- Email: [email protected]
Surgical Approaches to Hepatocellular Carcinoma
Author's Accepted Manuscript
Surgical Approaches to Hepatocellular Carcinoma Audrey E. Ertel MD, Shimul A. Shah MD, MHCM
PII: DOI: Reference:
S0037-198X(16)00010-9 http://dx.doi.org/10.1053/j.ro.2016.02.004 YSROE50541
To appear in:
Seminar in Roentgenology
www.elsevier.com/locate/enganabound
Cite this article as: Audrey E. Ertel MD, Shimul A. Shah MD, MHCM, Surgical Approaches to Hepatocellular Carcinoma, Seminar in Roentgenology, http://dx.doi.org/ 10.1053/j.ro.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Surgical Approaches to Hepatocellular Carcinoma
Audrey E. Ertel MD1 and Shimul A Shah MD, MHCM1 Cincinnati Research in Outcomes and Safety in Surgery (CROSS) 1 Department of Surgery, University of Cincinnati School of Medicine Cincinnati, OH Running Title: Surgical options for hepatocellular carcinoma
Grants and Financial Support Funding was from the University of Cincinnati Department of Surgery. The authors report no financial disclosures.
Category: Review article
Corresponding Author: Shimul A. Shah, MD, MHCM Associate Professor of Surgery Division of Transplant Surgery University of Cincinnati College of Medicine 231 Albert Sabin Way, ML 0558, MSB 2006C Cincinnati, OH 45267-0558 Phone: 513-558-3993 Fax: 513-558-8689 E-mail: [email protected]
Ertel et al. 2 Abstract Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, the sixth most prevalent cancer and, the second leading cause of cancer-related deaths worldwide. In the United States, cancer of the liver and intrahepatic bile ducts was responsible for an estimated 23,000 deaths in the year 2014 alone.1 However, recent decades have shown significant increases in North America, likely due to the increased prevalence of chronic hepatitis infections (viral hepatitis B & C), alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH)2. Operative interventions remain the only potential treatment that offers cure to patients diagnosed with HCC. However, due to the aggressive nature of the disease, very few patients remain eligible for surgical intervention. Recent advances in the surgical field, specifically within transplantation and the advent of ablative therapies, have increased the opportunity for cure to many of these patients.
Introduction Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, the sixth most prevalent cancer worldwide and, in recent years, has surpassed stomach cancer to become the second leading cause of cancerrelated deaths worldwide (World Cancer Report 2014). Historically, rates of HCC have been low in the U.S. as compared to Southeast Asia and sub-Saharan Africa. However, recent decades have shown significant increases in the incidence of HCC in the U.S. likely due to the increased prevalence of chronic
Ertel et al. 3 hepatitis infections (viral hepatitis B & C), alcoholic steatohepatitis, and nonalcoholic steatohepatitis (NASH) in developed countries.2 In the United States, cancer of the liver and intrahepatic bile ducts was responsible for an estimated 23,000 deaths in the year 2014 alone.1 This is due, in part, to it’s dismal prognosis with overall 1- and 3- year survival rates of only 36% and 17%.3 Hepatic resection, liver transplantation, and ablative therapies (at early stages) are the only available interventions that have the potential for cure. However, due to the aggressive nature of this disease, only 15% of patients are eligible for curative treatments at the time of presentation.4 Diagnosis If caught at an early stage, HCC is associated with a 90% survival rate following treatment 5 however, diagnosis is often delayed due to small tumor burden and lack of symptoms (Figure 1). Currently 70-90% of cases of HCC develop in the setting of chronic liver disease6 and the aggressive nature of this tumor leaves the majority without the opportunity for curative intervention. As a result, surveillance for HCC has become a key factor in reducing HCC mortality. A randomized controlled trial by Zhang et al. demonstrated a 37% reduction in mortality with the institution of biannual screening program using ultrasound and alpha-fetoprotein (AFP) levels in high-risk patients. 7 Patients suspected on screening to have evidence of disease undergo additional testing including computed tomography (CT) or magnetic resonance imaging (MRI). Because the typical radiographic appearance of HCC is quite specific, both contrast enhanced CT and gadolinium enhanced MRI are often able to establish the diagnosis of
Ertel et al. 4 HCC without the need for biopsy. However, both MRI and CT have limited ability to detect lesions <1cm, further complicating the ability to discover very early stage HCC. Biopsy may be required for smaller lesions lacking the typical radiographic features consistent with HCC. Additional scans to detect vascular invasion and metastasis may be necessary prior to surgical planning. Staging Staging is critical in establishing the appropriate treatment modality for patients with a diagnosis of HCC. Several staging systems exist for HCC however no consensus has been reached as to which system is the most accurate in predicting long-term outcomes and survival. The most commonly used staging system for patients undergoing surgical intervention remains the Tumor, Node, Metastasis (TNM) system with the Barcelona Clinical Liver Cancer (BCLC) system preferred for patients with advanced stage disease.8 The BCLC classification system stratifies patients based upon tumor characteristics (size, number, proximity to vascular structures, and metastatic disease) as well as degree of underlying liver dysfunction and assigns subsequent treatments strategies. (Figure 2) Prognosis and degree of underlying liver dysfunction must be established concomitantly with staging. Cirrhosis of the liver has been discovered in nearly 90% of HCC cases and plays a vital role in determination of treatment modalities and outcomes.9 Surgical treatment including hepatic resection, liver transplantation, and ablative therapies (for very early stage tumors) are considered the only options for cure and often, the degree of underlying liver
Ertel et al. 5 disease or extent of HCC prevents patients from being eligible for curative intervention. All possible treatment options for HCC are included on Figure 3. Surgical Options Historically, surgical resection has been the only option for cure in patients with HCC. In the past 20 years orthotopic liver transplantation (LT) and ablative therapies have emerged as treatment options for patients who were deemed unsuitable for surgical resection due to underlying liver disease, extent of HCC, or tumor burden. Therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) have been utilized both independently and in combination with resection and/or LT to achieve tumor free survival in selected patients with HCC. Hepatic Resection Resection remains first-line treatment for patients with solitary tumors confined to the liver, lacking vascular invasion, and without underlying hepatic dysfunction. Very few patients are afforded the opportunity for early diagnosis but for those patients with a single, asymptomatic lesion less than 2cm in diameter survival rates near 90% following surgical resection.5 Patients with limited liver disease (Child-Pugh A) as evidenced by normal bilirubin, hepatic venous pressure gradient <10 mmHg, platelet count >100,000, and/or no esophageal varices on endoscopy have 5-year survival rates ranging between 41% and 74% following surgical resection.4 The degree of underlying liver dysfunction has been shown to be a major predictor of post-operative outcomes, specifically demonstrating a sharp increase in peri-operative mortality and morbidity as
