General Surgery, Mayo Clinic, Rochester, MN; and Department of Surgery, Hôpital Beaujon, Paris, France.

Address reprint requests to Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: jvauthey{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) fails to stratify patients adequately with respect to prognosis.

PATIENTS AND METHODS: The ability of the currently proposed tumor (T) categories to effectively stratify the survival of 557 patients who underwent complete resection for HCC at four centers was examined. Independent predictors of survival were combined into a new staging system.

RESULTS: Using the current AJCC T classification, patients with T1 and T2 tumors had similar 5-year survivals (P = .6). In addition, the survival of patients with multiple bilobar tumors (T4) matched that of T3 patients (P = .5). Independent predictors of death were major vascular invasion (P < .001), microvascular invasion (P = .001), severe fibrosis/cirrhosis of the host liver (P = .001), multiple tumors (P = .007), and tumor size greater than 5 cm (P = .01). Based on our results, a simplified stratification is proposed: (a) patients with a single tumor and no microvascular invasion, (b) patients with a single tumor and microvascular invasion or multiple tumors, none more than 5 cm, and (c) patients with either multiple tumors, any more than 5 cm, or tumor with major vascular invasion (P < .001). Severe fibrosis/cirrhosis had a negative impact on survival within all categories. The survival of patients with lymph node involvement matched that of patients with major vascular invasion (P = .3).

CONCLUSION: The current AJCC staging system for HCC is unnecessarily complex. We propose a simplified model of stratification that is based on vascular invasion, tumor number, and tumor size and incorporates the effect of fibrosis on survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
APPROXIMATELY 75% of patients with hepatocellular carcinoma (HCC) present with advanced, unresectable disease and some element of hepatic dysfunction. Several clinical staging systems that rely on liver function parameters are often used to guide initial therapy in these patients. These systems include the Okuda staging system,¹ the Cancer of the Liver Italian Program score,² and the Barcelona Clinic Liver Cancer staging classification.³ Over the past decade, screening programs and advances in surgical and perioperative care have increased the resectability rate of HCC.^4,5 Several of the clinical staging systems predict survival after resection; however, for accurate prognostic assessment after resection and patient selection for adjuvant therapy, pathologic staging systems have traditionally been used.

The American Joint Committee on Cancer (AJCC)/International Union Against Cancer staging system for HCC uses a tumor-node-metastasis (TNM) classification scheme to stratify patients with respect to predicted survival after resection.^6,7 The AJCC T classification is based on the number and location of tumor nodules, the size of the largest nodule, and the presence of vascular or adjacent organ invasion. Recent data based on hepatic resection for HCC suggest that the current AJCC staging system fails to stratify patients adequately with respect to prognosis and may be unnecessarily complex.^6,8-10

In this study, we reviewed follow-up data from 557 patients who underwent complete resection of HCC to analyze the ability of the current AJCC staging system to stratify patients according to predicted survival. Using multivariate analysis, the independent predictors of survival after resection were identified and integrated in a simplified T classification and staging system.

	PATIENTS AND METHODS

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Patients and Clinicopathologic Variables
We identified 591 patients who underwent complete resection of HCC between 1980 and 1998 at four major hepatobiliary centers: The University of Texas M.D. Anderson Cancer Center (Houston, TX), Mayo Clinic (Rochester, MN), Hôpital Beaujon (Paris, France), and Kyoto University Graduate School of Medicine (Kyoto, Japan). Clinical data were reviewed on-site by two of the investigators (J.N.V. and D.M.N.), with the assistance of translators with specialized hepatobiliary training if needed. Because we were interested in identifying the clinicopathologic predictors of long-term survival after resection for HCC, we excluded 29 patients who died during the immediate postoperative period (ie, within 30 days). Five patients with incomplete survival data were also excluded, leaving 557 patients in the final cohort. All patients underwent attempted curative resections. Three hundred five patients (55%) underwent minor resections, 188 patients (34%) underwent formal right or left hepatectomy, and 63 patients (11%) required extended hepatectomy.

