Journal of Pediatric Surgery 50 (2015) 1227–1231
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Operative Techniques
Associating liver partition with portal vein ligation and staged hepatectomy (ALPPS) for the treatment of liver tumors in children☆ Julio Cesar Wiederkehr a,b,⁎, Sylvio Gilberto Avilla b, Elisângela Mattos b, Izabel Meister Coelho b, Jorge Alberto Ledesma c, Alexandra Fernandes Conceição b, Henrique Aguiar Wiederkehr b, Barbara Aguiar Wiederkehr b a b c
Federal University of Paraná, Curitiba Brazil Division of Liver Transplantation and Surgery, Hospital Pequeno Príncipe, Curitiba Brazil Department of Radiology, Hospital Pequeno Príncipe, Curitiba Brazil
a r t i c l e
i n f o
Article history: Received 22 June 2014 Received in revised form 28 September 2014 Accepted 1 October 2014 Key words: Liver tumor Surgery Pediatrics Hepatectomy
a b s t r a c t Resection is the only curative treatment option for primary and secondary malignant tumors of the liver. Although curative resection is associated with long-term survival rates, it can only be performed in 10% of patients with primary tumors and 25% of patients with liver metastases. Liver insufficiency is one of the most serious postoperative complications of patients undergoing extensive liver resections. When total liver resection is necessary liver transplant is mandatory, with the burden of long-term immunosuppression and its complications. Among several different strategies to increase the resectability of liver tumors, portal vein occlusion (embolization or ligature), bilateral tumor resection in two stages, and resection combined with loco regional therapy are the most popular. A new strategy for patients with marginally resectable liver tumors previously considered to be unresectable was formally reported by Baumgart et al. in 2011, originally developed by Hans Schlitt in 2007. This technique consists of a two-staged hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma, and it is known as ALPPS (associating liver partition with portal vein ligation for staged hepatectomy). The aim of this study is to present the first series of pediatric patients with marginally resectable liver tumors previously considered to be unresectable treated with two-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma. Two patients were diagnosed with hepatoblastoma, and one each with rhabdomyosarcoma, hepatocellular carcinoma, and nodular focal hyperplasia. ALPPS technique was considered whenever the future liver remnant (FLR) was 40% or less of the total liver volume (TLV) determined by CT or MRI scans. The ratio of FLR to TLV before the first procedure ranged from 0.15 to 0.38, with a mean ± sd of 0.253 ± 0.07. In all patients, a rapid growth of the FLR was observed. Estimates of the FRL volume prior to surgical treatment ranged from 110 cc to 750 cc, with a mean ± sd of 361.6 ± 213.75 cc. Just before the second procedure, the volume of the remnant liver ranged from 225 cc to 910 cc, with a mean ± sd of 563.6 cc ± 221.7 cc. The FRL volume increase had a mean ± sd of 72.56% ± 29.05%, with a median of 83.8%. The second procedure was performed after 7 to 12 days with a median of 11 days. The only postoperative complication observed in one patient was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications. ALPPS was shown to be effective and a safe procedure to treat large tumors in children. © 2015 Elsevier Inc. All rights reserved.
Resection is the only curative treatment option for primary and secondary malignant tumors of the liver. Although curative resection is associated with long-term survival rates, it can only be performed in 10% of patients with primary tumors and 25% of patients with liver metastases [1]. Large resections of the liver are limited by the remaining liver volume, referred to as future liver remnant (FLR). Liver insufficiency is one of the most serious postoperative complications of patients ☆ From the Division of Liver Transplantation and Surgery, Hospital Pequeno Príncipe, Curitiba, Brazil. ⁎ Corresponding author. E-mail address: [email protected] (J.C. Wiederkehr). http://dx.doi.org/10.1016/j.jpedsurg.2014.10.019 0022-3468/© 2015 Elsevier Inc. All rights reserved.
undergoing extensive liver resections [2–4]. To avoid this complication, it is recommended that the future liver remnant be at least 25% of the total liver volume of healthy livers, and in patients who underwent previous chemotherapy, the FLR is recommended to be approximately 40% of the total liver volume of healthy livers [2]. In pediatric populations, hepatoblastoma is the most frequent liver tumor, representing approximately 2/3 of all hepatic malignancies in children [5], and hepatocellular carcinoma is the second most common tumor in children [6]. Frequently, children with hepatoblastoma have unresectable tumors due to the involvement of multiple sectors of the liver. In more than 60% of children with hepatoblastoma chemotherapy is necessary. Although neoadjuvant chemotherapy is associated with
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good results, some children of initially unresectable hepatoblastomas remain resistant to chemotherapy [5]. A method for determining the safety of large liver resections is to determine the relationship between FLR and body weight, which should not be less than 0.5 [7]. Although this equation has been frequently used in adult patients, especially in the living-donor liver transplantation setting, it has not been tested in children. Central liver tumors can be treated by central hepatectomy. Although this technique spares tumor-free right and left lateral sections, there is a risk of thin resection margins and, therefore, a potential risk for local recurrence [8]. Two other surgical options are extended right hepatectomy and left extended hepatectomy, but they carry the risk of postoperative liver insufficiency. Among several different strategies to increase the resectability of liver tumors, portal vein occlusion (embolization or ligature), bilateral tumor resection in two stages, and resection combined with loco regional therapy are the most popular [9]. A new strategy for patients with marginally resectable liver tumors previously considered to be unresectable was formally reported by Baumgart et al. [10] in 2011, originally developed by Hans Schlitt in 2007 [11]. This technique consists of a two-staged hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma, and it is known as ALPPS (associating liver partition with portal vein ligation for staged hepatectomy). ALPPS provides a rapid and consistent hypertrophy of the remnant future liver, avoiding postoperative hepatic insuficiency [10]. A number of series of adult patients with liver tumors, mainly metastatic disease from colorectal cancer, previously considered unresectable, were treated with ALPPS with excellent results [7,12]. The aim of this study is to present the first series of pediatric patients with marginally resectable liver tumors previously considered to be unresectable treated with two-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma.
