Author Affiliations: Department of Surgery, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, China (Cheung TT, Wong TCL and Chan SC)

Corresponding Author: Tan To Cheung, MD, PhD, Chief of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, China (Tel: +852-22553025; Fax: +852-28165284; Email: tantocheung@hotmail.com)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60414-3

Published online September 9, 2015.

 

 

Contributors: CTT, WTCL and CSC performed the operation and prepared and approved the manuscript. CTT is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

ABSTRACT: Patients with hepatocellular carcinoma have a very short life expectancy if they receive no surgical intervention. A relatively new surgical technique termed “Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy” (ALPPS) has been employed for inducing rapid hypertrophy of the future liver remnant for patients waiting for hepatectomy. As portal vein embolization may not result in satisfactory hypertrophy before tumor progression occurs, ALPPS can be an alternative for patients with advanced hepatocellular carcinoma. Herein we describe an ALPPS procedure with tumor thrombectomy for a patient who had a small left liver lobe and a large hepatocellular carcinoma involving the whole right liver lobe and the middle hepatic vein and extending into the inferior vena cava. In the first-stage operation, the right portal vein was controlled and divided with a Hemolock. The right hepatic artery was well protected. Hepatic transection was performed with a 1-cm margin from the tumor. The middle hepatic vein trunk was preserved. Ten days afterwards, there was significant hypertrophy of the left lateral section of the liver, and the second-stage operation was conducted. Extended right hepatectomy and tumor thrombectomy were performed under sternotomy and total vascular exclusion. The patient had good recovery and was free of disease 10 months after the operation. ALPPS may be a good treatment option even for patients with advanced disease if carried out at high-volume centers.

 

(Hepatobiliary Pancreat Dis Int 2016;15:319-323)

 

KEY WORDS: anatomy; hepatocellular carcinoma; therapeutics; survival; surgical procedure

Patients with hepatocellular carcinoma (HCC) have a very short life expectancy if they receive no surgical intervention. According to the Barcelona Clinic Liver Cancer Staging and Treatment Strategy, targeted therapy is the suggested treatment option for patients who have large HCCs with major vascular invasion.^[1] Sorafenib is a kinase inhibitor in use for advanced HCC, but its therapeutic effect differs with different populations; generally Westerners with hepatitis C virus fare far better than Asians with hepatitis B virus. Hepatitis-B-related HCC is common in Asia, and the life expectancy for Asians with hepatitis-B-related advanced HCC treated with sorafenib is less than 8 months.^[2]

 

In the treatment of advanced HCC, hepatectomy can achieve acceptable surgical outcomes and satisfactory patient survival.^{[3, 4]} However, generally patients who have hepatitis-B-related HCC also have liver cirrhosis, portal hypertension and a small future liver remnant and thus are not suitable for hepatectomy.

 

Although liver transplantation can tackle HCC and cirrhosis at the same time, it is usually not given to patients with advanced HCC because of the great likelihood of HCC recurrence and the universal problem of liver graft shortage. Liver transplant recipients beyond selection criteria have poor surgical outcomes and early mortality.

 

Portal vein embolization before hepatectomy is a solution for patients with inadequate future liver remnant. Nonetheless, satisfactory results are seen in some patients but not others. Moreover, hypertrophy after portal vein embolization takes 4-8 weeks, during which tumor progression would occur in patients with large tumors or tumor infiltration to major vessels.^[5-7]

 

A relatively new surgical technique termed “Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy” (ALPPS) has been employed for inducing rapid hypertrophy of the future liver remnant for patients waiting for hepatectomy.^[8] As portal vein embolization may not result in satisfactory hypertrophy before tumor progression occurs, ALPPS can be an alternative for patients with advanced HCC.

