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  • 1. PERSPECTIVES OPINION Hepatocellular carcinoma—resection or transplant? Sheung Tat Fan Abstract | Resection and liver transplantation are considered effective treatments for early-stage hepatocellular carcinoma (HCC). As data from randomized trials are lacking, the choice of technique is controversial. Retrospective analyses suggest that for patients with suboptimal liver function, transplantation is the preferred treatment. For patients with preserved liver function and HCC within the Milan criteria, the overall survival rate is similar for both techniques; therefore resection is the preferred treatment. For tumours beyond the Milan criteria but within acceptable expanded criteria, transplantation has a more favourable outcome than resection. As liver grafts are in short supply, resection followed by transplantation once intrahepatic recurrence is detected would spare patients with favourable or very aggressive tumours from transplantation and enable patients with moderately aggressive tumours to undergo timely transplantation. Currently, resection and transplantation are considered complementary in the management of HCC. Expanding the transplantation and resection criteria of HCC needs to be investigated. Fan, S. T. Nat. Rev. Gastroenterol. Hepatol. 9, 732–737 (2012); published online 11 September 2012; doi:10.1038/nrgastro.2012.158 Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignancy globally and its incidence is rising worldwide. Each year, about 500,000–1,000,000 new cases are reported and approximately 600,000 patients die globally from the disease. 1 Hepatectomy (resection) and liver transplantation are considered effective treatments. How to choose between resection and transplantation for an individual patient is controversial. To date, no randomized trial has been conducted to show that one treatment is superior to the other. The choice depends on the extent of comorbidities and the liver function of the patient, availability of a liver graft and transplant service, and the technical skill of the surgical team. The long-term outcome of hepatectomy or transplantation depends on, among many other factors, the biological behaviour of the tumour, which varies greatly between patients. The aim of this article is to provide a perspective on the outcomes after treatment of HCC by Competing interests The author declares no competing interests. 732  |  DECEMBER 2012  |  VOLUME 9 transplantation or resection and the future development of surgical treatment of HCC. Biology of HCC HCC evolves from a monoclonal focus into a low-grade dysplastic nodule, a highgrade dysplastic nodule, an early cancer, and, finally, an advanced HCC.2 A few years might be required for the high-grade dysplastic nodule to progress to HCC. Stromal invasion in the portal tract is characteristic of malignancy in early HCC.2 Tumours >2 cm tend to grow expansively; a fibrous capsule might form around the tumour as a host defence against tumour growth.3 The capsule is eventually ineffective because the tumour can grow across the capsule to form microsatellites. Thereafter, the tumour grows by replacing and destroying neighbouring liver cells. HCC might also show a sinusoidal growth pattern (cancer cells infiltrate the sinusoids at the tumour boundaries, engulfing hepatocytes4), which is observed mostly in poorly differentiated, undifferentiated and sarcomatous HCC. Venous permeation occurs in the early development of a tumour and is found in 27% of small and distinctively nodular HCC (2 cm).4 As the tumour grows, invasion into the portal vein and hepatic vein leads to dissemination into the adjacent liver and systemic circulation, respectively. Tumour invasion into the peripheral bile duct is common but is not clinically important until the tumour grows into the common bile duct. Rapid growth of the tumour might result in intratumoural bleeding, sudden expansion of the tumour and spontaneous rupture in about 10% of patients.5 Massive bleeding and dissemination of cancer cells into the peritoneal cavity as a result of tumour rupture lead to rapid mortality. HCC tends to be multicentric, which could be attributable to portal vein invasion but could also be the result of malignant transformation of hepatocytes occurring in different parts of the liver either simultaneously or sequentially. Simultaneous malignant transformation of many hepatocytes probably accounts for the diffuse type of HCC, which is the most malignant form of HCC, for which neither resection nor transplantation is effective. The growth rate of HCC varies from patient to patient. The average time it takes for the HCC to double in size (up to around 3 cm) ranges from 3 months to 6 months.6 Slow-growing HCCs are frequently welldifferentiated, whereas fast-growing HCCs are often poorly differentiated. The growth rate of HCC might be