Serologic presence of any hepatitis B antigen or antibody was considered as positive evidence of hepatitis B serology. The pathologic material of all patients was reviewed on site by one of the investigator (G.Y.L.). In all centers hematoxylin and eosin (H&E) was the stain of choice. A total of 2,286 sections of hepatocellular carcinoma were available. One to 21 sections per tumor were reviewed (mean, 4.3 sections per case). Tumor size was based on the largest dimension of the tumor specimen. Minor vascular invasion was defined as either gross or microscopic involvement of the lobar or segmental branches of the portal or hepatic veins. Microscopic vascular invasion was defined by the presence of tumor emboli within either the central hepatic vein, the portal, or the large capsular vessels. For the purpose of the study, minor vascular invasion and microscopic vascular invasion were grouped as one category, defined as microvascular invasion. Major vascular invasion was defined by gross invasion of the right or left main branches of the portal or hepatic veins.¹¹ Invasion of adjacent organs was based on gross involvement of an adjacent organ other than the gallbladder requiring en-bloc resection. The surgical margin was defined as less than 10 mm versus 10 mm as previously described.^5,12 Lymph node involvement was based on lymph node biopsy at the time of surgery. Tumor grade was assessed using the scheme outlined by Edmondson and Steiner,¹³ and was based on the area showing the highest grade. The degree of fibrosis of the surrounding parenchyma was graded according to the classification of Ishak et al.¹⁴ Fibrosis was assessed on trichrome-stained slides, which were available in most cases, and on sections distant from the tumor to avoid secondary changes due to mass effect. To stratify patients, the latest AJCC TNM classification was used.⁷ For the purpose of analysis of the subsets within each T category, T subcategories defined as a, b, and c were used within T2, T3 and T4 categories.

Statistical Analysis
Age, alpha-fetoprotein level, and tumor size were treated as both continuous and dichotomous variables, using their respective medians as the breakpoints for the statistical analyses. Because of sample size limitations, patients with poorly differentiated and undifferentiated tumors were combined into a single group. Survival was measured from the time of resection, and death was the end point. Survival curves were constructed using the Kaplan-Meier product-limit method¹⁵ and compared using long-rank tests.¹⁶ Univariate prognostic factors were entered into a Cox proportional hazards model using stepwise selection to identify independent predictors of death. Statistical significance was defined as a P value .05. The SPSS software package (Version 10.0; SPSS Inc., Chicago, IL) was used for the statistical analyses.

	RESULTS

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Patient and Tumor Characteristics
The demographic and clinicopathologic characteristics of the 557 patients in the study cohort are listed in Table 1. The median follow-up was 35 months (range, 1 to 209 months) for all patients. When stratified by survival status, the median follow-up for survivors was 66 months (range, 3 to 209 months) for survivors, compared with 25 months (range, 1 to 157 months) for patients who died. The majority of patients in the series were dead by the end of the follow-up period (n = 381; 68%).

View larger version (11K): [in this window] [in a new window]   Fig 1. Survival according to AJCC T classification: (A) T1 versus T2c; (B) T3 versus T4a/T4c.

Univariate and Multivariate Predictors of Long-Term Survival
The median survival duration of our study cohort was 45 months, and the 5- and 10-year survival rates ± SE were 38% ± 2% and 17% ± 2%, respectively. Fifty-two percent of patients in Japan presented with T1 or T2 tumors, compared with 35% of patients in France or the United States (P = .001). Conversely, 65% of patients in Japan presented with severe fibrosis/cirrhosis of the underlying liver, compared with 51% and 21% of patients in France and the United States, respectively (P < .001). Overall, the 5-year survival rates of patients treated in France, Japan, and the United States were not statistically different: 33% ± 4%, 43% ± 3%, and 34% ± 4%, respectively (P = .4). Overall survival rates according to several patient and clinicopathologic characteristics are shown in Table 3. Because the survival of patients with mild/moderate fibrosis in the adjacent liver was statistically similar, these groups were combined in the subsequent analysis. Age, hepatitis B status, hepatitis activity, type of resection, and resection margin had no effect on survival.

The effect of tumor size within the three groups was analyzed. In patients with a single tumor, tumor size had no effect on survival in patients with no vascular invasion or microvascular invasion, irrespective of how tumor size was dichotomized (ie, 2, 3, 4, 5, or 10 cm) (P = .7 and P = .3; Fig 2A and Fig 2B, respectively). In patients with multiple tumors, however, tumor size had a significant effect on survival. The 5-year survival rate of patients with multiple tumors, none more than 5 cm, was 36% ± 6%, compared with 15% ± 5% for patients with any tumor more than 5 cm (Fig 2C; P = .007). In fact, the survival of patients with multiple tumors any more than 5 cm matched that of patients with major vascular invasion (P = .5), leading us to combine these patients into a single group. In contrast, tumor size had no effect on survival in patients with tumors with major vascular invasion.