1. Patients and methods We had the opportunity to treat five children using portal vein ligation associated with liver bipartition followed by hepatectomy (ALPPS) at the Department of Liver Transplantation and Hepatic Surgery of Hospital Pequeno Principe, Curitiba, Brazil. All patients were referred to our service as bearing otherwise unresectable liver tumors with a possible evaluation for liver transplantation. Three patients were girls and two were boys; their ages ranged from 3.16 to 17.25 years with a mean age ± sd of 9.4 ± 5.9 years and a median age of 10.25 years. The demographic characteristics of the patients are listed in Table 1. Preoperative diagnoses were obtained for all five patients from tumor biopsies. Two patients were diagnosed with hepatoblastoma, and one each with rhabdomyosarcoma, hepatocellular carcinoma, and nodular focal hyperplasia. Tumor location was determined by abdominal computed tomography (CT) scan and/or abdominal magnetic nuclear resonance (MR) scan. The tumor locations and extensions are shown in Table 2. Preoperatively, the ALPPS technique was considered whenever the future liver remnant (FLR) was 40% or less of the total liver volume (TLV) determined by CT or MRI scans. In all patients, the tumor was limited to the liver and no metastases were detected.
Table 2 Operative data for patients submitted to portal vein ligation and staged hepatectomy. Patient
Remnant liver
Total liver volume (cc)
Remnant liver volume (cc)
% FLR/TLV
1 2 3 4 5
I, II, III I, VI, VII I, VI, VII I, II, III I, II, III
1508 770 1193 5098 414
385 303 260 750 110
25.5 39.3 21.7 14.7 26.5
All patients, except for the girl with focal nodular hyperplasia, underwent preoperative chemotherapy. The patients and their parents were consented for ALPPS with the knowledge that portal vein embolization was an alternative approach. The first operation consisted of a bilateral subcostal laparotomy using a pediatric or adult subcostal retractor (patent pending). A thorough inspection of the abdominal cavity was carried out in order to detect any previously missed metastases. A cholecystectomy and hepatic hilum dissection were then performed. The right and left hepatic arteries, as well as the arteries for segment IV were dissected and identified. The common bile duct was dissected. The left or right portal vein was ligated. When the tumor was located on the right hemiliver with involvement of segment IV, the portal branch for segment 4 was ligated and divided. Full mobilization of the liver was obtained by sectioning the falciform, coronary, and right and left triangular ligaments of the liver. The right or left hepatic vein of the liver to be resected was dissected and encircled with a vessel loop. An intraoperative ultrasound was performed to verify a tumor free parenchymal transection line. The liver parenchyma was transected using combined ultrasonic energy (Ultracision®), monopolar and bipolar electrocautery, and ligation of the blood vessels and bile ducts. Biologic fibrin sealant was applied to both surfaces of the split liver. Closed drainage was placed in the liver hilum. We did not use any plastic film, mesh, or plastic bag to separate both surfaces of the liver. The patient was transferred to the pediatric surgical intensive care unit and was discharged to the normal ward according to his/her postoperative course. Prophylactic antibiotics were given for 24 hours. All patients received oral diet on the first postoperative day (POD). Total parenteral ou enteral nutrition was not necessary in any patient. For all patients, a postoperative CT scan was performed for reevaluation of liver volume. First CT exam was performed on the 3rd POD, and the second CT on the 7th POD. A third CT scan was performed whenever necessary. When the FRL was shown to have reached at least 50% of total liver volume, a second stage procedure was carried out on the next available operative day. During the second operation, the hepatic artery, and the bile duct of the diseased liver were ligated and transected. A clamp was applied at the right or left hepatic vein, and the vein was then transected. A 4-0 Prolene® running suture was applied to the stump of the hepatic vein. Liver segment I was preserved in all patients. No patient had hilar tumor involvement, and in all patients, the common bile duct was preserved. An incisional biopsy was obtained from the future remnant liver at the end of the first and second procedures for histological analysis.
