Author Affiliations: Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories (Lau WY); Department of Surgery, Pamela Youde Nethersole Eastern Hospital (Lai ECH); and Department of Surgery, Queen Elizabeth Hospital (Lau SHY), Hong Kong, China

Corresponding Author: Prof. Wan Yee Lau, MD, FRCS, FACS, FRACS (Hon), Professor of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China (Tel: +852-26322626; Fax:+852-26325459; Email: josephlau@cuhk.edu.hk)

 

© 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60174-1

Published online January 16, 2017.

 

 

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been developed to induce rapid liver hypertrophy and reduce post-hepatectomy liver failure in patients with insufficient future liver remnant (FLR). ALPPS is still considered to be in an early developmental phase because surgical indications and techniques have not been standardized. This article aimed to review the current role and future developments of ALPPS.

 

DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles from January 2007 to October 2016 using the keywords “associating liver partition and portal vein ligation for staged hepatectomy” and “ALPPS”. Additional papers were identified by a manual search of references from key articles.

 

RESULTS: ALPPS induces more hypertrophy of the FLR in less time than portal vein embolization or portal vein ligation. The benefits of ALPPS include rapid hypertrophy 47%-110% of the liver over a median of 6-16.4 days, and 95%-100% completion rate of the second stage of ALPPS. The main criticisms of ALPPS are centered on its high morbidity and mortality rates. Morbidity rates after ALPPS have been reported to be 15.3%-100%, with ≥ the Clavien-Dindo grade III morbidity of 13.6%-44%. Mortality rates have been reported to be 0%-29%. The important questions to ask even if oncologic long-term results are acceptable are: whether the gain in quality and quantity of life can be off balance by the substantial risks of morbidity and mortality, and whether stimulation of rapid liver hypertrophy also accelerates rapid tumor progression and spread. Up till now, the documentations of the ALPPS procedure come mainly from case series, and most of these series include heterogeneous groups of malignancies. The numbers are also too small to separately evaluate survival for different tumor etiologies.

 

CONCLUSIONS: Currently, knowledge on ALPPS is limited, and prospective randomized studies are lacking. From the reported preliminary results, safety of the ALPPS procedure remains questionable. ALPPS should only be used in experienced, high-volume hepatobiliary centers.

 

(Hepatobiliary Pancreat Dis Int 2017;16:17-26)

 

KEY WORDS: associating liver partition and portal vein ligation for staged hepatectomy; portal vein embolization; laparoscopy; colorectal liver metastases; hepatocellular carcinoma

L

iver surgery for malignancy aims at R0 resection with sufficient postoperative liver remnant and functional reserve to provide possible long-term survival. An inadequate volume of future liver remnant (FLR) is associated with an increase risk in postoperative liver failure. There are two effective methods to increase the volume of the FLR: portal vein ligation (PVL)/percutaneous portal vein embolization (PVE), and two-stage hepatectomy. These strategies, however, carry a considerable failure rate because a significant proportion of patients eventually drop out from subsequent curative resection due to tumor progression in the waiting interval between the two stages, or because of failure of the FLR to adequately grow. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been developed to induce rapid liver hypertrophy so as to reduce post-hepatectomy liver failure. Schlitt first performed this technique in 2007^[1-3]. He originally planned to perform an extended right hepatectomy in a patient with hilar cholangiocarcinoma. During surgery, he realized that the FLR was too small for the patient to survive so he quickly made an intraoperative decision to carry out a hepaticojejunal bypass operation. For optimal exposure and positioning of the hepaticojejunostomy, he performed an in situ split of the liver parenchyma along the right border of the falciform ligament. He then ligated the right portal vein to induce hypertrophy of liver segments 2 and 3. Out of curiosity he performed a computed tomography (CT) scan on postoperative day 8 and found the left lateral section of the liver had hypertrophied rapidly. He then decided to carry out the original planned liver resection and the patient recovered well. This novel approach was formally presented in 2011 by Baumgart and colleagues in the 9th European-African Hepato-Pancreatico-Biliary Association Congress in Cape Town, South Africa.^[1] In the same year, de Santibañes and his colleagues reported their data on 3 patients [colorectal liver metastases (CRLM), n=2 and hilar cholangiocarcinoma, n=1].^[2] Schnitzbauer and his colleagues reported the technique of “right portal vein ligation combined with in situ splitting” on 25 patients [hepatocellular carcinoma (HCC), n=3, intrahepatic cholangiocarcinoma, n=2, extrahepatic cholangiocarcinoma, n=2, malignant epithelioid hemangioendothelioma, n=1, gallbladder cancer, n=1, CRLM, n=14, ovarian cancer with liver metastasis, n=1, gastric cancer with liver metastasis, n=1). After a median of 9 days (range 5-28), the median preoperative volume of the left lateral liver section increased from 310 mL (range 197-444) to 536 mL (range 273-881), representing a median volume increase of 74% (range 21%-192%).^[3] The description by Schnitzbauer et al, together with reports from regions around the world were then published with overwhelming enthusiasm. In 2012, de Santibañes and Clavien proposed the acronym for this procedure as associating liver partition and portal vein ligation for staged hepatectomy, or ALPPS in short.^[4] ALPPS is still considered to be in an early developmental phase and its surgical indications and techniques have not yet been standardized. This article aimed to review the current role and development of ALPPS.