 

 

A 55-year-old known hepatitis B virus carrier had right upper quadrant pain and was found to have hepatomegaly 8 cm below the costal margin upon physical examination. Computed tomography showed a 14-cm tumor involving the whole right liver lobe and the middle hepatic vein and extending into the inferior vena cava (IVC). The patient was considered not suitable for hepatectomy because of the small volume of his left liver lobe and was given transarterial chemoembolization before being referred to the Department of Surgery, The University of Hong Kong, for further treatment.

 

The patient’s liver function was normal although he had a mildly raised level of alkaline phosphatase. His clotting profile was normal, with an international normalized ratio of 1.2 and a platelet count of 349×10⁹/L. His alpha-fetoprotein level was 7941 ng/mL. Computed tomography of the abdomen with contrast showed progression of disease. A 14-cm tumor was seen in the right liver lobe with a few small satellite nodules. The middle hepatic vein and the IVC suffered tumor infiltration but both remained patent. He had an indocyanine green retention rate of 13.3% at 15 minutes. His estimated future liver remnant was 302 mL, which was 22% of his estimated standard liver volume (Fig. 1). Dual-tracer positron emission tomography showed tumor thrombosis in the IVC and confirmed the absence of extrahepatic metastasis.

 

Since the patient had liver cirrhosis, portal hypertension and a small future liver remnant, upfront hepatectomy was considered unsafe. Portal vein embolization might induce hypertrophy of his left liver lobe but his tumor was likely to progress very rapidly due to invasion of the IVC. So ALPPS was planned.

 

In the first-stage operation, the left lateral section of the liver was found small and thin (Fig. 2A), and there was a large right-lobe tumor compressing the right portal pedicle. Ligation and transfixion of the right portal vein was not possible due to the close proximity of the tumor to the main portal vein. The right portal vein was controlled with a Hemolock and the right hepatic artery was well preserved (Fig. 2B). A Cavitron ultrasonic surgical aspirator was used to transect the liver parenchyma (Fig. 2C). The middle hepatic vein was not transected. The abdomen was closed. No drain was placed in the first-stage operation.

 

The patient had good recovery from the first-stage operation. His bilirubin level was 30 µmol/L on day 7 and his international normalized ratio was 1.3. Computed tomography with contrast was performed on day 9. The volume of his left liver lobe was 399 mL (a 32% increase) and the future liver remnant was 29% of the estimated standard liver volume (Fig. 3).

 

Ten days after the first-stage operation, the second-stage operation was conducted. Approximately 800 mL of ascites was found upon laparotomy. The right hepatic artery was ligated and divided. Transection of the liver parenchyma was continued to the anterior surface of the IVC. The middle hepatic vein was also divided. Intraoperative transesophageal echocardiography showed that the tumor thrombus in the IVC had extended to the junction of the IVC and the right atrium. Sternotomy with supradiaphragmatic control of the junction was performed (Fig. 4A). With total hepatic vascular exclusion (by clamping of the infrahepatic IVC and the Pringle maneuver), the right hepatic vein was incised and the tumor thrombus was retrieved from venotomy (Fig. 4B, C, D). The venotomy was then closed with a 5/0 Prolene suture in a continuous manner (Fig. 4E). Extended right hepatectomy was performed after mobilization of the right liver lobe. The total operating time was 4 hours and 37 minutes. There was 8 L of blood loss. No circulatory bypass was needed. The patient had uneventful recovery and was discharged two weeks after the second-stage operation. Pathological examination of the resected specimen showed a poorly differentiated HCC with vascular invasion. The margin was 1 cm away from the tumor (Fig. 4F).

 

The patient was followed up every month. He had good recovery and remained asymptomatic and free of disease 10 months after the operation. Computed tomography with contrast performed at 10 months showed no disease recurrence (Fig. 5).

 

 

Treatment of large advanced HCCs is technically challenging. Evidence has shown that hepatectomy still provides a better survival outcome.^[3] The decision on hepatectomy or nonsurgical approaches usually depends on the balance between surgical safety and anticipated survival performance.

