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Originally published as JCO Early Release 10.1200/JCO.2003.07.979 on October 27 2003 © 2003 American Society for Clinical Oncology
Liver Transplantation and Hepatocellular Carcinoma Biology: Beginning of the End of the Era of Educated GuessesDepartments of Surgical Oncology and Gastrointestinal, Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX OVER THE last decade, there has been an increase in the incidence of hepatocellular carcinoma (HCC) in the United States as a result of an increasing number of patients with hepatitis C and chronic liver disease. While hepatic resection remains the mainstay of potentially curative therapy for patients with HCC, liver transplantation is now an accepted option in selected patients. The principal advantage of transplantation over resection is that it eliminates the field of cancerization associated with hepatitis and fibrosis.1 The indications for transplantation in HCC have evolved amid a saga of trial and error. In the 1980s, the results of liver transplantation were poor, in part because patients were indiscriminately selected regardless of stage or histopathologic features.2 In 1993, Bismuth et al3 retrospectively compared the results of resection and transplantation, and reported that patients with small tumors (no larger than 3 cm, no more than two nodules, and no portal vein invasion) had better survival with transplantation than with resection. In 1996, on the basis of a retrospective review of 48 patients who underwent transplantation, Mazzaferro et al4 reported that in patients with a single tumor no larger than 5 cm or with up to three tumors, none larger than 3 cm, transplantation resulted in a 4-year overall survival rate of 75% and a 4-year recurrence-free survival rate of 83%. Most transplant centers and the United Network for Organ Sharing (UNOS) have since adopted these criteria, which are now commonly referred to as the "Milan criteria." In this issue of the Journal of Clinical Oncology, Yoo et al5 report improvements over the past decade in the 5-year survival rate after liver transplantation in patients with HCC (25% for 1987 to 1991, compared to 47% for 1992 to 1996, and 61% for 1997 to 2001). We applaud the authors for their extensive review of the UNOS database. We believe it is fair to assume that these improvements in survival resulted from improved selection criteria, even though the study did not specifically compare the patients for stage or histopathologic variables across eras, and therefore one has to assume no change in the initial stage or tumor biology over time. However, the conclusion of Yoo et al5 that survival after transplantation for HCC is now excellent should perhaps be tempered. The 5-year survival rate after transplantation (61%) was inferior to the 5-year survival rate after transplantation for benign disease (75%), and was also inferior (4-year survival rate, 61%) to the survival predicted by the Milan criteria (4-year survival rate, 75%).4 Further, an intent-to-treat analysis of survival after liver transplantation would likely yield a realistic 5-year survival rate of around 54%, assuming that 7% of patients drop out while waiting for transplantation.6 The difference between the expected survival based on the Milan criteria and the observed survival in the current study suggests that recurrence of HCC after transplantation remains problematic. In fact, recurrence is important even in patients selected according to the Milan criteria because of diagnostic inaccuracy and progression after initial imaging.7 The selection of patients using the Milan criteria is based solely on imaging criteria (tumor size, tumor number, and macroscopic vascular invasion) and therefore does not fully account for the biology of HCC. The most important feature not reflected in the current selection criteria is microscopic vascular invasion, which on multivariate analyses is the main prognostic factor for survival after resection and after transplantation.8–10 Microscopic vascular invasion is reported in 30% to 50% of HCCs measuring 2 to 5 cm.11 Interestingly, of the 48 transplanted patients reported by Mazzaferro et al,4 none had microscopic vascular invasion, which supports the selection of favorable patients. Preliminary results show that, in the absence of microscopic vascular invasion, transplantation in HCCs larger than 5 cm is associated with excellent survival.12 As noted by Yoo et al,5 recent reports have proposed the expansion of the selection criteria to include patients with a single tumor up to 7 cm or up to three tumors with an aggregate size up to 8 cm.6,13 However, these criteria are based on studies with small number of patients, at specialized centers, and if broadly applied may negatively affect the survival by the inclusion of large tumors (up to 8 cm) with a high incidence of vascular invasion. In an era of worsening organ shortage with increasing mortality on the liver transplantation waiting list, optimization of outcome is unlikely to occur with expanded criteria. As much as it will be important to develop new criteria in order to increase eligibility for transplantation, it will be equally important to obtain the survival results for patients selected for transplantation on the basis of the new Model for Endstage Liver Disease score.14 These new rules reduce the waiting time and alter the process by which patients with tumors with unfavorable biology drop off the waiting list.