Table 1 Demographic characteristics of patients submitted to portal vein ligation and staged hepatectomy. Patient
Age
Sex
Height (cm)
Weight (kg)
Liver seg. involved
Diagnosis
1 2 3 4 5
12 y 4 mo 4y 10 y 3 m 17 y 3 m 3y2m
Male Male Female female Female
140 106 135 154 93
49 23 34 43 13
IV, VII, VIII I, II, III, IV, V, VIII IV, VIII IV, V, VI, VII, VIII IV, V, VIII
Rhabdomyosarcoma Hepatocarcinoma Focal nodular hyperplasia Hepatoblastoma Hepatoblastoma
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2. Results All patients underwent surgical treatment from January, 2014 to April, 2014. In three patients, the remnant liver was the left lateral sector, and in two patients the remnant liver was the right posterior sector. The ratio of FRL to TLV before the first procedure ranged from 0.15 to 0.38, with a mean ± sd of 0.253 ± 0.07. The second procedure was performed after 7 to 12 days with a median of 11 days. When considering the standard liver volume using the formula proposed by Herden et al. [13], we found an estimated standard liver volume ranging from 460.75 cc to 1089.76 cc, with a median of 876.37 cc, a mean ± sd of 820.81 ± 245.69 cc. The percentage of future liver remnant (FLR) of total liver volume (TLV) ranged from 14.7% to 39.3%, with a median of 25.5%, a mean ± sd of 25.5 ± 8%. The percentage of FLR of the standard liver volume (SLV) ranged from 23.8% to 70.8%, with a median of 35.3%, a mean ± sd of 40.3% ± 16.4%. In all patients, a rapid growth of the FLR was observed. Estimates of the FRL volume prior to surgical treatment ranged from 110 cc to 750 cc, with a mean ± sd of 361.6 ± 213.75 cc. Just before the second procedure, the volume of the remnant liver ranged from 225 cc to 910 cc, with a mean ± sd of 563.6 cc ± 221.7 cc. The FRL volume increase had a mean ± sd of 72.56% ± 29.05%, with a median of 83.8%. These results are shown in Table 2. In one patient, due to the size of the tumor and its compression of the intrahepatic inferior vena cava (Fig. 1), the lateral aspect of the abdominal wall was left open, with closure of only the skin. The resected liver with the tumor of this particular patient weighted 3755 g. Her diagnosis was a giant hepatoblastoma resistant to chemotherapy. At the time of the first operation her FLR corresponded to 14.7% of total liver volume, 5098 cc. Although the segments I, II, and III–FLR, corresponded to 70.8% of her standard liver volume, we have made the option for staged hepatectomy due to the large size of tumor. All patients had an uneventful postoperative course. In one patient, a right pleural effusion was noticed on postoperative CT scan, but no treatment was required. Laboratory data indicated a speedy recovery from the surgical procedure for all patients. The only postoperative complication observed in one patient was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications (Figs. 2–5).
Fig. 1. CT image of a girl with a large hepatoblastoma. (a) Compression of intrahepatic inferior vena cava. (b) Portal vein with its right branch compressed by tumor.
Fig. 2. MR image of a boy with a large rhabdomyosarcoma of the liver.
3. Discussion Complete liver tumor resection is the only chance for patients with primary or metastatic hepatic malignant tumors of the liver to achieve long-term survival. However, in some patients with large tumors or small tumors located close to central structures, the functional remaining liver mass after tumor resection may not be sufficient to maintain normal liver function7. The indication for ALPPS procedure instead of resection was due to the large amount of liver mass to be resected in all children. Considering total liver volume, measured by CT scan, all patients had an FLR of less than 40%. Four children have received chemotherapy prior to resection,
Fig. 3. Postoperative CT image of a boy who underwent portal vein ligation and staged hepatectomy. (a) Line of liver bipartition. (b) Right hepatic vein encircled with vessel loop.
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1000
800 1
600
2 3
400
4
5
200
0 preoperative
postoperative
Fig. 4. Growth of remnant liver volume after liver bipartition and portal vein ligation after a median of 11 days.
two due to hepatoblastoma, one to treat a hepatocarcinoma, and one to treat a rhabdomyosarcoma. The child who had focal nodular hyperplasia, and did not receive chemotherapy had an FLR corresponding to only 21.7% of the total liver volume, and only 29.6% of estimated standard liver volume. The indication for resection was a symptomatic abdominal mass, with impairment of nutrition and normal social activities. One of the first advances to address this issue was introduced by Makuuchi et al. [14] in 1980 and consists of portal vein embolization. Occlusion of the branch of the portal vein of the liver bearing the tumor to induce contralateral liver hypertrophy has been reported as a treatment option by several authors [7,14–16]. Portal vein ligature has been compared with portal vein embolization for portal vein occlusion. Capussotti et al. [17] found an increase in liver size of 53% and 43% after ligature and portal vein embolization, respectively. Others have not been able to show the superiority of one technique over the other [7,16,18]. In contrast, Broering et al. [16] reported better results with portal vein embolization than with portal vein ligature. Portal vein occlusion is the most commonly used procedure for induction of FLR hypertrophy. However, this process requires a mean time of 4–6 weeks to achieve sufficient growth of the remnant liver; this time period increases the risk of tumor progression, when treating patients with metastasis from colorectal or hepatocellular carcinoma [1]. With this procedure hypertrophy ranges from 10% to 46% of the original liver lobe volume and requires between 2 and 8 weeks to develop; this increases the risk of tumor progression and prevents an R0 resection in 70% to 100% of cases [19,20]. In the present series, although hepatoblastoma is known to have a lower progression rate than adult malignant tumors, a consistent and rapid growth is desired.
% of total liver volume 80 70 60 50
1
40
2 3
30
4
20
5
10 0 preoperative
postoperative
Fig. 5. Growth of the remnant liver measured as percentage of total liver volume.