Ertel et al. 6 degree of liver dysfunction increases.10 However, more than 90% of patients diagnosed with HCC have evidence of underlying cirrhosis at the time of presentation and as such, limits the access to cure for many patients.9 Some high-volume centers have pushed the limits of patient selection, performing surgical resections on patients with varying degrees of cirrhosis with minimal increases in peri-operative mortality and 5-year survival rates greater than 50%.11, 12 It is unlikely that these results can be generalized outside of highvolume tertiary care centers and the guidelines from The National Comprehensive Cancer Network (NCCN) remain that surgical resection is recommended for early HCC in patients without underlying liver dysfunction or vascular invasion. Size has been proven to be an important determinant of outcomes following surgical resection and as such, most surgical groups will limit resection eligibility to patients with tumors less than 5 cm in diameter. The five-year survival rates of patients with tumors less than 5 cm ranges from 57%-63% compared with 37% in patients with tumors >5 cm. Additionally, those with tumors larger than 10 cm have been found to have a survival rate of 32%.13-15 As tumor diameter increases so does risk of vascular invasion and distant metastasis. However, more recent data from single-center studies have shown that in carefully selected patients resection for tumors over 10 cm showed similar overall and recurrence-free survival as compared to patients with smaller tumors.16 Multi-focality, although not a definite contraindication to surgical resection, is often viewed as one by many centers due to the association with
Ertel et al. 7 recurrence (>90%) and worse overall survival (<30%).17 Surgical resection for multi-focal HCC, inside the Milan criteria, remains a potentially curative alternative for those patients not suitable for LT. Malignant vascular invasion remains a strict contraindication to surgical resection of HCC with 5-year survival rates as low as 6%.18 Perioperative mortality rates in patients undergoing surgical resection for HCC are reported at 3%-5%. This low mortality rate is in part due to refinements in patient selection, surgical techniques including introduction of laparoscopic resections, CT guided instruments enabling precise tumor location, and reliable dissection instruments that achieve relatively bloodless dissections. 19 Tumor recurrence following surgical resection of HCC remains a major disadvantage of surgical resection and affects nearly 70% of patients. These patients are at risk for development of de novo HCC arising within the remnant liver as it remains susceptible to malignant degeneration due to the ongoing chronic liver disease.20-23 The majority of recurrences, however, occur within the first 2 years suggesting dissemination from the primary tumor as a more commonly encountered cause of recurrence. Re-resection has been attempted in highly selected patients though many factors complicate this management option and it is rarely utilized. Due to the consistently high recurrence rates, several studies have evaluated the use of locoregional therapies to help reduce the risk of tumor recurrence following surgical resection. Interferon therapy has been met with some success although specific treatment regimens are not yet available due to lack of uniform data.20 The most effective means of preventing recurrence
Ertel et al. 8 remains salvage LT. Patients who are identified as being high risk for recurrence experience a 25% recurrence rate following salvage LT as compared to 70-90% following surgical resection.24 Additionally, overall survival rates in patients undergoing LT for HCC recurrence after surgical resection are similar to those patients undergoing primary LT for HCC. 25 Post-resection hepatic failure is a dreaded complication following hepatic resection that often results in death. This is seen most often when the residual liver remnant is “small-for-size” or, due to underlying parenchymal dysfunction, is unable to meet the synthetic and waste processing demand placed on the hepatic system. Planning for future liver remnant (FLR) following surgical resection of HCC is crucial in pre-operative evaluation. The NCCN recommends that the liver remnant be at least 20% of total volume in patients without underlying liver disease. In those patients having early stage cirrhosis, or some degree of underlying liver dysfunction, recommendations increase to 30%-40% FLR. CT volumetrics is used by many centers to assess total liver volume preoperatively so as predict FLR following resection. Those patients with inadequate reserve as determined by CT or MRI volumetrics (Figure 6) will often undergo procedures to induce liver hypertrophy in hopes of growing the FLR to the threshold of 20-25%. The mainstay of treatment in this regard is portal vein embolization (PVE), a widely used practice that has been successful in growing liver volume from 8%-27%.26 Through PVE, a branch of the portal venous system is occluded (routinely the area in which the tumor resides) which results in compensatory contralateral hypertrophy and thus, increase in FLR. Morbidity
Ertel et al. 9 following PVE is low at 2.2% with no mortality reported and a post PVE resection rate of 85% in a meta-analysis of 1088 patients.26 Other methods of preoperative liver hypertrophy exist, including associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) a more invasive approach that involves a 2-stage procedure in which the first stage consisted of portal vein ligation and in situ splitting of the liver flowed by a second stage procedure involving completion hepatectomy. While ALPPS resulted in significant liver volume hypertrophy with increased liver volume ranging from 74%-192% morbidity and mortality rates of 68% and 12% respectively limit its use to highly selected patients. 27 Liver Transplantation Over the past 2 decades, LT has established itself as a viable treatment option for patients with unresectable disease. LT is optimal because it results in the widest resection margins, cures the patient of their cirrhosis – a wellestablished risk factor for further development of de novo HCC - and restores hepatic function. A landmark study published in 1996 by Mazzaferro et al increased enthusiasm in LT for patients with HCC by publishing their findings in 48 patients with small, unresectable disease who underwent LT. Their criteria for LT, which came to be known as the Milan criteria, included a solitary tumor measuring less than 5 cm or no more than 3 tumors measuring less than 3 cm each without significant vascular invasion. Survival rates for patients who met these criteria (75% at 4 years) rivaled routine LT recipients for end-stage liver disease without HCC.28 Not long after publication, the United Network for Organ