 

 

Studies were identified by searching MEDLINE and PubMed for articles published from January 2007 to October 2016 using the keywords “associating liver partition and portal vein ligation for staged hepatectomy” and “ALPPS”. Additional papers were identified by a manual search of references from key articles.

 

 

The pathophysiological mechanism of ALPPS in enhancing rapid liver hypertrophy remains unclear. In addition to disrupting the main portal vein supply to the two parts of the partitioned liver and blocking the portal venous supply to a part of the liver, ALPPS also divides any venous collaterals within the liver parenchyma. It is hypothesized that liver grows faster when total portal blood flow redistributes to the FLR. Animal studies showed that the hypertrophic effects of ALPPS are more complicated. Apart from increased blood flow, hepatocyte proliferation is part of the reason of liver volume increase. Liver damage at the first stage of ALPPS triggers inflammatory response and plays an important role in inducing hepatocyte proliferation.

 

Hepatocyte cellular and molecular changes associated with liver hypertrophy during ALPPS have been studied in experimental models. de Santibañes et al^[5] found that proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) ratio, an proliferative index, was significantly increased from -3.78 cells/mm² in stage 1 to 2.32 cells/mm² in stage 2. The median FLR hypertrophy was 104% in 6 days, with a significant mean difference between the preoperative and postoperative volumes of 361 mL. The mean hepatocyte number significantly increased from 52.7 cells/mm² in stage 1 to 89.6 cells/mm² in stage 2. The PCNA expression increased by 190% between the 2 stages with a linear correlation (r=0.58) with macroscopic hypertrophy. The results of this study indicated the rapid FLR volumetric increase in ALPPS being accompanied by histological and molecular evidences of hepatocyte cell proliferation. Shi et al in animal study found that the regeneration rate in the FLR after ALPPS was 2 times relative to those after PVL, whereas rats with parenchymal transection alone showed minimal volume increase.^[6] The expression levels of Ki-67 and PCNA were about ten-fold higher after ALPPS compared with rats which underwent transection or left lateral section resection, and four-fold higher compared with rats after PVL. The levels of TNF-α, IL-6 and HGF in the regenerating liver remnant were about three-fold higher after ALPPS compared with controls. There were more significant activations of NF-κB p65, STAT3 and Yap after ALPPS, suggesting synergistic activation of the pathways by PVL and transection, which might play an important role in liver regeneration after ALPPS.

 

An experimental model using mice by Schlegel et al gave important information about the mechanism of accelerated hypertrophy in ALPPS.^[7] The ALPPS group received 90% PVL combined with liver parenchymal transection. The controls underwent either transection or PVL alone. Liver regeneration was assessed by liver weight and proliferation-associated molecules. The PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from the ALPPS-treated mice was injected into the mice after PVL. Hypertrophy of the remnant liver after ALPPS was doubled relative to the mice after PVL, whereas mice with transection alone disclosed minimal signs of regeneration. The markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with the controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. These results support the hypothesis that liver damage at the first procedure of ALPPS raises inflammatory signals and promotes liver hypertrophy.

 

However, the rapid gain in FLR may not always be translated directly into improved liver function. Matsuo et al showed that hepatocytes which regenerated early after ALPPS were smaller and less mature and did not function normally.^[8] Specimens obtained from 8 patients treated with ALPPS and from 14 patients treated with hepatectomy after PVE were examined by light and electron microscopy. Extrapolated kinetic growth of the FLR after ALPPS was 14.4±4.8 mL/day, which was significantly faster than that after PVE (3.6±2.2 mL/day). Microscopically, the FLR showed significantly greater hepatocyte cell density and smaller hepatocyte size in ALPPS than in PVE. Bright-appearing hepatocytes and sinusoidal narrowing were significantly more frequent in ALPPS (50% and 50%) than in PVE (0% and 8.3%). In the deportalized ventral aspect of the anterior section, hepatocyte atrophy, hepatocyte degeneration or necrosis, sinusoidal dilation, fibrosis, and congestion were significantly more frequent in ALPPS than in PVE. Electron microscopy frequently showed vacant-appearing hepatocytic cytoplasm filled with glycogen granules in the FLR in ALPPS. Fewer cytoplasmic organelles and lipofuscin granules were also observed in ALPPS than in PVE.