 

This patient was not eligible for liver transplantation because his tumor was too large and had invaded the IVC. Without appropriate hypertrophy, extended right hepatectomy would be risky because his liver remnant would be too small. He was not a good candidate for right portal vein embolization for inducing hypertrophy of his future liver remnant because he already had autoembolization of right portal vein branches, and he had a marginal indocyanine green retention rate at 15 minutes. At our center, preoperative indocyanine green retention rate is regarded as an operative safety measurement,^[9] and dual-tracer positron emission tomography is used for the detection of metastases undetected by conventional computed tomography.^{[10, 11]} For this patient, other treatment options would only be palliative.

 

Portal vein embolization with chemotherapy is a good option for patients with liver metastasis.^{[5, 7]} Effective bridging chemotherapy prevents tumor progression during the two months’ wait for adequate hypertrophy of the future liver remnant. In the treatment of large HCCs, the role of portal vein embolization is restricted. Intrahepatic metastasis to the contralateral lobe and extrahepatic metastasis can occur in a short period of time. Moreover, liver hypertrophy is largely unpredictable in the presence of cirrhosis.

 

ALPPS appears to be an ideal solution for HCC patients who would have a small liver remnant after hepatectomy. The new concept of in situ liver partition with portal vein ligation for a fast and significant contralateral parenchymal hypertrophy was first carried out in 2007 by Dr. Hans Schlitt.^[8] Baumgart et al^[12] published the first report in 2011. The technique was later popularized by Santibañes et al.^[13] Interest in the technique is growing as it renders many more patients eligible for hepatectomy.

 

Our patient had no splenomegaly and his platelet count and international normalized ratio were normal. In the first-stage operation, around 100 mL of ascites was found on the liver surface, and the liver surface was nodular. In the second-stage operation, there was 1000 mL of ascites, signifying the presence of clinical portal hypertension. Portal vein occlusion and liver cirrhosis might be the causes. Histological examination revealed that the patient had cirrhosis and bridging fibrosis. His 8-L operative blood loss was a little bit on the high side probably because of IVC and hepatic vein obstruction. He lost 2500 mL of blood during hepatic transection. Since the outflow of the liver was completely obstructed, there was severe venous oozing during transection although the inflow was controlled at the beginning of the operation. There was also oozing of blood from the sternotomy wound split open for suprahepatic IVC control. He also lost some blood during IVC venotomy and tumor thrombectomy. Totally 12 units of packed cells were transfused.

 

Rapid liver hypertrophy is an observational phenomenon reproducible worldwide, but the underlying mechanism is still unknown. A lot of research is still underway to resolve the myth. It might involve tissue edema. It might also involve growth factor stimulation, which could also induce tumor growth. Long-term follow-up on tumor recurrence pattern is needed.

 

Initial results of ALPPS were unsatisfactory. The hospital mortality rates were between 12% and 28%.^{[8, 13-15]} Many deaths were related to the complex procedures. The rates of complications (Clavien-Dindo grade III or above) were around 40%. Patients with obstructive cholangiopathy such as cholangiocarcinoma would be more likely to develop complications like bile leakage and sepsis.

 

In order to prevent the development of sepsis, we did not wrap the liver with a plastic bag although the measure could prevent adhesion as well as leakage of bile into the peritoneal cavity. The use of any foreign material would add a source of infection. The liver parenchymal transection followed the protocol for donor hepatectomy so as to prevent bile leakage or fistula formation.^[16] Meticulous dissection and clipping of the small vessels and ducts prevented leakage from the liver. To render the future liver remnant ischemic as a preparation for extended hepatectomy in the second-stage operation, the inflow to segment 4 of the liver was divided in the first-stage operation. This could cause infection. However, from our experience from liver transplantation using split-liver or reduced-size grafts, we knew that the risk of bile leakage would be low as long as the liver parenchymal transection follows the protocol for donor hepatectomy.^{[17, 18]} Our center has so far conducted 16 ALPPS procedures for HCC patients; this patient had additional tumor thrombectomy under total vascular control.