Ertel et al. 10 Sharing (UNOS) incorporated the Milan criteria and supported LT for those HCC patients who qualified. Subsequent experience with LT for small hepatocellular carcinomas in the setting of cirrhosis has confirmed similar findings with 5-year survival rates over 70% and recurrence rates less than 15%.29-31 The management of a small HCC in a compensated cirrhotic remains controversial. 32 While outcome measures remain excellent following LT for HCC, due to the shortage of donor organs the long wait list times in some regions has become a major disadvantage. Progression of disease often occurs during waitlist time, placing patients outside of the Milan criteria and without the opportunity for curative intervention. Under the current UNOS policy, patients with unresectable HCC but who are within the Milan criteria start with Model for End-Stage Liver Disease (MELD) score of 22 and experience stepwise increase in MELD every 3 months – with each increase being the equivalent of an additional 10% increase in candidate mortality risk. Despite MELD exception points, many patients are still progressing beyond the Milan criteria while awaiting transplatnation. As a result, several centers have expanded their threshold for transplant in these patients. Most notably, University of California-San Francisco (UCSF) implemented a modified Milan criteria with promising results. (Table 1) The UCSF criteria included patients with a solitary tumor up to 6.5 cm or no more than 3 tumors each measuring less than 4.5 cm in diameter without gross vascular invasion. Results from their initial experience demonstrated 5-year survival rates of 90% and 75%.33 Follow up studies have shown that patients meeting Milan criteria had similar 5-year survival compared to patients meeting
Ertel et al. 11 the UCSF criteria both by pre-operative imaging (79% vs. 64%) and pathology of explanted liver (86% vs. 71%). 34 Surgical resection as a bridge to LT has been proposed as a potential strategy for patients who otherwise would not be candidates for surgical resection in hopes of stalling progression during time on the waitlist for donor organs. Although survival after salvage LT for recurrent HCC within the Milan criteria has been shown to be comparable to survival after primary LT in patients with HCC,25 over 30% of patients experienced recurrences that placed them outside of the Milan criteria and therefore ineligible for transplant. 35 Lastly, down-staging and/or pre-treatment of patients awaiting LT has been successfully implemented using loco-regional therapies such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). Patients with stage III or IV HCC are not eligible for LT under the Milan criteria. However, recent data out of Washington University in St. Louis showed successful downstaging of 23.7% (18 of 76) of patients with advanced stage HCC using TACE, a procedure in which a chemotherapeutic agent is selectively infused into hepatic artery circulation followed by gelfoam embolization, which results in targeted tumor necrosis. Of the 18 patients who were successfully down-staged, 17 went on to undergo LT under Milan criteria and demonstrated a 5-year survival rate of 93.8%.36 UCSF implemented a similar down-staging protocol using TACE to place advanced stage HCC patients within the UCSF criteria and experienced similar results with an overall 4-year survival rate of 92.1%.37 TACE has also been successfully used in bridging HCC transplant candidates when progression
Ertel et al. 12 of disease threatens their eligibility to receive a donor organ. Tumor necrosis rates following TACE for bridging therpay were reported to be 27%-57%36 with 5year survival rates (post-transplant) of 93.8%, 13.2 percent higher than those patients undergoing LT without pre-treatment.37 While TACE remains the most commonly used bridging therapy, radiofrequency ablation has emerged as an attractive alternative. RFA entails direct application of thermal energy to the liver parenchyma that has been replaced by HCC. As the temperature of the surrounding tissue rises, cells die and a rim of coagulation necrosis around the thermal probe results. Complete tumor necrosis has been reported in 47%-75% of cases with the rate of necrosis highest among smaller tumors.38 3-year posttransplant survival rates were reported to be 83%. Local Ablation Percutaneous local ablation includes RFA and percutaneous ethanol injections (PEI). These therapies are the standard of care for patients with BCLC stage 0-A who are not suitable for surgical resection. PEI was the most widely accepted local ablation technique prior to the introduction of RFA and involves injection of ethanol directly into the tumor that induces local coagulation necrosis resulting in fibrosis. For tumors less than 3 cm in diameter, PEI and RFA (Figure 4) are successful in complete tumor necrosis in 80%-90% of cases.39 As RFA has been gaining momentum in the United States, recent publications have highlighted its reliability in complete tumor necrosis over that of PEI. Recommendations for use of RFA as primary treatment of HCC remain limited to tumors less than 4 cm in diameter or patients with less than 3 nodules, none
Ertel et al. 13 greater than 3 cm in diameter.4 Use of laparoscopy (Figure 5) or percutaneous approach has been center dependent. Conclusion Surgical approaches to hepatocellular carcinoma remain limited as compared to other solid-tumor malignancies due to the aggressive nature of this disease. Surgical resection remains the mainstay of treatment for patients with early-stage HCC without significant underlying liver disease and can offer hope for cure in well-selected patients. The long-term effectiveness of this strategy is dependent upon disease recurrence-which remains quite high. Loco-regional therapies, however have offered solutions to those patients who experience disease recurrence after resection. Since introduction of the Milan criteria, LT has become the most favorable of surgical options for patients with underlying cirrhosis. The excellent recurrence-free survival rate encountered following LT for HCC has sparked the debate between surgical resection in borderline cases versus LT. Unfortunately this potentially curative intervention is limited by the shortage of donor livers that is being experienced world-wide within the field of transplantation. Loco-regional therapies show promising potential in downstaging and bridging therapy to hepatic resection and LT. Metastatic disease and malignant vascular invasion remain contraindications to surgical intervention.