In the last decade, various techniques have been described to improve the result of PVE, such as “two-stage hepatectomy”. However, this technique does not allow any further increase in FLR hypertrophy, which is typically indicated for bilateral liver malignancies [21]. Recently, this technique has been modified by performing a portal vein ligation with in situ splitting, which is named the ALPPS procedure. First described by Baumgart et al. [10] in 2011, ALPPS consists of a combination of portal vein occlusion and staged liver resection [1,4,7,10]. During the first stage of the procedure, the liver is completely divided from the FLR with concomitant portal vein ligation of the lobe that will be removed [10]. The arterial blood supply, bile duct, and hepatic vein drainage of the tumor bearing liver are kept intact. The second stage of the procedure is usually performed 1–2 weeks later, with removal of the liver with its portal vein ligated. A consecutive series of patients undergoing in situ liver transection with portal vein ligation (ISLT) and extended right hepatectomy between 2009 and 2011 were compared with consecutive patients undergoing extended right hepatectomy after PVE. Fifteen patients who had PVE and seven who underwent ISLT before extended right hepatectomy were evaluated. ISLT induced rapid growth of the FLR within 3 days, particularly after insufficient PVE, from a mean ± sd of 293 ± 58 ml to 477 ± 85 ml, corresponding to a volume increase of 63% ± 29% [22]. Staged liver resection can be performed in cases of bilateral tumors in the liver. Initially, the tumors of the future remnant liver are resected or treated with ablation therapy, and after a 4 to 6 week period, when hypertrophy of the free-tumor liver segments has occurred, complete resection of the tumor is performed [23,24]. Liver separation during the first operation, in situ splitting, seems to play a more essential role in the rapid hypertrophy of the future remnant liver than portal vein occlusion alone [7]. The complete isolation of both sides of the parenchyma precludes the formation of collateral circulation between both liver lobes, resulting in a much stronger stimulus for remnant liver lobe hypertrophy [7]. The disconnection of all possibly persisting intrahepatic shunts or recanalized portal vein branches after PVE might explain the effectiveness of ISLT by increasing portal blood flow through the FLR22. In this series of pediatric patients, we noticed a rapid growth of the remnant livers in all but one patient. The increase in the ratio of FLR to TLV ranged from 62% to 102% in four patients. The FRL to TLV ratio was only 13% in one girl even though her left lateral segment volume, FLR volume, had grown from 750 cc to 910 cc after only 11 days of portal vein ligation and liver bipartition. Her total liver volume, including the large hepatoblastoma, was 5098 cc. Due to right portal vein compression by the tumor, she most likely had experienced left liver compensation. After resection, her tumor weighed 3755 g. In our opinion, although the total liver volume measured by CT included the tumor mass, we did not have a study on standard liver volume in our pediatric population. With the exception of the girl bearing the giant hepatoblastoma, the difference between standard liver volume and total liver volume was not sufficient to change the option for ALPPS. The only postoperative complication observed in this group of patients was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications. The ALPPS procedure should be considered when bilateral multiple malignancies are present in the liver, when FLR volume calculated during the preoperative workout is not adequate, or finally, in an unexpected intraoperative scenario when we find the previous mentioned conditions [1]. To our knowledge, this is the first series of pediatric patients who underwent this technique, which has been shown to be of great value in adult patients with liver tumors previously considered to be unresectable. Because of their rapid liver regeneration of the FLR, pediatric patients, particularly small children, are known to tolerate major hepatic resection better than adults, with an FLR as small as 20% to 25%. Therefore, ALPPS technique should only rarely be indicated for the treatment of liver tumors in children.
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References [1] Ielpo B, Caruso R, Ferri V, et al. ALLPS procedure: our experience and state of the art. Hepatogastroenterology 2013;60:51–7. [2] Shirabe K, Shimada M, Gion T, et al. Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume. J Am Coll Surg 1999;188:304–9. [3] Dokmak S, Belghiti J. Which limits to the “ALPPS” approach? Ann Surg 2012;256(3): e6 [author reply e16-17]. [4] Torres OJ, Moraes-Junior JMA, Lima NCL, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): a new approach in liver ressections. Arq Bras Cir Dig 2012;25:290–2. [5] Litten JB, Tomlinson GE. Liver tumor in children. Oncologist 2008;13:812–20. [6] Bassan AJ, Wang B, Davis JS, et al. A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg 2014;49:166–71. [7] 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-for-size settings. Ann Surg 2012;255:405–14. [8] Guérin F, Gauthier F, Martelli H, et al. Outcome of central hepatectomy for hepatoblastomas. J Pediatr Surg 2010;45:555–63. [9] Tashiro S. Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different? J Hepatobiliary Pancreat Surg 2009;16:292–9. [10] Baumgart J, Lang S, Lang H. A new method for induction of liver hypertrophy prior to right trisectionectomy: a report of three cases. HPB 2011;13:71–2. [11] Alvarez FA, Ardiles V, Claria RS, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): tips and tricks. J Gastrointest Surg 2013;17: 814–21. [12] Conrad C, Shivayhirthan N, Carmelo A, et al. Laparoscopic portal vein ligation with in situ liver split for failed portal vein embolization. Ann Surg 2012;256(3):e14–5 [author reply e16-17].