accelerated if nonsurgical treatments, such as transcatheter arterial chemoembolization, cannot induce complete tumour necrosis because the residual cancer cells might be activated and become more aggressive.7 The behaviour of the HCC might also be altered by liver injury 8 and immunosuppression.9 Resection of HCC Conventionally, major hepatectomy (resection of three or more Couinaud’s liver segments) is indicated for HCC confined to one lobe of the liver. Accumulated experience and innovations of surgical techniques in the past two decades have enabled an expansion of indications to include resection of additional nodules in the contra­ lateral lobe, extraction of tumour thrombus in the portal vein, inferior vena cava or bile duct and resection of major blood vessels in conjunction with the tumour followed by www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved
  • 2. PERSPECTIVES reconstruction. The hospital mortality rate is low (3%) and transfusion requirement is minimal (10%) if the patient has preserved liver function (Child–Pugh class A or indocyanine green retention rate 14%), minimal intraoperative blood loss, nontumorous liver volume and function preserved, and has received optimum care during and after surgery. 10 The minimum remnant liver volume that enables safe major hepatectomy is 20% for patients with normal liver, 30% for patients with chronic hepatitis and 40% for patients with cirrhosis.11 In case the remnant liver volume is insufficient and the liver is normal or mildly cirrhotic, the contra­ lateral liver can be induced to hyper­ rophy t by ipsilateral portal vein embolization 12 or Yttrium‑90 radioembolization.13 Major hepatectomy is contraindicated in patients with portal hypertension. However, if these patients have a tumour that is confined to one liver segment and have controllable ascites (by diuretics), they could survive a minor hepatectomy if portal hypertension is not aggravated by division of collaterals in the subcutaneous tissues and umbilical ligament, if only minimal blood volume is lost and if maximal non­tumorous liver is preserved.14 After resection, tumours recur in about 40% of patients within the first year.10 Such recurrence can be intrahepatic, extra­hepatic or both. Intrahepatic recurrence might be detected in the rest of the liver as new primaries or near to the resection margin, which indicates that regional dissemination from the original tumour via the portal vein or its branches has not been totally eradicated. Molecular profiling can be used to differentiate a new primary from intra­ hepatic spread. 15 Clinically, intra­ epatic h recurrences that occur more than 2 years after hepatectomy are considered de novo or new primaries.16 As a result of the evermutating nature of hepatocytes affected by viral hepatitis, new primaries can occur any time after hepatectomy. Extrahepatic recurrences are related to circulating tumour cells or cancer stem cells.17 These cells are deposited in extra­ epatic organs and even h in the liver remnant itself to grow into tumours when a favourable microenvironment for tumour growth is present. Thus, post­ perative complications that induce a o systemic inflammatory response and hence a favourable microenvironment for tumour growth are associated with an increased incidence of tumour recurrence.18 Owing to the high incidence of recurrence after hepatectomy, the 5‑year disease-free survival rate is low. The 5‑year disease-free survival rates for tumour-nodemetastasis (TNM) stage I, II, IIIA and IVA are 50%, 55%, 25% and 13%, respectively. About 17% of patients might survive for 10 years without tumour recurrence (S. T. Fan, unpublished work). The 5‑year overall survival rates for TNM stage I, II, IIIA and IVA are 82%, 77%, 44% and 28%, respectively.10 The higher overall survival rate than disease-free survival rate despite a high tumour recurrence rate is attributable to the fact that after hepatectomy, patients are under close surveillance and prompt treatment of small recurrences is generally effective. About 25% of patients might survive for 10 or more years after hepatectomy (S. T. Fan, unpublished work). Factors that determine survival of patients after a hepatectomy are TNM stage, the volume of blood lost during surgery, complications after surgery, tumour nodule number, microvascular invasion and positive resection margins.10 Genomic changes in the nontumorous liver rather than the tumour itself might be more important in prognostication.19 Clinically, of all the risk factors, a positive resection margin has the most profound influence on long-term survival. These findings demonstrate the need for a meticulous technique to attain a tumour-free resection margin while retaining sufficient nontumorous liver. Radiofrequency ablation is increasingly used instead of resection of HCC for its simplicity of application. It is applicable to HCC located in