Ertel et al. 14 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Seigel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA Cancer J. Clin. 2014;64:20. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60:17671775. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27-34. Crissien AM, Frenette C. Current management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2014;10:153-161. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118-1127. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis. 2010;30:3-16. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417-422. Munene G, Vauthey JN, Dixon E. Summary of the 2010 AHPBA/SSO/SSAT Consensus Conference on HCC. Int J Hepatol. 2011;2011:565060. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35-50. Belghiti J, Fuks D. Liver resection and transplantation in hepatocellular carcinoma. Liver Cancer. 2012;1:71-82. Poon RT, Fan ST, Lo CM, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg. 2002;236:602611. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology. 2008;134:1908-1916. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229:790-799; discussion 799-800. Zhou XD, Tang ZY, Yang BH, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479-1486. Shah SA, Wei AC, Cleary SP, et al. Prognosis and Results After Resection of Very Large (>/=10 cm) Hepatocellular Carcinoma. J.Gastrointest.Surg. 2007;11:589-595. Liau KH, Ruo L, Shia J, et al. Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma. Cancer. 2005;104:1948-1955. Wang BW, Mok KT, Liu SI, et al. Is hepatectomy beneficial in the treatment of multinodular hepatocellular carcinoma? J Formos Med Assoc. 2008;107:616626. Lang H, Sotiropoulos GC, Brokalaki EI, et al. Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers. J Am Coll Surg. 2007;205:27-36.
Ertel et al. 15 19. 20. 21. 22. 23. 24. 25.
26. 27.
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Fong ZV, Tanabe KK. The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: a comprehensive and evidence-based comparison and review. Cancer. 2014;120:2824-2838. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181-200. Mancuso A. Management of hepatocellular carcinoma: Enlightening the gray zones. World J Hepatol. 2013;5:302-310. Wong R, Frenette C. Updates in the management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2011;7:16-24. Shah SA, Greig PD, Gallinger S, et al. Factors associated with early recurrence after resection for hepatocellular carcinoma and outcomes. J Am Coll Surg. 2006;202:275-283. Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl. 2004;10:1294-1300. Zhu Y, Dong J, Wang WL, Li MX, Lu Y. Short- and long-term outcomes after salvage liver transplantation versus primary liver transplantation for hepatocellular carcinoma: a meta-analysis. Transplant Proc. 2013;45:33293342. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247:49-57. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-forsize settings. Ann Surg. 2012;255:405-414. 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. 1996;334:693-699. Bruix J, Sherman M, Practice Guidelines Committee AeAftSoLD. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236. Bruix J, Sherman M, Diseases AAftSoL. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022. Liver EAFTSOT, Cancer EOFRATO. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943. Shah SA, Cleary SP, Tan JC, et al. An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Annals of surgical oncology. 2007;14:2608-2614. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394-1403. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg. 2007;246:502-509; discussion 509-511.
Ertel et al. 16 35. 36. 37. 38. 39.
Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg. 2003;238:508-518; discussion 518-509. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008;248:617-625. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-totreat analysis. Hepatology. 2008;48:819-827. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg. 2004;240:900-909. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999;210:655-661.
Figure Legends Figure 1: Operative exposure of HCC lesion before resection Figure 2: Barcelona Clinical Liver Cancer (BCLC) staging system Figure 3: Treatment modalities for HCC Figure 4: a) Enhanced CT of the abdomen demonstrating arterial enhancement of hepatocellular carcinoma in the right hepatic lobe pre-RFA; b) high T1 signal on a fat saturated T1-weighted pre-contrast MRI post-RFA within the lesion indicating coagulative necrosis; c) calcifications within treated hepatocellular carcinoma post-RFA. Figure 5: Laparoscopic approach with ultrasound guidance to radiofrequency ablation Figure 6: a) Enhanced CT of the abdomen demonstrating a 2 cm hepatocellular carcinoma in the left hepatic lobe; b) postprocessing to determine right hepatic lobe liver volume after resection; c) MIP with total right hepatic lobe volume of 703 cm3.
Ertel et al. 17
Table 1 AJCC TNM staging, Seventh Edition41
Classification
Definition
Stage
Primary Tumor(T) TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Solitary tumor w/o vascular
Stage l
invasion T2
Solitary tumor w/ vascular
Stage ll
invasion or multiple tumor none 5cm T3a
Multiple tumors 5cm
Stage lllA
T3b
Single tumor or multiple tumors
Stage lllB
of any size involving a major branch of the portal vein or hepatic vein T4
Tumors w/ direct invasion of adjacent organs other than gallbladder or with perforation of visceral peritoneum
Regional Lymph Nodes(N) NX
Regional LN cannot be assessed
Stage lllC
Ertel et al. 18 N0
No regional node metastasis
Stage lVA
N1
Regional LN metastasis
Stage lVB
Distant Metastasis(M) M0
No distant metastasis
M1
Distant metastasis
Histologic Grade(G) G1
Well differentiated
G2
Moderately differentiated
G3
Poorly differentiated
G4
Undifferentiated
Fibrosis Score(F)
the fibrosis score as defined by
Ishak F0
Fibrosis score 0–4 (none to moderate fibrosis)
F1
Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Ertel et al. 19 Table 2 Comparison of Milan & UCSF Criteria for Liver Transplantation in Patients with HCC
Size
Milan
UCSF
Solitary tumor: 5cm
Solitary tumor: 6.5cm
Multifocal Disease: 3
Multifocal Disease: 3
tumors each 3cm
tumors each 4.5cm, & total not exceeding 8cm.