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[13] Herden U, Wischhusen F, Heinemann A, et al. A formula to calculate the standad liver volume in children and its application in pediatric liver transplantation. Transpl Int 2013;26:1217–24. [14] Makuuchi M, Thai BL, Takayasu K, et al. Preoperatove portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107:521–7. [15] Aussilhou B, Lesurtel M, Sauvanet A, et al. Right portal vein ligation is as efficient as portal vein embolization to induce hypertrophy of the left liver remnant. J Gastrointest Surg 2008;12:297–303. [16] Broering DC, Hillert C, Krupski G, et al. Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant. J Gastrointest Surg 2002;6:905–13. [17] Capussotti L, Muratore A, Baracchi F, et al. Portal vein ligation as an efficient method of increasing the future liver remnant volume in the surgical treatment of colorectal metastases. Arch Surg 2008;143:978–82. [18] Belghiti J, Benhaim L. Portal vein occlusion prior to extensive resection in colorectal liver metastasis: a necessity rather than an option! Ann Surg Oncol 2009;16:1098–9. [19] 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. [20] Liu H, Zhu S. Present status and future perspectives of preoperative portal vein embolization. Am J Surg 2009;197:686–90. [21] de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg 2012;255(3):415–7. [22] Knoefel WT, Gabor I, Rehders A, 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;100:388–94. [23] Tanaka K, Shimada H, Matsuo K, et al. Remnant liver regeneration after two-stage hepatectomy for multiple bilobar colorectal metastases. Eur J Surg Oncol 2007;33:329–35. [24] Karoui M, Vigano L, Goyer P, et al. Combined first-stage hepatectomy and colorectal resection in a two-stage hepatectomy strategy for bilobar synchronous liver metastases. Br J Surg 2010;97:1354–62.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Operative Techniques
Associating liver partition with portal vein ligation and staged hepatectomy (ALPPS) for the treatment of liver tumors in children☆ Julio Cesar Wiederkehr a,b,⁎, Sylvio Gilberto Avilla b, Elisângela Mattos b, Izabel Meister Coelho b, Jorge Alberto Ledesma c, Alexandra Fernandes Conceição b, Henrique Aguiar Wiederkehr b, Barbara Aguiar Wiederkehr b a b c
Federal University of Paraná, Curitiba Brazil Division of Liver Transplantation and Surgery, Hospital Pequeno Príncipe, Curitiba Brazil Department of Radiology, Hospital Pequeno Príncipe, Curitiba Brazil
a r t i c l e
i n f o
Article history: Received 22 June 2014 Received in revised form 28 September 2014 Accepted 1 October 2014 Key words: Liver tumor Surgery Pediatrics Hepatectomy
a b s t r a c t Resection is the only curative treatment option for primary and secondary malignant tumors of the liver. Although curative resection is associated with long-term survival rates, it can only be performed in 10% of patients with primary tumors and 25% of patients with liver metastases. Liver insufficiency is one of the most serious postoperative complications of patients undergoing extensive liver resections. When total liver resection is necessary liver transplant is mandatory, with the burden of long-term immunosuppression and its complications. Among several different strategies to increase the resectability of liver tumors, portal vein occlusion (embolization or ligature), bilateral tumor resection in two stages, and resection combined with loco regional therapy are the most popular. A new strategy for patients with marginally resectable liver tumors previously considered to be unresectable was formally reported by Baumgart et al. in 2011, originally developed by Hans Schlitt in 2007. This technique consists of a two-staged hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma, and it is known as ALPPS (associating liver partition with portal vein ligation for staged hepatectomy). The aim of this study is to present the first series of pediatric patients with marginally resectable liver tumors previously considered to be unresectable treated with two-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma. Two patients were diagnosed with hepatoblastoma, and one each with rhabdomyosarcoma, hepatocellular carcinoma, and nodular focal hyperplasia. ALPPS technique was considered whenever the future liver remnant (FLR) was 40% or less of the total liver volume (TLV) determined by CT or MRI scans. The ratio of FLR to TLV before the first procedure ranged from 0.15 to 0.38, with a mean ± sd of 0.253 ± 0.07. In all patients, a rapid growth of the FLR was observed. Estimates of the FRL volume prior to surgical treatment ranged from 110 cc to 750 cc, with a mean ± sd of 361.6 ± 213.75 cc. Just before the second procedure, the volume of the remnant liver ranged from 225 cc to 910 cc, with a mean ± sd of 563.6 cc ± 221.7 cc. The FRL volume increase had a mean ± sd of 72.56% ± 29.05%, with a median of 83.8%. The second procedure was performed after 7 to 12 days with a median of 11 days. The only postoperative complication observed in one patient was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications. ALPPS was shown to be effective and a safe procedure to treat large tumors in children. © 2015 Elsevier Inc. All rights reserved.