 

ALPPS can induce more hypertrophy of the FLR in shorter time than PVE or PVL. The benefits of ALPPS include rapid liver hypertrophy of 47%-110% over a median of 6-16.4 days, and 95%-100% completion rate of the second stage of ALPPS (Table 1).^{[3, 9-27]} In pediatric patients, hypertrophy of 46.1%-83.8% in 8-11 days has been reported.^{[28, 29]} The most common indication for ALPPS was CRLM in normal livers. However, liver regeneration in chronic liver diseases is less predictable. Only successful case reports have been documented.^[30-34] The hypertrophy rates varying from 18.7%-100% over a median of 7 days have been reported in patients with severe steatosis, liver fibrosis and cirrhosis.^[30-34] From the International ALPPS Registry, D’Haese et al reported 35 patients with HCC and 225 with CRLM. The majority of patients who underwent ALPPS for HCC fell into the intermediate-stage category of the Barcelona Clinic algorithm.^[35] The liver hypertrophy rate of the HCC patients was significantly lower than that of the CRLM patients (47% vs 76%). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality to treat HCC using ALPPS was significantly higher than that to CRLM (31% vs 7%).

 

Neoadjuvant chemotherapy damages hepatocytes and may impair hepatic regeneration. Kremer et al analyzed 19 consecutive patients who underwent ALPPS (CRLM, n=11; cholangiocarcinoma, n=7; gallbladder carcinoma, n=1). Only the 11 patients with CRLM received neoadjuvant chemotherapy. ALPPS induced sufficient hypertrophy of the FLR, with an increase in volume of 74%±35%.^[18] Neoadjuvant chemotherapy was shown to significantly impair hypertrophy, but it did not have any impact on either the morbidity or in-hospital mortality rates. The volume of the FLR in the non-chemotherapy patients increased by 98%±35%, while the increase was 59%±22% in patients who received neoadjuvant chemotherapy.

 

The main criticisms of ALPPS are centered on its high morbidity and mortality rates. Morbidity rates after ALPPS are 15.3%-100%, with ≥ the Clavien-Dindo grade III morbidity rates being 13.6%-44%. Mortality rates are 0%-29% (Table 1).^{[3, 9-27]} The main morbidities include bile leakage and sepsis, and the main cause of mortality is hepatic insufficiency. The 90-day mortality (means mortality after ALPPS) rate reported in the Registry which included 320 patients from 55 international centers was 8.8%, 75% was due to postoperative liver failure.^[36] The data from the ALPPS Registry suggested that the high morbidity rate associated with ALPPS was less in patients younger than 60 years of age and those with CRLM, whereas patients with gallbladder cancer and cholangiocarcinoma had poorer outcomes. These studies raise important points for future patient selection for ALPPS.

 

Also, the high mortality rate, its substantial postoperative complications and long hospital stays, may jeopardize oncologic outcomes by delaying adjuvant treatments. Furthermore, whether stimulation of liver hypertrophy can also accelerate tumor progression is still an open question.

 