View larger version (19K): [in this window] [in a new window]   Fig 2. Effect of tumor size in patients with (A) single tumors without vascular invasion, (B) single tumors with microvascular invasion, and (C) multiple tumors.

View larger version (19K): [in this window] [in a new window]   Fig 3. Survival according to new T classification system: sT1 versus sT2 versus sT3.

View larger version (25K): [in this window] [in a new window]   Fig 4. Effect of severe fibrosis or cirrhosis on survival in patients with sT1, sT2, and sT3.

View larger version (20K): [in this window] [in a new window]   Fig 5. Survival according to proposed stage grouping: stage I, sT1N0M0; stage II, sT2N0M0; stage IIIA/B, sT3N0M0 or s any TN1M0 tumors.

	DISCUSSION

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Previous studies have indicated a lack of adequate stratification with the AJCC staging system^6,8-10 and an overlap of the T subcategories.^18,19 In 1994, Izumi et al⁸ analyzed the ability of the AJCC staging system to stratify patients with respect to survival in a series of 104 HCC patients treated with complete resection. Similar to the case with the current study, no difference in survival was noted between patients with T1 and T2 disease. Further, the survival of patients with multiple bilobar tumor (T4a) or adjacent organ invasion (T4c) was better than that of patients with tumors with major vascular invasion (T4b), and matched that of patients with T3 disease. Using multivariate analysis, Izumi et al proposed a new T classification system that excluded size and was based solely on the number of tumors and the macroscopic presence of minor and major vascular invasion as defined by the Liver Cancer Study Group of Japan.²⁰

The current study is unique because it is based on a detailed pathologic review of resected specimens at hepatobiliary centers worldwide and encompasses the broad spectrum of tumor and liver disease factors associated with the prognosis of HCC. Of particular importance is the systematic study of microscopic vascular invasion that has recently been emphasized.^21-23 In the current study, the detailed analysis of microscopic vascular invasion identified a subset of patients with single tumors and no vascular invasion (sT1) who had a favorable prognosis irrespective of size, suggesting unique tumor biology. Likewise, tumor size had no effect in patients with single tumors with vascular invasion.

Tsai et al²² recently noted an association between tumor size and increasing rates of both microscopic and macroscopic vascular invasion. The fact that tumor size may be a marker for invasiveness^24,25 may explain why size often fails to affect survival in studies that control for vascular invasion.^17,21 Clearly, a prognosis based on size does not apply to the majority of HCC, because other major factors (major vascular invasion, microvascular invasion, and tumor number) determine the prognosis. In our series, the effect of tumor size was limited to patients with multiple tumors, in whom tumor size served to stratify patients between the sT2 and sT3 categories.

Multiple tumors can be due to either intrahepatic metastases or multicentric carcinogenesis. Kosuge et al²⁴ noted an association between number of tumors and vascular invasion. In our series, 41% of patients with single tumors had evidence on microscopic or macroscopic vascular invasion, compared with 65% of patients with multiple tumors (P < .001). When patients were stratified according to vascular invasion, the number of tumors (ie, single v multiple) had no effect on survival in patients with sT2 or sT3 tumors. Furthermore, the survival of patients with single tumors and microvascular invasion and multiple tumors 5 cm with or without microscopic vascular invasion was not statistically different, leading to the combination of these groups into a single sT2 category.

The proposed sT classification is further simplified in that it eliminates separate categories for multiple bilobar tumors and tumors invading adjacent organs. These factors failed to predict survival, and were eliminated from the multivariate analysis. Previous studies have shown that invasion of an adjacent organ is not associated with worse survival.^26-29

The impact of cirrhosis in the nontumorous liver on recurrence and long-term survival after resection of HCC is controversial. Several studies have documented an association between cirrhosis and recurrence, presumably caused by continued carcinogenesis in the affected liver remnant.^12,22,30-32 Kosuge et al²⁴ reported an unfavorable effect of liver disease, particularly cirrhosis, on disease-free survival, which became more pronounced over time. In our recent analysis of 145 patients who survived 5 or more years after resection of HCC, the presence of moderate to severe fibrosis/cirrhosis was the most important predictor of death,¹²overshadowing all other tumor factors. In contrast, when these 145 patients were compared with the 446 patients surviving less than 5 years, tumor factors (including microvascular invasion) predicted prognosis, implying that early demise resulted from tumor recurrence of the index HCC.