difficult positions for resection. However, the 5‑year disease-free survival rate of patients treated with radiofrequency ablation (33.9%) is lower than with resection (54.8%) and radiofrequency ablation is not applicable to large tumours.20 Transplantation for HCC Currently, patients with early-stage HCC and Child–Pugh class B or C liver function are selected for liver transplantation. The Milan criteria (solitary tumour ≤5 cm in diameter, or ≤3 tumours, each ≤3 cm in diameter) was adopted as a gold standard for selection because it was shown that the disease-free survival rates at 4 years for patients whose tumour status exceeded or was within the Milan criteria were 59% and 92%, respectively.21 The low survival rate for patients with tumour status beyond the Milan criteria argues against liver transplantation for these patients because the rate is lower than that of patients without HCC. Therefore, allocation of deceased donor NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved grafts to patients beyond the Milan criteria would jeopardize the survival of patients without HCC who are on the waiting list. However, subsequent studies have demonstrated that the Milan criteria might be too restrictive.22 Modest expansion of the selection criteria (for example, University of California, San Francisco criteria) results in survival comparable to that of patients with tumour status within the Milan criteria (Table 1).22 In China, where no national organ allocation system is available, recruitment of patients with HCC for liver transplantation is liberal. A study performed under such a liberal policy has shown that liver transplantation could be extended to patients with total tumour diameter 8 cm, if the tumour is well or moderately differentiated and associated with a preoperative α‑fetoprotein level 400 μg/l.23 The 5‑year survival rate of such patients was 72%.23 These results have been corroborated by a Canadian study.24 The use of living donor grafts eliminates the consideration of collective and societal benefits of liver transplantation using deceased donor grafts and enables early transplantation. Living donor liver transplantation (LDLT) for HCC is frequently used in some centres with the argument that LDLT can maximize individual patient benefit and a patient’s choice. A further argument is that even though the outcome of all types of liver transplantation for patients with tumour status beyond the Milan criteria is less favourable than patients within the Milan criteria, the outcome is still much better than with resection. In a large-volume centre, LDLT was extended to patients in whom the largest tumour was ≤5 cm in diameter and ≤6 tumours were present. The overall 5‑year survival rate was 76%.25 How widely LDLT can be expanded is not known. In view of potential living donor morbidity (15%) and mortality (0.5%),26 the acceptance of patients with HCC for LDLT should not be too liberal. A trend exists towards worse outcome with LDLT compared with deceased donor liver transplantation (DDLT) for patients with tumour status beyond the Milan and University of California, San Francisco criteria; however, it is not known why this trend exists.27 The benchmark of a 5‑year overall survival rate of 70% for transplant recipients should be adopted to avoid donor dissatisfaction and, more importantly, loss of confidence in the transplant team within the community. The dilemma is how to VOLUME 9  |  DECEMBER 2012  |  733
  • 3. PERSPECTIVES Table 1 | Expanded selection criteria of transplantation for hepatocellular carcinoma Study Criteria Additional patients benefitted compared with Milan criteria (%) University of California, San Francisco22 One tumour ≤6.5 cm; up to three tumours each ≤4.5 cm, total tumour diameter ≤8 cm 30 Kyoto45 Tumour number ≤10, all ≤5 cm and PIVKA-II ≤400 mAu/ml 11 Tokyo ≤5 nodules, each ≤5 cm 6 Seoul25 Tumour number ≤6, largest ≤5 cm 10 Hangzhou Total tumour diameter ≤8 cm, or total tumour diameter 8 cm with histopathologic grade I/II and AFP 400 μg/l 37.5 Toronto24 No tumour size or number restrictions; no systemic symptoms; not poorly differentiated (beyond Milan tumours only) 46.6 46 23 Abbreviations: AFP, α‑fetoprotein; PIVKA-II, proteins induced by vitamin K absence II. achieve a comparable result with expanded indications. As the outcome of liver transplantation depends on the biological behaviour of the tumour, which cannot be altered, surgical techniques to reduce dissemination of cancer cells during surgery and complications that might induce systemic inflammatory responses and subsequent tumour recurrences should be the appropriate approach until an effective adjuvant treatment is found. In my opinion, liver transplantation is the best treatment for patients with earlystage HCC because the tumour itself and the liver harbouring the potential recurrent foci are removed, and complications of liver failure