Before ALPPS, two approaches have been used to manage patients with insufficient FLR volumes. The first technique manipulates portal blood flow to induce hypertrophy of the FLR. Initially this was achieved by laparotomy and PVL. Such a technique has now evolved and replaced by percutaneous PVE. Increasing evidence has suggested that hypertrophy of the FLR induced by portal flow modulation is associated with improved safety in major hepatectomies. The second approach is ‘‘two stage surgery’’ for resection of multiple hepatic lesions in both hemilivers. Success of this two-stage approach has been reported in patients with extensive CRLM. The main drawback of these two approaches is the long-time interval of several weeks to achieve complete clearance of the tumor burden within the liver. The risk of drop out from completion of tumor clearance due to tumor progression during the waiting time or insufficient hypertrophy of FLR is significant. Table 2 shows the outcomes of comparative studies of ALPPS versus PVL/PVE or two-stage hepatectomy.^[37-41] In the study by Shindoh et al, the incidences of bile leak (grade B or C), sepsis, and relaparotomy for postoperative complications were significantly higher with the ALPPS group (24%, 20%, and 28%, respectively) compared to the percutaneous right plus segment 4 PVE group (5.8%, 0%, and 2.9%, respectively).^[38] In addition, the rates of overall morbidity, major morbidity, and liver-related mortality tended to be higher in patients in the ALPPS group. In the study by Schadde et al, major complications were more common in ALPPS after both the two stages compared with PVL/PVE, but the numbers were too small to show any significance.^[39] In the two groups, there were no significant differences in bile leak and in postoperative liver failure. In the study by Ratti et al, when compared with two-stage hepatectomy, the rate of morbidities in stage 1 and 2 of ALPPS was significantly higher in patients treated with ALPPS.^[40] Both the major complication rate and the mortality rate were significantly higher after stage 2 in the ALPPS group. Among the patients with complications in stage 2, pleural effusion (58.3% vs 11.8%), fever (16.7% vs 8.8%) and abscess (25% vs 5.9%) were significantly higher in the ALPPS group. There were no significant differences in bile leak and postoperative liver failure between the two groups. In the study by Tanaka et al, the mortality rate in the ALPPS group tended to be higher than that in the classical two-stage hepatectomy group (9% vs 2%).^[41]

 

These studies provided evidence that ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors at the cost of high morbidity and mortality rates. The lack of data on long-term survival in patients operated by ALPPS should sound the caution that more studies are necessary before ALPPS can be considered to be an alternative to the conventional strategies which have been shown to be safe and efficient in the long-term. ALPPS has also been reported to play a role in salvage treatment for failed PVE or as an intraoperative rescue when the FLR is too small for hepatectomy.^{[37, 42-49]} Salvage ALPPS appears successful after both PVE and PVL with acceptable clinical outcomes.

 

The current literature demonstrates a large variation in techniques in ALPPS which limits meaningful statistical comparisons of outcomes because of small sample sizes. Many variations and types of resection have been performed successfully. Unfortunately, all the reports were case reports or small case series only. Validation of each of the techniques is still lacking. Technical standardization of ALPPS is needed before safety of these modifications of ALPPS can be clarified.

 

The technical modifications of ALPPS aim to reduce perioperative mortality and complications, improve long-term survival, and increase the resection rate. Technical modifications of the first stage of the operation aim to reduce damage and adhesions and to obtain better general condition of the patient with rapid liver hypertrophy before the second stage operation. Table 3 illustrates the reported technical modifications of ALPPS.^{[3, 19, 24, 25, 50-59]} However, these technical modifications have not been widely adopted because some of the technical modifications make the procedure more difficult and the final outcomes may not be improved.

 

Major modifications of the ALPPS technique have been developed to increase resectability of different extent and locations of liver tumors, and they have also been used as a rescue procedure in patients with insufficient FLR after portal vein embolization or ligation.

 

The ALPPS technique in the classical form consists of ligation of the right portal vein, and transection of the liver parenchyma along the falciform ligament. The right side of the liver is then resected in the second stage. To increase resectability of liver tumors, variations of the ALPPS technique have been developed.^[60-64] The first variation is “ALPPS preserving liver segments 5, 6, 7, 8” by ligation of the left portal vein, multiple resections in the right hemiliver and splitting the liver parenchyma along the main portal fissure. The second variation is “ALPPS preserving liver segments 4, 5, 8”, which consists of ligation of the posterolateral branch of the right portal vein, left lateral sectionectomy, multiple liver resections in the right anterior and left medial sections and splitting the liver parenchyma along the right portal fissure. The third variation is “ALPPS preserving liver segments 2, 3, 4”, which consists of ligation of the right portal vein and splitting the liver parenchyma along the main portal fissure.^[60] The fourth variation is “ALPPS procedure with double in situ split for staged mesohepatectomy”.^[61] This consists of a double in situ splitting of the liver parenchyma, and resection of the central liver segments (segments 1, 4, 5 and 8). This induces rapid hypertrophy of the left lateral section (segments 2/3) and right posterior section (segments 6/7). The other variation is “monosegment ALPPS”.^[62-64] ALPPS induces extensive hypertrophy and allows surgeons to perform extensive liver resections.