Another interesting approach to the treatment of patients with HCC is resection, followed by transplantation at the time of recurrence. This is an option increasingly recognized as valid for many patients with chronic liver disease at presentation.15,16 The very low perioperative mortality after resection for HCC makes this a meaningful bridge to subsequent transplantation.17 Recent resection series report 51% to 57% 5-year survival rates with small HCC ( As it does not include microscopic vascular invasion, the current selection criteria for transplantation represent only an educated guess regarding HCC biology. Should we go beyond these educated guesses? Do we have the tools to refine the selection criteria? Currently, the best surrogate markers for vascular invasion are tumor size greater than 4 cm and high-grade histopathology.11 The latter cannot be evaluated by imaging, and although percutaneous biopsy of HCC is not part of the current algorithm before transplantation, the 1.6% risk of biopsy tract seeding from gaining critical knowledge of the biology should weigh against the minimum 10% 1-year risk of death associated with liver transplantation and the consequences of transplantation in patients with high-grade HCC.21,22 Further, the evaluation of grade in a needle biopsy specimen could be coupled with evaluations of other biologic or molecular prognostic features, including proliferation rate23 and human telomerase reverse transcriptase.24 We argue that perhaps we should routinely assess molecular profiles of the HCC for patients being considered for transplantation or resection with oligonucleotide microarray gene expression.25 In addition, other methods for evaluating the biology of HCC are warranted. For example, serum vascular endothelial growth factor level is of prognostic value after resection, and requires correlation with microscopic vascular invasion and prognosis.26,27 The identification of a multiple gene marker reverse transcriptase-polymerase chain reaction assay for detection of micrometastases of HCC could be another step in the appropriate selection of patients who would benefit from transplantation,28 and more rationally select patients who are most likely to benefit from liver transplantation. It is also conceivable that the study of somatic genotypic (polymorphisms) and phenotypic abnormalities may prove complementary to HCC molecular biology and imaging studies in identifying patients for transplantation or resection. Regardless of the approach, excellent survival will be achieved only once we explore the biology of HCC and the genomics of the patient and exploit them to end the era of educated guesses. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS We thank Dr Alan W. Hemming of the University of Florida for helpful assistance and comments. REFERENCES
1. Bilimoria MM, Lauwers GY, Doherty DA, et al: Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 136:528–535, 2001 2. Iwatsuki S, Gordon RD, Shaw BW Jr, et al: Role of liver transplantation in cancer therapy. Ann Surg 202:401–407, 1985[Medline] 3. Bismuth H, Chiche L, Adam R, et al: Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 218:145–151, 1993[Medline]
4. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699, 1996
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24. Yeh TS, Chen TC, Chen MF: Dedifferentiation of human hepatocellular carcinoma up-regulates telomerase and Ki-67 expression. Arch Surg 135:1334–1339, 2000 25. Iizuka N, Oka M, Yamada-Okabe H, et al: Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 361:923–929, 2003[CrossRef][Medline] 26. Poon RT, Ng IO, Lau C, et al: Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: A prospective study. Ann Surg 233:227–235, 2001[CrossRef][Medline]
27. Chao Y, Li CP, Chau GY, et al: Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 10:355–362, 2003 28. Miyamoto A, Fujiwara Y, Sakon M, et al: Development of a multiple-marker RT-PCR assay for detection of micrometastases of hepatocellular carcinoma. Dig Dis Sci 45:1376–1382, 2000[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 cm), emphasizing the need for thoughtful consideration of both resection and transplantation in all patients presenting with small HCCs.