and portal hypertension are eliminated. The 5‑year overall survival rates for TNM stage I, II, IIIA and IVA are 94%, 83%, 83% and 74%, respectively (S. T. Fan, unpublished work). The 5‑year disease-free survival rates for TNM stage I, II, IIIA and IVA are 94%, 80%, 84% and 73%, respectively (S. T. Fan, unpublished work). Recurrence occurs in about 15% of patients, presumably as a result of engraftment of circulating tumour cells.28 The recurrence might manifest as long as 6 years after transplantation. Most patients succumb to recurrence rapidly because the cancer cells are resistant to treatment.28 Some concern exists that a living donor graft that is small-for-size sustains more graft injury and might harbour more tumour recurrence than a deceased donor graft, but a study published in 2011 showed that the outcome of LDLT was similar to that of DDLT.27 Risk factors for HCC recurrence after LDLT are related to tumour stage and to previous treatments that failed to control the HCC (and thus the indication for liver transplantation).29 In this situation (salvage transplantation), multiple unsuccessful 734  |  DECEMBER 2012  |  VOLUME 9 treatments might have resulted in the most malignant cancer cells, which have a high metastatic potential, remaining in the patient. In our series, after taking out the patients who underwent salvage transplantation, the outcome of LDLT as the primary treatment for HCC was comparable with that of DDLT.30 Primary transplantation for HCC is therefore preferred if a liver graft is available. For predicting the longterm survival after DDLT, the risk factor of microvascular invasion seems to not be as important as it is in patients undergoing resection. 23,24,31 Rather, tumour differentiation grade is the most important predictor of survival.32 Evaluation of tumour biopsy samples taken before transplant for microvascular invasion is therefore not necessary. Thus, if a tumour biopsy is performed, information regarding tumour cell differentiation would be more valuable for selecting patients with advanced but well or moderately differentiated HCC for transplantation.24 Apart from tumour recurrence, the underlying viral disease might recur and adversely affect the survival of transplant recipients. Fortunately, the use of new antiviral agents almost eliminates recurrence of hepatitis B.33 Thus, long-term survival is not affected by a patient’s hepatitis B status. For hepatitis C, a study published in 2011 indicated that the long-term outcome of patients with HCC who undergo a liver transplantation is not seriously affected by their hepatitis C status.34 Resection versus transplantation In selecting resection or transplantation for an individual patient, the following factors have to be taken into consideration: comorbid illness; liver function; extent of tumour growth; graft availability; and long-term results of the treatment modality. For hepatectomy, the age of the patient is not a limiting factor as long as the physical condition of the patient means that he or she is not suffering from renal failure.35 For transplantation, many centres have set an arbitrary age limit of 65 years because an elderly patient’s organ function reserve might not tolerate the transplant operation. These patients are also at an increased risk of complications related to immuno­ uppression, such as dia­ s betes mellitus, cardiovascular disease and opportunistic infections. Currently, liver transplantation is restricted to patients with HCC who have expected favourable outcomes. Although expanded criteria have been attempted in some centres, large tumours (8 cm) and HCC with portal vein, hepatic vein or inferior vena cava invasion are generally contraindicated for transplantation. However, such patients are readily accepted for hepatectomy, which might be their only chance of a cure. Therefore, primary liver transplantation could benefit about 2% of patients with HCC, whereas primary resection could be performed in about 25% of patients with HCC (S. T. Fan, unpublished work). Hepatectomy can be performed readily without incurring major expenses, whereas the timing of liver transplantation depends on the availability of a liver graft, and the transplant workup and operations are expensive. Moreover, a stay in the intensive care unit is mandatory after a transplant, whereas nearly all patients who have undergone a hepatectomy can be cared for in a general ward. As a tumour might grow and disseminate whilst a patient is waiting for a liver graft, the opportunity for timely treatment might be lost. Thus, the longterm outcome of patients listed for liver transplantation is not different from that of www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved
  • 4. PERSPECTIVES a b c Figure 1 | Salvage transplantation. a | A patient with left-liver hepatocellular carcinoma (arrows) and portal vein invasion (single arrowhead) underwent left hepatectomy and portal vein tumour thrombus extraction. The patient survived the hepatectomy despite the fact that he had portal hypertension and varices (double arrowhead). b | 5 months after the hepatectomy, the patient had recurrence in the right liver and the residual tumour was resistant to chemoembolization (arrow). c | The patient underwent right-liver living donor liver transplantation. The patient has remained disease-free for 5 years after the transplantation. those who underwent resection. Resection might also be associated with better results than transplantation for patients with earlystage HCC and low Model for End-stage Liver Disease (MELD) score who are listed for transplantation.36 Liver function status remains the most important determinant of selection of a treatment modality. Although some centres have advocated liver transplantation to patients with Child–Pugh class A liver function or normal liver, most centres offer transplantation only to patients with Child–Pugh class B or C liver function or a MELD score 14 for whom hepatectomy cannot be performed safely.28 Despite the major differences in patients’ liver function, both resection and transplantation can be performed with a low hospital mortality rate (3%).10,28 The reported long-term outcomes of the two techniques are vastly different.28 Liver transplantation results in a much lower recurrence rate and a longer overall survival rate than resection. However, the excellent results for transplantation are artefactual because only patients with an early-stage tumour and anticipated favourable outcomes are allowed to receive the scarce resource of a transplanted liver, whereas many patients with advanced TNM stage undergo hepatectomy. When patients with the same early-stage tumour status (for example, within the Milan criteria) are compared, the overall survival rate of the patients undergoing hepatectomy was not different from that of those undergoing liver transplantation.28 The major difference, though, was a higher tumour recurrence rate among patients undergoing hepatectomy than in those who received a transplant. However, treatment of small recurrence is effective in patients who have undergone resection, but not in patients who have undergone transplantation. 28 Immunosuppression is perhaps the major reason accounting for the difference. For patients with more advanced tumours (for example, up‑to‑7 criteria, that is, HCC with seven as the sum of the size of the largest tumour [in cm] and the number of tumors37), the advantage of liver transplantation starts to emerge. The 5‑year disease-free survival rate of patients with microvascular invasion who have undergone liver transplantation is twice as good as that of patients with microvascular invasion who have undergone resection (88.2% versus 41.2%).35 In comparing the results among patients with late TNM stages, the difference is also obvious. These findings might imply that a more liberal policy could be adopted, which would enable more patients with HCC to undergo transplantation. However, given the current restricted organ allocation policy in most countries around the world, it is diffi­ cult to show the superiority of DDLT over resection for advanced tumours. Centres that perform large numbers of LDLT might have accumulated sufficient data to validate such an approach. Resection then transplantation Salvage transplantation can be considered when the intrahepatic recurrence NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved after hepatectomy cannot be treated with resection because of a difficult location or cannot be treated with nonsurgical therapy as a result of deteriorated liver function. Salvage transplantation is also considered when repeated nonsurgical treatments fail to control the recurrent tumour; the 5‑year survival rate of these patients after transplantation is about 40%. 38 Salvage transplantation is also adopted as the intention-­ o-treat policy, so that patients t with a tumour status within the Milan criteria and good liver function are offered resection as the first-line treatment followed by transplantation in case of recurrence. The 5‑year survival rate of the transplant recipients is about 70%.39 In an intention-to-treat analysis, the long-term outcome of salvage transplantation is similar to that of primary transplantation.40 This policy assumes that the patient is suitable for transplantation when recurrence is detected and that recurrence is mainly intrahepatic. However, in a survey by Fuks et al.,40 about 20% of recurrences were extrahepatic and the transplantability was only 28%. The reasons for the exclusion from salvage transplantation were advanced age, acquired comorbidities and recurrence beyond the Milan criteria. After hepatectomy, increased vigilance during surveillance could increase the transplantability rate by detecting early recurrence.41 The fact that some HCCs are more aggressive than others implies that not every patient is suitable for transplantation. Despite the low transplantability rate, the policy of resection first followed by transplantation is still advantageous, as patients with favourable tumour biology (and thus no recurrence, which accounts for 20% of patients) and those with very aggressive cancer behaviour (and thus rapid recurrence beyond the Milan criteria, which accounts for 27% of patients) could be spared from liver transplantation, whereas those with moderate tumour aggressiveness (53% of patients) could benefit from timely transplantation. 