Resection is the only curative treatment option for primary and secondary malignant tumors of the liver. Although curative resection is associated with long-term survival rates, it can only be performed in 10% of patients with primary tumors and 25% of patients with liver metastases [1]. Large resections of the liver are limited by the remaining liver volume, referred to as future liver remnant (FLR). Liver insufficiency is one of the most serious postoperative complications of patients ☆ From the Division of Liver Transplantation and Surgery, Hospital Pequeno Príncipe, Curitiba, Brazil. ⁎ Corresponding author. E-mail address: [email protected] (J.C. Wiederkehr). http://dx.doi.org/10.1016/j.jpedsurg.2014.10.019 0022-3468/© 2015 Elsevier Inc. All rights reserved.
undergoing extensive liver resections [2–4]. To avoid this complication, it is recommended that the future liver remnant be at least 25% of the total liver volume of healthy livers, and in patients who underwent previous chemotherapy, the FLR is recommended to be approximately 40% of the total liver volume of healthy livers [2]. In pediatric populations, hepatoblastoma is the most frequent liver tumor, representing approximately 2/3 of all hepatic malignancies in children [5], and hepatocellular carcinoma is the second most common tumor in children [6]. Frequently, children with hepatoblastoma have unresectable tumors due to the involvement of multiple sectors of the liver. In more than 60% of children with hepatoblastoma chemotherapy is necessary. Although neoadjuvant chemotherapy is associated with
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good results, some children of initially unresectable hepatoblastomas remain resistant to chemotherapy [5]. A method for determining the safety of large liver resections is to determine the relationship between FLR and body weight, which should not be less than 0.5 [7]. Although this equation has been frequently used in adult patients, especially in the living-donor liver transplantation setting, it has not been tested in children. Central liver tumors can be treated by central hepatectomy. Although this technique spares tumor-free right and left lateral sections, there is a risk of thin resection margins and, therefore, a potential risk for local recurrence [8]. Two other surgical options are extended right hepatectomy and left extended hepatectomy, but they carry the risk of postoperative liver insufficiency. Among several different strategies to increase the resectability of liver tumors, portal vein occlusion (embolization or ligature), bilateral tumor resection in two stages, and resection combined with loco regional therapy are the most popular [9]. A new strategy for patients with marginally resectable liver tumors previously considered to be unresectable was formally reported by Baumgart et al. [10] in 2011, originally developed by Hans Schlitt in 2007 [11]. This technique consists of a two-staged hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma, and it is known as ALPPS (associating liver partition with portal vein ligation for staged hepatectomy). ALPPS provides a rapid and consistent hypertrophy of the remnant future liver, avoiding postoperative hepatic insuficiency [10]. A number of series of adult patients with liver tumors, mainly metastatic disease from colorectal cancer, previously considered unresectable, were treated with ALPPS with excellent results [7,12]. The aim of this study is to present the first series of pediatric patients with marginally resectable liver tumors previously considered to be unresectable treated with two-stage hepatectomy with initial portal vein ligation and in situ splitting of the liver parenchyma.
1. Patients and methods We had the opportunity to treat five children using portal vein ligation associated with liver bipartition followed by hepatectomy (ALPPS) at the Department of Liver Transplantation and Hepatic Surgery of Hospital Pequeno Principe, Curitiba, Brazil. All patients were referred to our service as bearing otherwise unresectable liver tumors with a possible evaluation for liver transplantation. Three patients were girls and two were boys; their ages ranged from 3.16 to 17.25 years with a mean age ± sd of 9.4 ± 5.9 years and a median age of 10.25 years. The demographic characteristics of the patients are listed in Table 1. Preoperative diagnoses were obtained for all five patients from tumor biopsies. Two patients were diagnosed with hepatoblastoma, and one each with rhabdomyosarcoma, hepatocellular carcinoma, and nodular focal hyperplasia. Tumor location was determined by abdominal computed tomography (CT) scan and/or abdominal magnetic nuclear resonance (MR) scan. The tumor locations and extensions are shown in Table 2. Preoperatively, the ALPPS technique was considered whenever the future liver remnant (FLR) was 40% or less of the total liver volume (TLV) determined by CT or MRI scans. In all patients, the tumor was limited to the liver and no metastases were detected.
Table 2 Operative data for patients submitted to portal vein ligation and staged hepatectomy. Patient
Remnant liver
Total liver volume (cc)
Remnant liver volume (cc)
% FLR/TLV
1 2 3 4 5
I, II, III I, VI, VII I, VI, VII I, II, III I, II, III
1508 770 1193 5098 414
385 303 260 750 110
25.5 39.3 21.7 14.7 26.5
All patients, except for the girl with focal nodular hyperplasia, underwent preoperative chemotherapy. The patients and their parents were consented for ALPPS with the knowledge that portal vein embolization was an alternative approach. The first operation consisted of a bilateral subcostal laparotomy using a pediatric or adult subcostal retractor (patent pending). A thorough inspection of the abdominal cavity was carried out in order to detect any previously missed metastases. A cholecystectomy and hepatic hilum dissection were then performed. The right and left hepatic arteries, as well as the arteries for segment IV were dissected and identified. The common bile duct was dissected. The left or right portal vein was ligated. When the tumor was located on the right hemiliver with involvement of segment IV, the portal branch for segment 4 was ligated and divided. Full mobilization of the liver was obtained by sectioning the falciform, coronary, and right and left triangular ligaments of the liver. The right or left hepatic vein of the liver to be resected was dissected and encircled with a vessel loop. An intraoperative ultrasound was performed to verify a tumor free parenchymal transection line. The liver parenchyma was transected using combined ultrasonic energy (Ultracision®), monopolar and bipolar electrocautery, and ligation of the blood vessels and bile ducts. Biologic fibrin sealant was applied to both surfaces of the split liver. Closed drainage was placed in the liver hilum. We did not use any plastic film, mesh, or plastic bag to separate both surfaces of the liver. The patient was transferred to the pediatric surgical intensive care unit and was discharged to the normal ward according to his/her postoperative course. Prophylactic antibiotics were given for 24 hours. All patients received oral diet on the first postoperative day (POD). Total parenteral ou enteral nutrition was not necessary in any patient. For all patients, a postoperative CT scan was performed for reevaluation of liver volume. First CT exam was performed on the 3rd POD, and the second CT on the 7th POD. A third CT scan was performed whenever necessary. When the FRL was shown to have reached at least 50% of total liver volume, a second stage procedure was carried out on the next available operative day. During the second operation, the hepatic artery, and the bile duct of the diseased liver were ligated and transected. A clamp was applied at the right or left hepatic vein, and the vein was then transected. A 4-0 Prolene® running suture was applied to the stump of the hepatic vein. Liver segment I was preserved in all patients. No patient had hilar tumor involvement, and in all patients, the common bile duct was preserved. An incisional biopsy was obtained from the future remnant liver at the end of the first and second procedures for histological analysis.