Survival Rate
75% at 4 years29
75.2% at 5 years33
Recurrence-free Survival
74% at 5 years34
65% at 5 years34
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Surgical Approaches to Hepatocellular Carcinoma Audrey E. Ertel MD, Shimul A. Shah MD, MHCM
PII: DOI: Reference:
S0037-198X(16)00010-9 http://dx.doi.org/10.1053/j.ro.2016.02.004 YSROE50541
To appear in:
Seminar in Roentgenology
www.elsevier.com/locate/enganabound
Cite this article as: Audrey E. Ertel MD, Shimul A. Shah MD, MHCM, Surgical Approaches to Hepatocellular Carcinoma, Seminar in Roentgenology, http://dx.doi.org/ 10.1053/j.ro.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Surgical Approaches to Hepatocellular Carcinoma
Audrey E. Ertel MD1 and Shimul A Shah MD, MHCM1 Cincinnati Research in Outcomes and Safety in Surgery (CROSS) 1 Department of Surgery, University of Cincinnati School of Medicine Cincinnati, OH Running Title: Surgical options for hepatocellular carcinoma
Grants and Financial Support Funding was from the University of Cincinnati Department of Surgery. The authors report no financial disclosures.
Category: Review article
Corresponding Author: Shimul A. Shah, MD, MHCM Associate Professor of Surgery Division of Transplant Surgery University of Cincinnati College of Medicine 231 Albert Sabin Way, ML 0558, MSB 2006C Cincinnati, OH 45267-0558 Phone: 513-558-3993 Fax: 513-558-8689 E-mail: [email protected]
Ertel et al. 2 Abstract Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, the sixth most prevalent cancer and, the second leading cause of cancer-related deaths worldwide. In the United States, cancer of the liver and intrahepatic bile ducts was responsible for an estimated 23,000 deaths in the year 2014 alone.1 However, recent decades have shown significant increases in North America, likely due to the increased prevalence of chronic hepatitis infections (viral hepatitis B & C), alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH)2. Operative interventions remain the only potential treatment that offers cure to patients diagnosed with HCC. However, due to the aggressive nature of the disease, very few patients remain eligible for surgical intervention. Recent advances in the surgical field, specifically within transplantation and the advent of ablative therapies, have increased the opportunity for cure to many of these patients.
Introduction Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, the sixth most prevalent cancer worldwide and, in recent years, has surpassed stomach cancer to become the second leading cause of cancerrelated deaths worldwide (World Cancer Report 2014). Historically, rates of HCC have been low in the U.S. as compared to Southeast Asia and sub-Saharan Africa. However, recent decades have shown significant increases in the incidence of HCC in the U.S. likely due to the increased prevalence of chronic
Ertel et al. 3 hepatitis infections (viral hepatitis B & C), alcoholic steatohepatitis, and nonalcoholic steatohepatitis (NASH) in developed countries.2 In the United States, cancer of the liver and intrahepatic bile ducts was responsible for an estimated 23,000 deaths in the year 2014 alone.1 This is due, in part, to it’s dismal prognosis with overall 1- and 3- year survival rates of only 36% and 17%.3 Hepatic resection, liver transplantation, and ablative therapies (at early stages) are the only available interventions that have the potential for cure. However, due to the aggressive nature of this disease, only 15% of patients are eligible for curative treatments at the time of presentation.4 Diagnosis If caught at an early stage, HCC is associated with a 90% survival rate following treatment 5 however, diagnosis is often delayed due to small tumor burden and lack of symptoms (Figure 1). Currently 70-90% of cases of HCC develop in the setting of chronic liver disease6 and the aggressive nature of this tumor leaves the majority without the opportunity for curative intervention. As a result, surveillance for HCC has become a key factor in reducing HCC mortality. A randomized controlled trial by Zhang et al. demonstrated a 37% reduction in mortality with the institution of biannual screening program using ultrasound and alpha-fetoprotein (AFP) levels in high-risk patients. 7 Patients suspected on screening to have evidence of disease undergo additional testing including computed tomography (CT) or magnetic resonance imaging (MRI). Because the typical radiographic appearance of HCC is quite specific, both contrast enhanced CT and gadolinium enhanced MRI are often able to establish the diagnosis of
Ertel et al. 4 HCC without the need for biopsy. However, both MRI and CT have limited ability to detect lesions <1cm, further complicating the ability to discover very early stage HCC. Biopsy may be required for smaller lesions lacking the typical radiographic features consistent with HCC. Additional scans to detect vascular invasion and metastasis may be necessary prior to surgical planning. Staging Staging is critical in establishing the appropriate treatment modality for patients with a diagnosis of HCC. Several staging systems exist for HCC however no consensus has been reached as to which system is the most accurate in predicting long-term outcomes and survival. The most commonly used staging system for patients undergoing surgical intervention remains the Tumor, Node, Metastasis (TNM) system with the Barcelona Clinical Liver Cancer (BCLC) system preferred for patients with advanced stage disease.8 The BCLC classification system stratifies patients based upon tumor characteristics (size, number, proximity to vascular structures, and metastatic disease) as well as degree of underlying liver dysfunction and assigns subsequent treatments strategies. (Figure 2) Prognosis and degree of underlying liver dysfunction must be established concomitantly with staging. Cirrhosis of the liver has been discovered in nearly 90% of HCC cases and plays a vital role in determination of treatment modalities and outcomes.9 Surgical treatment including hepatic resection, liver transplantation, and ablative therapies (for very early stage tumors) are considered the only options for cure and often, the degree of underlying liver
Ertel et al. 5 disease or extent of HCC prevents patients from being eligible for curative intervention. All possible treatment options for HCC are included on Figure 3. Surgical Options Historically, surgical resection has been the only option for cure in patients with HCC. In the past 20 years orthotopic liver transplantation (LT) and ablative therapies have emerged as treatment options for patients who were deemed unsuitable for surgical resection due to underlying liver disease, extent of HCC, or tumor burden. Therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) have been utilized both independently and in combination with resection and/or LT to achieve tumor free survival in selected patients with HCC. Hepatic Resection Resection remains first-line treatment for patients with solitary tumors confined to the liver, lacking vascular invasion, and without underlying hepatic dysfunction. Very few patients are afforded the opportunity for early diagnosis but for those patients with a single, asymptomatic lesion less than 2cm in diameter survival rates near 90% following surgical resection.5 Patients with limited liver disease (Child-Pugh A) as evidenced by normal bilirubin, hepatic venous pressure gradient <10 mmHg, platelet count >100,000, and/or no esophageal varices on endoscopy have 5-year survival rates ranging between 41% and 74% following surgical resection.4 The degree of underlying liver dysfunction has been shown to be a major predictor of post-operative outcomes, specifically demonstrating a sharp increase in peri-operative mortality and morbidity as