 

Application of the minimally invasive technique aims to facilitate the second stage of operation and to improve the patient’s recovery. Basically, the modification can be divided into three approaches as shown in Table 4. Again, the results have not been validated in comparative studies; almost all reports are either case reports or small case series only. The main drawback of the use of liver tourniquet/radiofrequency/microwave energy for liver partition is the possibility of incomplete partition. The other concern is the possibility of damage to the segment 2, 3 bile ducts and blood supply by radiofrequency or microwave energy during ablation. Machado et al^[69] recently reported a non-randomized comparative study between laparoscopic ALPPS (n=10) and open ALPPS (n=20). Hepatic parenchymal transection for liver partition was used in both the two arms. There were significant differences between the laparoscopic ALPPS and open ALPPS groups in blood loss in stage 1 (median, 200 vs 420 mL) and stage 2 (median, 320 vs 460 mL), complications > IIIa (severe) in both the two stages (0% vs 50%), liver failure in both the two stages (0% vs 40%), mortality rates (0% vs 5%) and median hospital stay (11 vs 14 days). Two patients in the open ALPPS group developed complications that precluded the second stage ALPPS.

 

The important question to ask is whether the oncologic long-term results gained can off-set the substantial risks of complication and mortality rates of ALPPS. In addition, whether stimulation of liver hypertrophy can also accelerate tumor progression. Up till now, the published outcomes of ALPPS came from case series only, and most of these series included heterogeneous groups of patients with different malignancies. The numbers are too small to evaluate survival separately for the different tumor etiologies. The survival outcomes have not been systematically reported in the various studies. Based on the current data, meaningful analysis of oncological outcomes is difficult.

 

Table 5 shows the oncological outcomes of ALPPS in treatment of CRLM. The study from Oldhafer et al focuses on the long-term outcomes of ALPPS in patients with unresectable CRLM.^[14] In this study, R0 resection was achieved in all the patients without postoperative mortality. On follow-up of more than 3 months, six of the 7 (85.7%) patients experienced tumor recurrence in the liver; 3 of the 7 patients presented with lung metastases which occurred earlier than the liver metastases in 2 of 3 patients; one patient on follow-up for 3 months showed no visible recurrent disease, but there was increasing carcinoembryonic antigen levels. In the study by Hernandez-Alejandro et al, recurrences developed in 2 (14.3%) patients after a median follow-up of 9 months.^[19] One patient developed recurrences in the liver and lungs 5 months after stage 2 ALPPS and the other patient developed recurrence in the liver remnant 9 months after stage 2 ALPPS. In the study by Kremer et al, six of the 11 (55%) patients developed local recurrences within a median of 4 months or a mean of 5.8 months after surgery.^[18] In the study by Björnsson et al, 78.3% of patients developed recurrences after a median follow-up of 22.5 months after surgery and 33.5 months from the diagnosis of liver metastases.^[79] Liver only recurrences occurred in 8 patients, lung only recurrences in 2 patients, and both liver and lung recurrences in 8 patients, respectively. Again, whether the rapid and extreme hypertrophy promotes recurrences remains uncertain and will require further studies.

 

 

Currently, the knowledge on ALPPS is still limited, and prospective randomized studies are lacking. Considering the preliminary results, safety of the ALPPS procedure remains questionable, and careful application of ALPPS is needed at this point of time. The application of ALPPS should currently be limited to experienced, high-volume hepatobiliary centers.

 

 

Contributors: LWY proposed the idea, structure, and content of this article. LECH and LSHY did the literature search and wrote the first draft. LWY and LECH also did the revision and final proof read of the article. LWY 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.

 

 

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50 Lau WY, Lau HYS. Surgical modifications on the conventional ALPPS. Chin J Pract Surg 2016;36:93-95.

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53 Andriani OC. Long-term results with associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Ann Surg 2012;256:e5; author reply e16-19. PMID: 22842129

54 de Santibañes E, Alvarez FA, Ardiles V, Pekolj J, de Santibañes M. Inverting the ALPPS paradigm by minimizing first stage impact: the Mini-ALPPS technique. Langenbecks Arch Surg 2016;401:557-563. PMID: 27084508

55 Petrowsky H, Györi G, de Oliveira M, Lesurtel M, Clavien PA. Is partial-ALPPS safer than ALPPS? A single-center experience. Ann Surg 2015;261:e90-92. PMID: 25706390

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58 Dokmak S, Belghiti J. Which limits to the “ALPPS” approach? Ann Surg 2012;256:e6. PMID: 22895355

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60 Gauzolino R, Castagnet M, Blanleuil ML, Richer JP. The ALPPS technique for bilateral colorectal metastases: three “variations on a theme”. Updates Surg 2013;65:141-148. PMID: 23690242

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69 Machado MA, Makdissi FF, Surjan RC. Totally laparoscopic ALPPS is feasible and may be worthwhile. Ann Surg 2012;256:e13. PMID: 22842130

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