Table 1 Demographic characteristics of patients submitted to portal vein ligation and staged hepatectomy. Patient
Age
Sex
Height (cm)
Weight (kg)
Liver seg. involved
Diagnosis
1 2 3 4 5
12 y 4 mo 4y 10 y 3 m 17 y 3 m 3y2m
Male Male Female female Female
140 106 135 154 93
49 23 34 43 13
IV, VII, VIII I, II, III, IV, V, VIII IV, VIII IV, V, VI, VII, VIII IV, V, VIII
Rhabdomyosarcoma Hepatocarcinoma Focal nodular hyperplasia Hepatoblastoma Hepatoblastoma
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2. Results All patients underwent surgical treatment from January, 2014 to April, 2014. In three patients, the remnant liver was the left lateral sector, and in two patients the remnant liver was the right posterior sector. The ratio of FRL to TLV before the first procedure ranged from 0.15 to 0.38, with a mean ± sd of 0.253 ± 0.07. The second procedure was performed after 7 to 12 days with a median of 11 days. When considering the standard liver volume using the formula proposed by Herden et al. [13], we found an estimated standard liver volume ranging from 460.75 cc to 1089.76 cc, with a median of 876.37 cc, a mean ± sd of 820.81 ± 245.69 cc. The percentage of future liver remnant (FLR) of total liver volume (TLV) ranged from 14.7% to 39.3%, with a median of 25.5%, a mean ± sd of 25.5 ± 8%. The percentage of FLR of the standard liver volume (SLV) ranged from 23.8% to 70.8%, with a median of 35.3%, a mean ± sd of 40.3% ± 16.4%. In all patients, a rapid growth of the FLR was observed. Estimates of the FRL volume prior to surgical treatment ranged from 110 cc to 750 cc, with a mean ± sd of 361.6 ± 213.75 cc. Just before the second procedure, the volume of the remnant liver ranged from 225 cc to 910 cc, with a mean ± sd of 563.6 cc ± 221.7 cc. The FRL volume increase had a mean ± sd of 72.56% ± 29.05%, with a median of 83.8%. These results are shown in Table 2. In one patient, due to the size of the tumor and its compression of the intrahepatic inferior vena cava (Fig. 1), the lateral aspect of the abdominal wall was left open, with closure of only the skin. The resected liver with the tumor of this particular patient weighted 3755 g. Her diagnosis was a giant hepatoblastoma resistant to chemotherapy. At the time of the first operation her FLR corresponded to 14.7% of total liver volume, 5098 cc. Although the segments I, II, and III–FLR, corresponded to 70.8% of her standard liver volume, we have made the option for staged hepatectomy due to the large size of tumor. All patients had an uneventful postoperative course. In one patient, a right pleural effusion was noticed on postoperative CT scan, but no treatment was required. Laboratory data indicated a speedy recovery from the surgical procedure for all patients. The only postoperative complication observed in one patient was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications (Figs. 2–5).
Fig. 1. CT image of a girl with a large hepatoblastoma. (a) Compression of intrahepatic inferior vena cava. (b) Portal vein with its right branch compressed by tumor.
Fig. 2. MR image of a boy with a large rhabdomyosarcoma of the liver.
3. Discussion Complete liver tumor resection is the only chance for patients with primary or metastatic hepatic malignant tumors of the liver to achieve long-term survival. However, in some patients with large tumors or small tumors located close to central structures, the functional remaining liver mass after tumor resection may not be sufficient to maintain normal liver function7. The indication for ALPPS procedure instead of resection was due to the large amount of liver mass to be resected in all children. Considering total liver volume, measured by CT scan, all patients had an FLR of less than 40%. Four children have received chemotherapy prior to resection,
Fig. 3. Postoperative CT image of a boy who underwent portal vein ligation and staged hepatectomy. (a) Line of liver bipartition. (b) Right hepatic vein encircled with vessel loop.