Ertel et al. 6 degree of liver dysfunction increases.10 However, more than 90% of patients diagnosed with HCC have evidence of underlying cirrhosis at the time of presentation and as such, limits the access to cure for many patients.9 Some high-volume centers have pushed the limits of patient selection, performing surgical resections on patients with varying degrees of cirrhosis with minimal increases in peri-operative mortality and 5-year survival rates greater than 50%.11, 12 It is unlikely that these results can be generalized outside of highvolume tertiary care centers and the guidelines from The National Comprehensive Cancer Network (NCCN) remain that surgical resection is recommended for early HCC in patients without underlying liver dysfunction or vascular invasion. Size has been proven to be an important determinant of outcomes following surgical resection and as such, most surgical groups will limit resection eligibility to patients with tumors less than 5 cm in diameter. The five-year survival rates of patients with tumors less than 5 cm ranges from 57%-63% compared with 37% in patients with tumors >5 cm. Additionally, those with tumors larger than 10 cm have been found to have a survival rate of 32%.13-15 As tumor diameter increases so does risk of vascular invasion and distant metastasis. However, more recent data from single-center studies have shown that in carefully selected patients resection for tumors over 10 cm showed similar overall and recurrence-free survival as compared to patients with smaller tumors.16 Multi-focality, although not a definite contraindication to surgical resection, is often viewed as one by many centers due to the association with
Ertel et al. 7 recurrence (>90%) and worse overall survival (<30%).17 Surgical resection for multi-focal HCC, inside the Milan criteria, remains a potentially curative alternative for those patients not suitable for LT. Malignant vascular invasion remains a strict contraindication to surgical resection of HCC with 5-year survival rates as low as 6%.18 Perioperative mortality rates in patients undergoing surgical resection for HCC are reported at 3%-5%. This low mortality rate is in part due to refinements in patient selection, surgical techniques including introduction of laparoscopic resections, CT guided instruments enabling precise tumor location, and reliable dissection instruments that achieve relatively bloodless dissections. 19 Tumor recurrence following surgical resection of HCC remains a major disadvantage of surgical resection and affects nearly 70% of patients. These patients are at risk for development of de novo HCC arising within the remnant liver as it remains susceptible to malignant degeneration due to the ongoing chronic liver disease.20-23 The majority of recurrences, however, occur within the first 2 years suggesting dissemination from the primary tumor as a more commonly encountered cause of recurrence. Re-resection has been attempted in highly selected patients though many factors complicate this management option and it is rarely utilized. Due to the consistently high recurrence rates, several studies have evaluated the use of locoregional therapies to help reduce the risk of tumor recurrence following surgical resection. Interferon therapy has been met with some success although specific treatment regimens are not yet available due to lack of uniform data.20 The most effective means of preventing recurrence
Ertel et al. 8 remains salvage LT. Patients who are identified as being high risk for recurrence experience a 25% recurrence rate following salvage LT as compared to 70-90% following surgical resection.24 Additionally, overall survival rates in patients undergoing LT for HCC recurrence after surgical resection are similar to those patients undergoing primary LT for HCC. 25 Post-resection hepatic failure is a dreaded complication following hepatic resection that often results in death. This is seen most often when the residual liver remnant is “small-for-size” or, due to underlying parenchymal dysfunction, is unable to meet the synthetic and waste processing demand placed on the hepatic system. Planning for future liver remnant (FLR) following surgical resection of HCC is crucial in pre-operative evaluation. The NCCN recommends that the liver remnant be at least 20% of total volume in patients without underlying liver disease. In those patients having early stage cirrhosis, or some degree of underlying liver dysfunction, recommendations increase to 30%-40% FLR. CT volumetrics is used by many centers to assess total liver volume preoperatively so as predict FLR following resection. Those patients with inadequate reserve as determined by CT or MRI volumetrics (Figure 6) will often undergo procedures to induce liver hypertrophy in hopes of growing the FLR to the threshold of 20-25%. The mainstay of treatment in this regard is portal vein embolization (PVE), a widely used practice that has been successful in growing liver volume from 8%-27%.26 Through PVE, a branch of the portal venous system is occluded (routinely the area in which the tumor resides) which results in compensatory contralateral hypertrophy and thus, increase in FLR. Morbidity
Ertel et al. 9 following PVE is low at 2.2% with no mortality reported and a post PVE resection rate of 85% in a meta-analysis of 1088 patients.26 Other methods of preoperative liver hypertrophy exist, including associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) a more invasive approach that involves a 2-stage procedure in which the first stage consisted of portal vein ligation and in situ splitting of the liver flowed by a second stage procedure involving completion hepatectomy. While ALPPS resulted in significant liver volume hypertrophy with increased liver volume ranging from 74%-192% morbidity and mortality rates of 68% and 12% respectively limit its use to highly selected patients. 27 Liver Transplantation Over the past 2 decades, LT has established itself as a viable treatment option for patients with unresectable disease. LT is optimal because it results in the widest resection margins, cures the patient of their cirrhosis – a wellestablished risk factor for further development of de novo HCC - and restores hepatic function. A landmark study published in 1996 by Mazzaferro et al increased enthusiasm in LT for patients with HCC by publishing their findings in 48 patients with small, unresectable disease who underwent LT. Their criteria for LT, which came to be known as the Milan criteria, included a solitary tumor measuring less than 5 cm or no more than 3 tumors measuring less than 3 cm each without significant vascular invasion. Survival rates for patients who met these criteria (75% at 4 years) rivaled routine LT recipients for end-stage liver disease without HCC.28 Not long after publication, the United Network for Organ