 

ALPPS has two obvious advantages. Its effect in liver hypertrophy is unparalleled by other methods, and the tumorous part of the liver is left in place in the first-stage operation, so it acts as auxiliary liver to prevent liver failure before hepatectomy. This technique may be beneficial even to patients who have advanced HCC with major vascular invasion and a small future liver remnant.

 

 

1 Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects.Semin Liver Dis 2010;30:61-74. PMID: 20175034

2 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. PMID: 19095497

3 Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691-1700. PMID: 24583061

4 Cheung TT, Ng KK, Chok KS, Chan SC, Poon RT, Lo CM, et al. Combined resection and radiofrequency ablation for multifocal hepatocellular carcinoma: prognosis and outcomes. World J Gastroenterol 2010;16:3056-3062. PMID: 20572310

5 Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB (Oxford) 2005;7:42-49. PMID: 18333160

6 Hayashi S, Baba Y, Ueno K, Nakajo M, Kubo F, Ueno S, et al. Acceleration of primary liver tumor growth rate in embolized hepatic lobe after portal vein embolization. Acta Radiol 2007;48:721-727. PMID: 17729001

7 Tanaka H, Hirohashi K, Kubo S, Shuto T, Higaki I, Kinoshita H. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000;87:879-882. PMID: 10931022

8 Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA, 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-for-size settings. Ann Surg 2012;255:405-414. PMID: 22330038

9 Cheung TT, Chan SC, Chok KS, Chan AC, Yu WC, Poon RT, et al. Rapid measurement of indocyanine green retention by pulse spectrophotometry: a validation study in 70 patients with Child-Pugh A cirrhosis before hepatectomy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2012;11:267-271. PMID: 22672820

10 Cheung TT, Chan SC, Ho CL, Chok KS, Chan AC, Sharr WW, et al. Can positron emission tomography with the dual tracers [11 C]acetate and [18 F]fludeoxyglucose predict microvascular invasion in hepatocellular carcinoma? Liver Transpl 2011;17:1218-1225. PMID: 21688383

11 Cheung TT, Ho CL, Lo CM, Chen S, Chan SC, Chok KS, et al. 11C-acetate and 18F-FDG PET/CT for clinical staging and selection of patients with hepatocellular carcinoma for liver transplantation on the basis of Milan criteria: surgeon’s perspective. J Nucl Med 2013;54:192-200. PMID: 23321459

12 Baumgart J, Lang S, Lang H. A new method for induction of liver hypertrophy prior to right trisectionectomy: A report of three cases. HPB (Oxford) 2011;13(suppl 2):71-72.

13 de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperativemliver failure: the “ALPPS” approach. Ann Surg 2012;255:415-417. PMID: 22330039

14 Nadalin S, Capobianco I, Li J, Girotti P, Königsrainer I, Königsrainer A. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons Learned from 15 cases at a single centre. Z Gastroenterol 2014;52:35-42. PMID: 24420797

15 Knoefel WT, Gabor I, Rehders A, Alexander A, Krausch M, Schulte am Esch J, et al. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013;100:388-394. PMID: 23124776

16 Chan SC, Chan AC, Sharr WW, Chok KS, Cheung TT, Fan ST, et al. Perpetuating proficiency in donor right hepatectomy for living donor liver transplantation. Asian J Surg 2014;37:65-72. PMID: 24210956

17 Lo CM, Fan ST, Liu CL, Yong BH, Lai CL, Lau GK, et al. Ten-year experience with liver transplantation at Queen Mary Hospital: retrospective study. Hong Kong Med J 2002;8:240-244. PMID: 12167726

18 Saing H, Fan ST, Chan KL, Lo CM, Wei WI, Tsoi NS, et al. Liver transplantation in infants. J Pediatr Surg 1999;34:1721-1724. PMID: 10591579