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Editorial |
1 Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77230-1402
2 Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Warren 256, Boston, Massachusetts 02114-2696
Correspondence: Address correspondence and reprint requests to: Jean-Nicolas Vauthey, MD; E-mail: jvauthey{at}mdanderson.org.
In this issue of the Annals of Surgical Oncology, Ramacciato et al.1 report the results of a study in which they evaluated the new (6th edition) American Joint Committee on Cancer and International Union Against Cancer (AJCC/UICC) staging system for hepatocellular carcinoma (HCC) in a series of 112 patients undergoing resection for HCC. The authors report a homogeneous group of patients (90% had cirrhosis, and 55% had cirrhosis induced by hepatitis C) with small (median tumor size, 4 cm) and solitary HCC (82% of patients). Microscopic vascular invasion was present in only 23 patients (21%). The authors conclude that the 6th edition AJCC/UICC staging system is superior to the preceding one because of its simplicity and more accurate stratification of patients into homogeneous subsets with similar prognosis. In agreement with the evaluation by Poon and Fan,2 the authors found no improved prognosis for tumors measuring 2 cm or smaller. Furthermore, in multivariate analysis, when the stage was analyzed with other prognostic factors determined in univariate analysis (cirrhosis of viral origin, multiple nodules, and microscopic vascular invasion), stage was the only independent predictor of prognosis.
The new staging system for HCC is one of the many staging systems updated in the 6th edition of the AJCC cancer staging manual. In this edition, the staging systems for upper gastrointestinal tract cancers, including HCC, were revised such that stage IV disease is uniformly defined as metastatic disease. The staging system for HCC, which was formerly based on the complex classification of the Liver Cancer Study Group of Japan,3 was simplified on the basis of a large multicenter multivariate analysis of more than 500 patients undergoing partial hepatectomy for HCC in the United States, Japan, and France.4 This study included a complete pathologic review of the tumor and underlying liver characteristics that account for the protean presentation of HCC. The T-categories in the new HCC staging system are based on the presence or absence and severity of vascular invasion (T1, solitary tumor without vascular invasion; T2, solitary tumor with vascular invasion or multiple tumors smaller than 5 cm; T3, any tumor with major vascular invasion or multiple tumors larger than 5 cm). Vascular invasion is important because it predicts prognosis after resection or transplantation.2,5–8 A substantial addition to the new system is the provision of a fibrosis factor to reflect the severity of underlying fibrosis (F0, no or moderate fibrosis; F1, severe fibrosis or cirrhosis). Each T-category of the new staging system is affected by the severity of the underlying fibrosis.4 Thus, the new system recommends that a fibrosis score (F0 or F1), similar to the Edmondson-Steiner nuclear grade (G1 to G4), be added to the tumor stage.9
What is the relevance of the new AJCC/UICC staging system with regard to other existing staging systems for HCC, such as the Barcelona Cancer Liver Clinic staging system, the Cancer of the Liver Italian Program (CLIP) score, the Okuda staging system, and the Chinese University Prognostic Index? In contrast to those, the AJCC/UICC staging system for HCC is based on a pathologic review of surgical specimens.
Thus, it stratifies early-stage disease better than other HCC staging systems, which focus on advanced liver disease and cancer stage and were mainly designed for classifying unresectable HCC. Of note, only 5% of patients (12 of 196) in the prospective study validating the CLIP score underwent hepatic resection.10 Similarly, the surgical stages of the Barcelona Cancer Liver Clinic classification (stages A1 to A4) are based on a single institution’s retrospective experience with only 77 patients undergoing resection for HCC.11 Given the broad spectrum of clinical presentations of HCC and the often advanced associated liver disease, a consensus conference recently recommended that two staging systems be alternatively used for HCC.12 The CLIP score seemed to be the most appropriate for patients with unresectable HCC and advanced liver disease, whereas the AJCC/UICC system was deemed most useful for patients who have undergone resection or transplantation because it is based on a pathologic review of specimens validated in a multivariate analysis.
How important is this new system for clinicians treating HCC? The staging is not based on tumor size because this factor is increasingly recognized as an inaccurate prognostic indicator after resection13 or transplantation.14,15 The new system provides an explanation for the favorable prognosis after resection or transplantation in the subset of patients with large tumors. It also accounts for the severity of the underlying fibrosis, recognized as a field of cancerization in previous studies,13,16 and appropriately stratifies patients with small tumors (those with high-grade tumors or vascular invasion) who may have a poor prognosis after liver transplantation or resection.17–19 Unlike staging systems that give equivalent prognostic weight to various prognostic factors (tumor size, tumor number, and vascular invasion),20 the AJCC/UICC staging system for HCC stratifies the T-categories, with each factor defining a level of increased severity in the prognosis. Also, unlike other staging systems, the AJCC/UICC system is not construed as a treatment algorithm, because treatment methods evolve, whereas biology remains unchanged.11
The article by Ramacciato et al.1 provides another validation of the new staging system in patients with HCC arising in a background of hepatitis C induced cirrhosis. It also confirms the recent finding that hepatitis serology and country of origin, although reflecting tumor and liver characteristics, do not per se predict prognosis.21,22 Ideally, more studies should be performed to validate this new staging system, particularly in patients undergoing liver transplantation, because this approach is increasingly being used to treat patients with HCC. We also hope that molecular studies will confirm the importance of vascular invasion as a prognostic factor for HCC,23–25 thereby further unfolding the inherent biology of HCC.
Received for publication December 9, 2004. Accepted for publication January 10, 2005.
REFERENCES
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