Ertel et al. 10 Sharing (UNOS) incorporated the Milan criteria and supported LT for those HCC patients who qualified. Subsequent experience with LT for small hepatocellular carcinomas in the setting of cirrhosis has confirmed similar findings with 5-year survival rates over 70% and recurrence rates less than 15%.29-31 The management of a small HCC in a compensated cirrhotic remains controversial. 32 While outcome measures remain excellent following LT for HCC, due to the shortage of donor organs the long wait list times in some regions has become a major disadvantage. Progression of disease often occurs during waitlist time, placing patients outside of the Milan criteria and without the opportunity for curative intervention. Under the current UNOS policy, patients with unresectable HCC but who are within the Milan criteria start with Model for End-Stage Liver Disease (MELD) score of 22 and experience stepwise increase in MELD every 3 months – with each increase being the equivalent of an additional 10% increase in candidate mortality risk. Despite MELD exception points, many patients are still progressing beyond the Milan criteria while awaiting transplatnation. As a result, several centers have expanded their threshold for transplant in these patients. Most notably, University of California-San Francisco (UCSF) implemented a modified Milan criteria with promising results. (Table 1) The UCSF criteria included patients with a solitary tumor up to 6.5 cm or no more than 3 tumors each measuring less than 4.5 cm in diameter without gross vascular invasion. Results from their initial experience demonstrated 5-year survival rates of 90% and 75%.33 Follow up studies have shown that patients meeting Milan criteria had similar 5-year survival compared to patients meeting
Ertel et al. 11 the UCSF criteria both by pre-operative imaging (79% vs. 64%) and pathology of explanted liver (86% vs. 71%). 34 Surgical resection as a bridge to LT has been proposed as a potential strategy for patients who otherwise would not be candidates for surgical resection in hopes of stalling progression during time on the waitlist for donor organs. Although survival after salvage LT for recurrent HCC within the Milan criteria has been shown to be comparable to survival after primary LT in patients with HCC,25 over 30% of patients experienced recurrences that placed them outside of the Milan criteria and therefore ineligible for transplant. 35 Lastly, down-staging and/or pre-treatment of patients awaiting LT has been successfully implemented using loco-regional therapies such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). Patients with stage III or IV HCC are not eligible for LT under the Milan criteria. However, recent data out of Washington University in St. Louis showed successful downstaging of 23.7% (18 of 76) of patients with advanced stage HCC using TACE, a procedure in which a chemotherapeutic agent is selectively infused into hepatic artery circulation followed by gelfoam embolization, which results in targeted tumor necrosis. Of the 18 patients who were successfully down-staged, 17 went on to undergo LT under Milan criteria and demonstrated a 5-year survival rate of 93.8%.36 UCSF implemented a similar down-staging protocol using TACE to place advanced stage HCC patients within the UCSF criteria and experienced similar results with an overall 4-year survival rate of 92.1%.37 TACE has also been successfully used in bridging HCC transplant candidates when progression
Ertel et al. 12 of disease threatens their eligibility to receive a donor organ. Tumor necrosis rates following TACE for bridging therpay were reported to be 27%-57%36 with 5year survival rates (post-transplant) of 93.8%, 13.2 percent higher than those patients undergoing LT without pre-treatment.37 While TACE remains the most commonly used bridging therapy, radiofrequency ablation has emerged as an attractive alternative. RFA entails direct application of thermal energy to the liver parenchyma that has been replaced by HCC. As the temperature of the surrounding tissue rises, cells die and a rim of coagulation necrosis around the thermal probe results. Complete tumor necrosis has been reported in 47%-75% of cases with the rate of necrosis highest among smaller tumors.38 3-year posttransplant survival rates were reported to be 83%. Local Ablation Percutaneous local ablation includes RFA and percutaneous ethanol injections (PEI). These therapies are the standard of care for patients with BCLC stage 0-A who are not suitable for surgical resection. PEI was the most widely accepted local ablation technique prior to the introduction of RFA and involves injection of ethanol directly into the tumor that induces local coagulation necrosis resulting in fibrosis. For tumors less than 3 cm in diameter, PEI and RFA (Figure 4) are successful in complete tumor necrosis in 80%-90% of cases.39 As RFA has been gaining momentum in the United States, recent publications have highlighted its reliability in complete tumor necrosis over that of PEI. Recommendations for use of RFA as primary treatment of HCC remain limited to tumors less than 4 cm in diameter or patients with less than 3 nodules, none
Ertel et al. 13 greater than 3 cm in diameter.4 Use of laparoscopy (Figure 5) or percutaneous approach has been center dependent. Conclusion Surgical approaches to hepatocellular carcinoma remain limited as compared to other solid-tumor malignancies due to the aggressive nature of this disease. Surgical resection remains the mainstay of treatment for patients with early-stage HCC without significant underlying liver disease and can offer hope for cure in well-selected patients. The long-term effectiveness of this strategy is dependent upon disease recurrence-which remains quite high. Loco-regional therapies, however have offered solutions to those patients who experience disease recurrence after resection. Since introduction of the Milan criteria, LT has become the most favorable of surgical options for patients with underlying cirrhosis. The excellent recurrence-free survival rate encountered following LT for HCC has sparked the debate between surgical resection in borderline cases versus LT. Unfortunately this potentially curative intervention is limited by the shortage of donor livers that is being experienced world-wide within the field of transplantation. Loco-regional therapies show promising potential in downstaging and bridging therapy to hepatic resection and LT. Metastatic disease and malignant vascular invasion remain contraindications to surgical intervention.