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1000
800 1
600
2 3
400
4
5
200
0 preoperative
postoperative
Fig. 4. Growth of remnant liver volume after liver bipartition and portal vein ligation after a median of 11 days.
two due to hepatoblastoma, one to treat a hepatocarcinoma, and one to treat a rhabdomyosarcoma. The child who had focal nodular hyperplasia, and did not receive chemotherapy had an FLR corresponding to only 21.7% of the total liver volume, and only 29.6% of estimated standard liver volume. The indication for resection was a symptomatic abdominal mass, with impairment of nutrition and normal social activities. One of the first advances to address this issue was introduced by Makuuchi et al. [14] in 1980 and consists of portal vein embolization. Occlusion of the branch of the portal vein of the liver bearing the tumor to induce contralateral liver hypertrophy has been reported as a treatment option by several authors [7,14–16]. Portal vein ligature has been compared with portal vein embolization for portal vein occlusion. Capussotti et al. [17] found an increase in liver size of 53% and 43% after ligature and portal vein embolization, respectively. Others have not been able to show the superiority of one technique over the other [7,16,18]. In contrast, Broering et al. [16] reported better results with portal vein embolization than with portal vein ligature. Portal vein occlusion is the most commonly used procedure for induction of FLR hypertrophy. However, this process requires a mean time of 4–6 weeks to achieve sufficient growth of the remnant liver; this time period increases the risk of tumor progression, when treating patients with metastasis from colorectal or hepatocellular carcinoma [1]. With this procedure hypertrophy ranges from 10% to 46% of the original liver lobe volume and requires between 2 and 8 weeks to develop; this increases the risk of tumor progression and prevents an R0 resection in 70% to 100% of cases [19,20]. In the present series, although hepatoblastoma is known to have a lower progression rate than adult malignant tumors, a consistent and rapid growth is desired.
% of total liver volume 80 70 60 50
1
40
2 3
30
4
20
5
10 0 preoperative
postoperative
Fig. 5. Growth of the remnant liver measured as percentage of total liver volume.
In the last decade, various techniques have been described to improve the result of PVE, such as “two-stage hepatectomy”. However, this technique does not allow any further increase in FLR hypertrophy, which is typically indicated for bilateral liver malignancies [21]. Recently, this technique has been modified by performing a portal vein ligation with in situ splitting, which is named the ALPPS procedure. First described by Baumgart et al. [10] in 2011, ALPPS consists of a combination of portal vein occlusion and staged liver resection [1,4,7,10]. During the first stage of the procedure, the liver is completely divided from the FLR with concomitant portal vein ligation of the lobe that will be removed [10]. The arterial blood supply, bile duct, and hepatic vein drainage of the tumor bearing liver are kept intact. The second stage of the procedure is usually performed 1–2 weeks later, with removal of the liver with its portal vein ligated. A consecutive series of patients undergoing in situ liver transection with portal vein ligation (ISLT) and extended right hepatectomy between 2009 and 2011 were compared with consecutive patients undergoing extended right hepatectomy after PVE. Fifteen patients who had PVE and seven who underwent ISLT before extended right hepatectomy were evaluated. ISLT induced rapid growth of the FLR within 3 days, particularly after insufficient PVE, from a mean ± sd of 293 ± 58 ml to 477 ± 85 ml, corresponding to a volume increase of 63% ± 29% [22]. Staged liver resection can be performed in cases of bilateral tumors in the liver. Initially, the tumors of the future remnant liver are resected or treated with ablation therapy, and after a 4 to 6 week period, when hypertrophy of the free-tumor liver segments has occurred, complete resection of the tumor is performed [23,24]. Liver separation during the first operation, in situ splitting, seems to play a more essential role in the rapid hypertrophy of the future remnant liver than portal vein occlusion alone [7]. The complete isolation of both sides of the parenchyma precludes the formation of collateral circulation between both liver lobes, resulting in a much stronger stimulus for remnant liver lobe hypertrophy [7]. The disconnection of all possibly persisting intrahepatic shunts or recanalized portal vein branches after PVE might explain the effectiveness of ISLT by increasing portal blood flow through the FLR22. In this series of pediatric patients, we noticed a rapid growth of the remnant livers in all but one patient. The increase in the ratio of FLR to TLV ranged from 62% to 102% in four patients. The FRL to TLV ratio was only 13% in one girl even though her left lateral segment volume, FLR volume, had grown from 750 cc to 910 cc after only 11 days of portal vein ligation and liver bipartition. Her total liver volume, including the large hepatoblastoma, was 5098 cc. Due to right portal vein compression by the tumor, she most likely had experienced left liver compensation. After resection, her tumor weighed 3755 g. In our opinion, although the total liver volume measured by CT included the tumor mass, we did not have a study on standard liver volume in our pediatric population. With the exception of the girl bearing the giant hepatoblastoma, the difference between standard liver volume and total liver volume was not sufficient to change the option for ALPPS. The only postoperative complication observed in this group of patients was an asymptomatic right pleural effusion that was aspirated during the second procedure with no further complications. The ALPPS procedure should be considered when bilateral multiple malignancies are present in the liver, when FLR volume calculated during the preoperative workout is not adequate, or finally, in an unexpected intraoperative scenario when we find the previous mentioned conditions [1]. To our knowledge, this is the first series of pediatric patients who underwent this technique, which has been shown to be of great value in adult patients with liver tumors previously considered to be unresectable. Because of their rapid liver regeneration of the FLR, pediatric patients, particularly small children, are known to tolerate major hepatic resection better than adults, with an FLR as small as 20% to 25%. Therefore, ALPPS technique should only rarely be indicated for the treatment of liver tumors in children.
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