40 However, uncertainty exists regarding the influence of the original tumour status and the time interval between resection and recurrence on the results of salvage transplantation. Perhaps, for the patient’s benefit, he or she should be eligible for transplantation as long as the recurrence is within the acceptable criteria (Figure 1). Another approach is ‘pre-emptive’ liver transplantation, that is, transplantation is carried out soon after resection before recurrence is detected.42,43 The selection of patients for pre-emptive transplantation VOLUME 9  |  DECEMBER 2012  |  735
  • 5. PERSPECTIVES is based on finding features of high risk of recurrence in the resected HCC. These features include microvascular invasion, microsatellites and poor differentiation of the tumour. Among these features, only microvascular invasion and micro­ satellites are chosen because patients with poorly differentiated HCC have uniformly poor outcomes after transplantation. Implementation of pre-emptive liver transplantation, however, could be difficult because the patient might not accept a second operation after experiencing the trauma of the first one. In addition, in some regions, a liver graft might not be readily available because the local organ allocation policy restricts graft allocation to patients with presence of tumours or deteriorated liver function. Moreover, as tumours might develop while the patient is waiting for a deceased donor graft, unless a graft is readily available (for example, from a living donor), the ultimate efficacy of pre-emptive liver transplantation is not different from the wait-and-see protocol. Therefore, to implement pre-emptive liver transplantation effectively, consideration should be given to changing the organ allocation policy. Conclusions In my opinion, liver transplantation is without doubt the best treatment for HCC. In the ideal situation of sufficient and prompt graft supply, liver transplantation should be the first choice, as primary transplantation might be more cost-effective than salvage transplantation.44 However, in real practice—because of graft shortage—primar y resection followed by transplantation for recurrence should be the protocol for patients with preserved liver function. Rather than considering resection and transplantation as mutually exclusive, resection and transplantation should be considered as complementary in helping our patients to struggle through the battle against HCC. Instead of restricting patients’ access to transplantation, the transplant community should strive to expand the criteria for transplantation such that many more patients can benefit from this procedure. Before the era of sufficient graft supply arrives, liver surgeons should continue to develop innovations that can expand the resectability of HCC. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong. stfan@hku.hk 736  |  DECEMBER 2012  |  VOLUME 9 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. International Agency for Research on Cancer. Liver cancer incidence, mortality and prevalence worldwide in 2008 [online], http://globocan. iarc.fr/factsheet.asp (2012). Roskams, T. Kojiro, M. Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis. Semin. Liver Dis. 30, 17–25 (2010). Torimura, T. et al. Mechanism of fibrous capsule formation surrounding hepatocellular carcinoma. Immunohistochemical study. Arch. Pathol. Lab. Med. 115, 365–371 (1991). Kojiro, M. in Pathology of Hepatocellular Carcinoma 31–49 (Blackwell Publishing, Malden, 2006). Zhu, L. X., Wang, G. S. Fan, S. T. Spontaneous rupture of hepatocellular carcinoma. Br. J. Surg. 83, 602–607 (1996). O’Malley, M. E., Takayama, Y. Sherman, M. Outcome of small (10–20 mm) arterial phaseenhancing nodules seen on triphasic liver CT in patients with cirrhosis or chronic liver disease. Am. J. Gastroenterol. 100, 1523–1528 (2005). Yang, Z. F., Poon, R. T., To, J., Ho, D. W. Fan, S. T. The potential role of hypoxia inducible factor 1α in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. Cancer Res. 64, 5496–5503 (2004). Man, K. et al. Molecular signature linked to acute phase injury and tumor invasiveness in small‑for‑size liver grafts. Ann. Surg. 251, 1154–1161 (2010). Penn, I. The effect of immunosuppression on pre-existing cancers. Transplantation 55, 742–747 (1993). Fan, S. T. et al. Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: a 20-year experience. Ann. Surg. 253, 745–758 (2011). Kubota, K. et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology 26, 1176–1181 (1997). Takayama, T. Makuuchi, M. Preoperative portal vein embolization: is it useful? J. Hepatobiliary Pancreat. Surg. 11, 17–20 (2004). Gaba, R. C. et al. Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium‑90 radioembolization. Ann. Surg. Oncol. 16, 1587–1596 (2009). Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008). Finkelstein, S. D. et al. Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology 37, 871–879 (2003). Sherman, M. Recurrence of hepatocellular carcinoma. N. Engl. J. Med. 359, 2045–2047 (2008). Fan, S. T. et al. Prediction of posthepatectomy recurrence of hepatocellular carcinoma by circulating cancer stem cells: a prospective study. Ann. Surg. 254, 569–576 (2011). Okamura, Y. et al. Prognostic significance of postoperative complications after hepatectomy for hepatocellular carcinoma. J. Surg. Oncol. 104, 814–821 (2011). Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008). Huang, J. et al. A randomized trial comparing radiofrequency ablation and surgical resection 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. for HCC conforming to the Milan criteria. Ann. Surg. 252, 903–912 (2010). Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–699 (1996). Yao, F. Y. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am. J. Transplant. 8, 1982–1989 (2008). Zheng, S. S. et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 85, 1726–1732 (2008). DuBay, D. et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann. Surg. 253, 166–172 (2011). Lee, S. G. et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl. 14, 935–945 (2008). Chan, S. C., Fan, S. T., Lo, C. M., Liu, C. L. Wong, J. Toward current standards of donor right hepatectomy for adult‑to‑adult live donor liver transplantation through the experience of 200 cases. Ann. Surg. 254, 110–117 (2007). Bhangui, P et al. Intention‑to‑treat analysis of . liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology 53, 1570–1579 (2011). Fan, S. T. et al. Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria. Br. J. Surg. 98, 1292–1300 (2011). Lo, C. M. et al. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br. J. Surg. 94, 78–86 (2007). Fan, S. T. in Living Donor Liver Transplantation, 2nd edn 322 (World Scientific, Singapore, 2011). Chan, S. C. et al. Survival advantage of primary liver transplantation for hepatocellular carcinoma within the up‑to‑7 criteria with microvascular invasion. Hepatol. Int. http:// dx.doi.org/10.1007/s12072-011-9318-3. Klintmalm, G. B. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann. Surg. 228, 479–490 (1998). Fung, J. et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 141, 1212–1219 (2011). Doyle, M. B. et al. Liver transplantation for hepatocellular carcinoma: long-term results suggest excellent outcomes. J. Am. Coll. Surg. 215, 19–28 (2012). Portolani, N. et al. Limited liver resection: a good indication for the treatment of hepatocellular carcinoma in elderly patients. Jpn J. Clin. Oncol. 41, 1358–1365 (2011). Koniaris, L. G. et al. Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma? Ann. Surg. 254, 527–538 (2011). Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2009). Ng, K. K. et al. Survival analysis of patients with transplantable recurrent hepatocellular carcinoma. Arch. Surg. 143, 68–74 (2008). Majno, P . E., Sarasin, F. P Mentha, G. ., Hadengue, A. Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved
  • 6. PERSPECTIVES hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology 31, 899–906 (2000). 40. Fuks, D. et al. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention‑to‑treat analysis. Hepatology 55, 132–140 (2012). 41. Poon, R. T., Fan, S. T., Lo, C. M., Liu, C. L. Wong, J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann. Surg. 235, 373–382 (2002). 42. Sala, M. et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl. 10, 1294–1300 (2004). 43. Scatton, O. et al. Hepatocellular carcinoma developed on compensated cirrhosis: resection as a selection tool for liver transplantation. Liver Transpl. 14, 779–788 (2008). 44. Landman, M. P Feurer, I. D., Pinson, C. W. ., Moore, D. E. Which is more cost-effective under NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved the MELD system: primary liver transplantation, or salvage transplantation after hepatic resection or after loco-regional therapy for hepatocellular carcinoma within Milan criteria? HPB (Oxford) 13, 783–791 (2011). 45. Ito, T. et al. Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation. Liver Transpl. 13, 1637–1644 (2007). 46. Sugawara, Y., Tamura, S. Makuuchi, M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig. Dis. 25, 310–312 (2007). VOLUME 9  |  DECEMBER 2012  |  737