In a series reported by Fong et al,¹⁷ the median tumor size was larger in patients without cirrhosis than in those with cirrhosis (10 v 6 cm; P < .05). As a result, the effect of cirrhosis on survival was evident only after patients were stratified by tumor size. In our series, the median tumor size in patients without cirrhosis was 7.5 cm, compared with 3.5 cm in patients with cirrhosis (P < .001). The presence of severe fibrosis/cirrhosis had a significant effect on survival across all three sT categories, most likely because stratifying patients according to vascular invasion removed the negative confounding effect of tumor size.

The strong effect of fibrosis/cirrhosis on survival provides an explanation for the absence of overall survival differences between centers despite different tumor stages at presentation. In Japan, ultrasonographic screening results in the early diagnosis of small tumors, but the survival remains adversely affected by the risk of death from advanced liver disease and multifocal recurrences.¹² Other investigators have noted an association between pathologic markers of underlying liver disease (eg, hepatitis grade),³³ liver cell dysplasia,³⁴ and poor prognosis. Because of the high prevalence of underlying liver disease and its grave prognostic significance,³⁵ we propose a separate reporting of fibrosis (F0/F1) in every case of HCC. Similar to the reporting of tumor grade for each tumor stage, the systematic reporting of underlying liver disease enhances the descriptive and prognostic ability of the new proposed staging system.

Sampling or dissection of lymph nodes is not routinely performed during hepatic resection for HCC, and lymph nodes were biopsied in only 22% of patients in this series. The survival of 18 patients with positive lymph nodes was similar to patients with major vascular invasion. For this reason, in the absence of definitive data on survival of a large number of patients with positive lymph nodes, we proposed to group these patients in stage III (stage IIIA for major vascular invasion and IIIB for positive lymph nodes). However, more data should be collected regarding the lymph node drainage of HCC and the survival of patients adequately sampled before an appropriate lymph node stage grouping can be determined for HCC.

A potential criticism of the simplified staging system proposed here is that it is based on the small subset (20% to 30%) of patients presenting with HCC who are amenable to surgical resection. A similar limitation exists for the majority of patients with biliary tract and pancreas cancer, who present with unresectable tumors.^36,37 The TNM staging systems used to stage these patients are also derived from survival analyses based on histopathologic data from resection.⁷ For this reason, we feel that any new staging proposal should be based on histopathology. Advances in imaging may in the future facilitate the validation and extension of the staging systems to include unresectable patients while minimizing the degree of extrapolation inherent to this approach.

Two reports have proposed new T classification schemes after resection of HCC. Both are based on vascular invasion, multiple tumors, and tumor size (> 2 cm or > 5 cm) as predictors of poor prognosis.^38,39 In both schemes, patients lacking all three factors are classified as T1, whereas patients with one, two, or three tumor factors are classified as T2, T3, or T4, respectively. Although these schemes are easier to use than the current AJCC T classification, they assume that each factor carries equivalent prognostic value similar to the case with a scoring system. This assumption is not supported by our results and could lead to erroneous estimations of prognosis. In particular, this classification would underestimate the prognosis of patients with large, solitary tumors without vascular invasion, whose disease would be classified as T2 rather than sT1. Conversely, the prognosis of patients with small, single tumors with major vascular invasion would be overestimated, as these tumors would be classified as T2 rather than sT3. These T classification schemes are inconsistent with the existing AJCC T classifications for other types of tumors, which rely on pathologic characteristics of progressive severity to define each T category.

The study reported here indicates that the current AJCC T classification for HCC is unnecessarily complex and fails to stratify patients adequately with respect to prognosis. Unlike other T classification systems that have recently been proposed, the sT classification that we propose represents a true staging system rather than a scoring system.^38,39 Our proposed stage grouping is also simplified with subcategories (A and B) in stage III only, whereas stage IV is reserved for (unresectable) metastatic disease. The ability of our simplified staging system to stratify patients and predict survival in patients treated by ethanol injection and transplantation for HCC remains to be tested, because most of these patients belong to specific subsets of HCC characterized by advanced liver disease and small tumors. Until then, the use of existing classifications that emphasize liver disease extent^1-3 or transplantation outcome^40,41 is appropriate.

	ACKNOWLEDGMENTS

 
We thank Prof Y. Yamaoka and Dr I. Ikai for access to the clinicopathologic data from patients of Kyoto University Graduate School of Medicine; Drs L. Sobin of the Armed Forces Institute of Pathology and F. Greene of the AJCC, and Prof C. Wittekind of the International Union Against Cancer for their thoughtful comments; Dr S. Fujita for translation of clinical data; and R.J. Haynes for secretarial assistance.

	REFERENCES

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Submitted July 17, 2001; accepted December 3, 2001.

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