Ertel et al. 14 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Seigel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA Cancer J. Clin. 2014;64:20. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60:17671775. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27-34. Crissien AM, Frenette C. Current management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2014;10:153-161. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118-1127. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis. 2010;30:3-16. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417-422. Munene G, Vauthey JN, Dixon E. Summary of the 2010 AHPBA/SSO/SSAT Consensus Conference on HCC. Int J Hepatol. 2011;2011:565060. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35-50. Belghiti J, Fuks D. Liver resection and transplantation in hepatocellular carcinoma. Liver Cancer. 2012;1:71-82. Poon RT, Fan ST, Lo CM, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg. 2002;236:602611. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology. 2008;134:1908-1916. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229:790-799; discussion 799-800. Zhou XD, Tang ZY, Yang BH, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479-1486. Shah SA, Wei AC, Cleary SP, et al. Prognosis and Results After Resection of Very Large (>/=10 cm) Hepatocellular Carcinoma. J.Gastrointest.Surg. 2007;11:589-595. Liau KH, Ruo L, Shia J, et al. Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma. Cancer. 2005;104:1948-1955. Wang BW, Mok KT, Liu SI, et al. Is hepatectomy beneficial in the treatment of multinodular hepatocellular carcinoma? J Formos Med Assoc. 2008;107:616626. Lang H, Sotiropoulos GC, Brokalaki EI, et al. Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers. J Am Coll Surg. 2007;205:27-36.
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Fong ZV, Tanabe KK. The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: a comprehensive and evidence-based comparison and review. Cancer. 2014;120:2824-2838. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181-200. Mancuso A. Management of hepatocellular carcinoma: Enlightening the gray zones. World J Hepatol. 2013;5:302-310. Wong R, Frenette C. Updates in the management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2011;7:16-24. Shah SA, Greig PD, Gallinger S, et al. Factors associated with early recurrence after resection for hepatocellular carcinoma and outcomes. J Am Coll Surg. 2006;202:275-283. Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl. 2004;10:1294-1300. Zhu Y, Dong J, Wang WL, Li MX, Lu Y. Short- and long-term outcomes after salvage liver transplantation versus primary liver transplantation for hepatocellular carcinoma: a meta-analysis. Transplant Proc. 2013;45:33293342. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247:49-57. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-forsize settings. Ann Surg. 2012;255:405-414. 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. 1996;334:693-699. Bruix J, Sherman M, Practice Guidelines Committee AeAftSoLD. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236. Bruix J, Sherman M, Diseases AAftSoL. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022. Liver EAFTSOT, Cancer EOFRATO. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943. Shah SA, Cleary SP, Tan JC, et al. An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Annals of surgical oncology. 2007;14:2608-2614. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394-1403. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg. 2007;246:502-509; discussion 509-511.
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Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg. 2003;238:508-518; discussion 518-509. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008;248:617-625. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-totreat analysis. Hepatology. 2008;48:819-827. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg. 2004;240:900-909. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999;210:655-661.
Figure Legends Figure 1: Operative exposure of HCC lesion before resection Figure 2: Barcelona Clinical Liver Cancer (BCLC) staging system Figure 3: Treatment modalities for HCC Figure 4: a) Enhanced CT of the abdomen demonstrating arterial enhancement of hepatocellular carcinoma in the right hepatic lobe pre-RFA; b) high T1 signal on a fat saturated T1-weighted pre-contrast MRI post-RFA within the lesion indicating coagulative necrosis; c) calcifications within treated hepatocellular carcinoma post-RFA. Figure 5: Laparoscopic approach with ultrasound guidance to radiofrequency ablation Figure 6: a) Enhanced CT of the abdomen demonstrating a 2 cm hepatocellular carcinoma in the left hepatic lobe; b) postprocessing to determine right hepatic lobe liver volume after resection; c) MIP with total right hepatic lobe volume of 703 cm3.
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Table 1 AJCC TNM staging, Seventh Edition41
Classification
Definition
Stage
Primary Tumor(T) TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Solitary tumor w/o vascular
Stage l
invasion T2
Solitary tumor w/ vascular
Stage ll
invasion or multiple tumor none 5cm T3a
Multiple tumors 5cm
Stage lllA
T3b
Single tumor or multiple tumors
Stage lllB
of any size involving a major branch of the portal vein or hepatic vein T4
Tumors w/ direct invasion of adjacent organs other than gallbladder or with perforation of visceral peritoneum
Regional Lymph Nodes(N) NX
Regional LN cannot be assessed
Stage lllC
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No regional node metastasis
Stage lVA
N1
Regional LN metastasis
Stage lVB
Distant Metastasis(M) M0
No distant metastasis
M1
Distant metastasis
Histologic Grade(G) G1
Well differentiated
G2
Moderately differentiated
G3
Poorly differentiated
G4
Undifferentiated
Fibrosis Score(F)
the fibrosis score as defined by
Ishak F0
Fibrosis score 0–4 (none to moderate fibrosis)
F1
Fibrosis score 5-6 (severe fibrosis or cirrhosis)
Ertel et al. 19 Table 2 Comparison of Milan & UCSF Criteria for Liver Transplantation in Patients with HCC
Size
Milan
UCSF
Solitary tumor: 5cm
Solitary tumor: 6.5cm
Multifocal Disease: 3
Multifocal Disease: 3
tumors each 3cm
tumors each 4.5cm, & total not exceeding 8cm.
Survival Rate
75% at 4 years29
75.2% at 5 years33
Recurrence-free Survival
74% at 5 years34
65% at 5 years34
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